WO2024147153A1

WO2024147153A1 - Peptide-histidinal conjugates as an anti-malarial agents

Info

Publication number: WO2024147153A1
Application number: PCT/IN2024/050002
Authority: WO
Inventors: Chhuttan Lal MEENA; Tejashri Bhimashankar HINGAMIRE; Rakesh Shamsunder JOSHI; Dhanasekaran Shanmugam; Gangadhar Jessy SANJAYAN
Original assignee: Council Of Scientific & Industrial Research
Priority date: 2023-01-03
Filing date: 2024-01-01
Publication date: 2024-07-11

Abstract

The present invention relates to a peptide-histidinal conjugates compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof. The present invention also provides a process for preparation of compound of formula (I) and its use as antimalarial agents.

Description

PEPTIDE-HISTIDINAL CONJUGATES AS AN ANTI-MALARIAL AGENTS TECHNICAL FIELD OF THE INVENTION The present invention relates to novel synthetic compounds having biological activity. Specifically, the present invention relates to a peptide-histidinal conjugate compound of formula (I) useful as an anti- malarial agent. Also, the present invention relates to a process for preparation of peptide-histidinal conjugate compounds of formula (I). BACKGROUND OF THE INVENTION Malaria is a global health issue, particularly in developing and poorer countries. The latest World Malaria Report revealed 241 million malaria cases in 2020, as compared to 227 million in 2019. It was estimated that 627000 malaria deaths occurred in 2020 - an increase of 69000 deaths compared to the previous year. Most people die from malaria caused by P. falciparum, the most common pathogenic parasite for humans. Most of the causes of morbidity are frequently reported in Africa, South East Asia, and South America, particularly in pregnant women and children under five years old. Clinical malaria cases were treated with chloroquine until a few decades ago. Due to drug resistance issues, chloroquine has become less effective in recent years, especially in certain geographic locations. So far, resistance has only been reported in two species, P. falciparum and P. vivax. Although there is a lack of new antimalarial drugs in development, the ones that are reaching the market may not fight resistant strains. As a result of rising drug resistance and the lack of an effective malarial vaccine, finding new, effective, safe, and affordable drugs for malaria treatment via novel targets is one of the most challenging global health priorities. Article titled “Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance” by Fidock et.al. published in Mol Cell. 2000 October; 6(4): 861–871 reports the Mutations in 13-exon gene, PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on digestive vacuole pH. Article titled “Chloroquine Resistance in Plasmodium falciparum Malaria Parasites Conferred by pfcrt Mutations” by Sidhu et. al. published in Science. 2002 October 4; 298(5591): 210–213 reports conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria. Article titled “Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine” published in Engineering 5 (2019) 32–39 reviews the Artemisinin and its derivatives use as a influential class of drugs in the fight against malaria The existing large numbers of antimalarial therapies are based on interfering in the heme polymerization process at the erythrocytic stage. Until a few decades ago, chloroquine was the standard drug of choice for treating clinical malaria cases. However, in recent times, chloroquine does not cure as many cases as it used to, based on location owing to drug resistance issues. Therefore, there is need in prior art to synthesize potent and selective inhibitors of malarial cysteine protease such as falcipain-2 (FP-2) and falcipain-3 (FP-3) by designing novel class of peptide-histidinal conjugates. Further, it is desirable to produce the molecules that could be used as antimalarial drugs, allowing for the development of novel treatments which might reduce the burden of resistance to antimalarial drugs. OBJECTIVE OF THE INVENTION The main objective of the present invention is to provide peptide-histidinal conjugates useful as an anti- malarial agent. Another objective of the present invention is to provide a process for preparation of peptide-histidinal conjugates. Another objective of the present invention is to provide peptide-histidinal conjugates compounds for inhibition of cysteine and aspartic acid proteases. SUMMARY OF THE INVENTION The primary objective of the present invention is to provide Peptide-histidinal conjugate compounds useful as an anti-malarial agent. In an aspect, the present invention relates to a peptide histidinal conjugate of compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof:

Formula (I) wherein: L is direct bond, CH(R¹), (CH(R¹))nNR⁴CHR⁵, (CH(R¹))nCONR²CHR³, (CH(R¹))n SO₂NR²CHR³, or (CH(R¹))nNR⁴CHR⁵CONR⁶CHR⁷, wherein n is 0 or 1; R is aryl, heterocyclyl, alkyl, NH-aryl, SO2-aryl, or aryl-heterocyclyl, wherein the aryl, heterocyclyl, alkyl is substituted or unsubstituted; R¹ is hydrogen, alkyl, or aryl; wherein the alkyl and aryl is substituted or unsubstituted; R² is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R³ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁴ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁵ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁶ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁷ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted and X is CF3COO-, or Cl-. In yet another aspect, the peptide-histidinal conjugate compounds of formula (I) useful for inhibition of cysteine and aspartic acid proteases. In an aspect, the present invention provides a process for the preparation of histidinal peptide conjugate compounds of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate thereof, wherein the process comprising the steps of: Formula (I) a) coupling N ^{^}-(((9H-fluoren-9-yl) methoxy) carbonyl)-N ^{^}-trityl-L-histidine with aminating agent or base in the presence of coupling reagent(s) in solvent to obtain precursor 1

Precursor 1; b) deprotecting Fmoc of precursor 1 of step a) by treating the precursor 1 in presence of tert- butylamine in a solvent at temperature in the range of 25-35 ºC for time period in the range of 3 to 5 hrs to obtain an intermediate c) coupling the intermediate obtained in step (b) with R-carboxylic acid in the presence of coupling reagent(s) in solvent to furnish compound selected from formula 2a-h d) Formula 2a-h reducing the

(c) using lithium aluminium hydride (LiAlH₄) in solvent at temperature in the range of 0 to -20 °C for time period of 45 to 120 minutes to obtain the compound selected from Formula 3a-h

e) Formula 3a-h; deprotecting using salt precursor trifluoroacetic acid (TFA) in solvent at temperature in the range of 25 to 40^oC for the time period in the range of 1 to 2 hours to obtain the histidinal peptide conjugate compound of formula (I) with salt form selected from compounds 4a-h;. Formula I

wherein X is trifluoroacetate R is the same as defined in claim 1, and wherein the compounds 4a-h recite X as trifluoroacetate salt form. In another aspect, said R-carboxylic acid (1a-h) is selected from 2-methylbenzoic acid (a), 1-hydroxy- 2-naphthoic acid (b), 3-hydroxy-2-naphthoic acid (c), benzo[b]thiophene-2-carboxylic acid (d), (S)-2- (6-methoxynaphthalen-2-yl) propanoic acid (e), 2-propylpentanoic acid (f), 2-(2-((2,6-dichlorophenyl) amino) phenyl) acetic acid (g), and 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-[1,1'-biphenyl]-2-carboxylic acid (h). In another aspect, the present invention provides a process for the preparation of peptide-histidinal conjugate compounds of formula (I), wherein the process comprising the steps of: i. deprotecting precursor 1 by treating the precursor 1 in presence of tert-butylamine in a solvent at temperature in the range of 25-35 ºC for time period in the range of 3 to 5 hrs to obtain an intermediate

ii. coupling Fmoc-Leu-OH with the precursor 1 as obtained in step (i) in the presence of coupling reagent(s) in solvent to obtain intermediate 5 iii. deprotecting Fmoc of the

(ii) by treating the intermediate 5 in presence of tert-butylamine in a solvent at temperature in the range of 25-35 ºC for time period in the range of 3 to 5 hrs to obtain an intermediate; iv. coupling the intermediate obtained in step (iii) with R-carboxylic acid in the presence of coupling reagent(s) in solvent to furnish compound selected from compounds of formula 6a-k;

v. Formula 6a-k reducing the compound obtained in step (iv) using lithium aluminium hydride (LiAlH₄) in solvent at 0 to -20°C to obtain the compound selected from compounds of formula 7a-k vi. formula 7a-k deprotecting

step (v) using salt precursor TFA in solvent at temperature in the range of 25 to 40°C for the time period in the range of 2 to 3 hours to obtain the histidinal peptide conjugate compound of formula (I) with trifluoroacetate salt form selected from compounds 8a-k; I wherein X is trifluoroacetate salt

as defined in claim 1, and wherein the compounds 8a-k recite X as trifluoroacetate salt form. In another aspect, said R-carboxylic acids are selected from (a-k) 2-methylbenzoic acid (a), 1H-indole- 2-carboxylic acid (b), 1-hydroxy-2-naphthoic acid (c), 3-hydroxy-2-naphthoic acid (d), benzo[b]thiophene-2-carboxylic acid (e), (S)-2-(6-methoxynaphthalen-2-yl) propanoic acid (f), 2- propylpentanoic acid (g), 2-(2-((2,6-dichlorophenyl) amino) phenyl) acetic acid (h), 4'-((1,7'-dimethyl- 2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-[1,1'-biphenyl]-2-carboxylic acid (i), 5- (dimethylamino) naphthalene-1-sulfonic acid (j), and 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4- d] imidazol-4-yl) pentanoic acid (k). In another aspect, the present invention relates to a process for the preparation of peptide-histidinal conjugate compounds of formula (I), comprising the steps of: i) coupling compound 10c with N, O-dimethylhydroxylamine to obtain compound 11 ; ii) reacting compound 10b with precursor 1 in presence of coupling reagent(s) to afford compound ; (iii)

intermediate 5 in presence of coupling reagent(s) to afford compound 16

; 16 iii) deducing the compounds obtained in step (i), (ii), (iii) using lithium aluminium hydride (LiAlH₄) in dry THF at -20°C to obtain the compounds 12, 14, 17 17; and sing trifluororacetic acid in solvent at temperature in the range of 25 to 40 ^{^}C for the time period in the range of 2 to 3 hours to produce histidinal-based trifluoroacetate salt compounds 15 and 18 18.

In another aspect, agent step from HBTU, HOBt and EDC·HCl or mixtures thereof. In another aspect, the aminating agent is selected from DIPEA, DMF, and N, O-dimethyl hydroxylamine. HCl. In another aspect, the precursor salt is selected from trifluororacetic acid and 4M HCl in 1,4-Dioxane. In another aspect, the solvent is selected from polar or non-polar solvent, and protic or aprotic solvent. In another aspect, the base is selected from organic base and inorganic base. In another aspect, the solvent is selected from DMF, THF, lower (C1-C5) alcohol, nitrile, ketone, halogenated hydrocarbon, TFA or combinations thereof. In another aspect, the organic base is selected from ethylamine, triethylamine, DIPEA, and pyridine. In another aspect, the inorganic base is selected from sodium hydroxide, alkali or alkaline earth metal carbonate and bicarbonate or combination thereof. The scheme for the synthesis of compound of formula I according to said process steps i) to v) is provided below in Scheme 1: The scheme for the synthesis of compound of formula I according to said process steps i) to vi) is provided below in Scheme 2:

In another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula I as claimed in claim 1 and pharmaceutically acceptable excipient(s). In another aspect, the present invention provides a method of inhibition of malaria cysteine proteases by contacting P.falciparum with the compound of formula I as claimed in claim 1 or the pharmaceutical composition as claimed in claim 17. BRIEF DESCRIPTION OF THE DRAWINGS: Fig 1: Scheme 3. Synthesis of 4a-h. Reagents and conditions. (i) HBTU/HOBt, DIPEA, DMF, N, O- dimethylhydroxylamine. HCl, DMF, rt, 4h; (ii) 50% tert-Butylamine in DCM, 45 min, rt; (iii) HBTU/EDC.HCl/HOBt, DIPEA, DMF, R= carboxylic acids; (iv) LiAlH4, dry THF, -20oC, 1h, citric acid; (v) 60% TFA in DCM, 2 - 4h rt. Note: EDC.HCl instated of HBTU for synthesis of compound 4b and 4c. Fig 2: Scheme 4. Synthesis of 8a-k. Reagents and conditions. (i) 50% tert-Butylamine in DCM, 45 min, rt; (ii) HBTU/HOBt/DIPEA, Fmoc-L-Leu-OH, DMF, rt, 12h; (iii) HBTU/HOBt/EDC.HCl, DIPEA, DMF, R= carboxylic acids; (iv) LiAlH4, dry THF, -20oC, 1h, citric acid; (v) 60% TFA in DCM, 2h rt. Note: (iii) EDC.HCl instated of HBTU for synthesis of compound 6c and 6d. Fig 3: Scheme 5. Synthesis of 12, 15 and 18. Reagents and conditions. (i) amino acids, phenol, 1500 C, 1-6h; (ii) HBTU/HOBt, DIPEA, DMF, N, O-dimethylhydroxylamine. HCl, DMF, rt, 4h; (iii) free amine of 1 (scheme 1), HBTU/HOBt, DIPEA, DMF; (iv) free amine of 5 (scheme 2); (v) LiAlH4, dry THF, -20oC, 1h.; (vi) 60% TFA in DCM, 2-3h rt. Fig 4: Phenotypic assays to determine effect of inhibitors on food vacuole. The top panel shows microscopic appearance of control parasites (1% DMSO treatment) while the middle and lower panels show appearance of parasites when treated with various inhibitors. All inhibitors were used at 25 μM concentration and two representative microscopic images are shown for each inhibitor. The white arrowheads indicate the swollen food vacuoles (due to accumulation of undigested hemoglobin) when parasites are treated with E64, 8g, and 8j compounds for 24 h and 36 h. ABBREVIATIONS: t-Boc = tert-butyloxycarbonyl; HBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate; HOBt = Hydroxy benzotriazoleEDC.HCl N-Ethyl-N′-(3- dimethylaminopropyl) carbodiimide hydrochloride; DIPEA- N, N-Diisopropylethylamine; DCM- dichloromethane; THF-Tetrahydrofuran; DMF- Dimethylformamide; TFA- Trifluoroacetic acid. DETAILED DESCRIPTION OF THE INVENTION The present invention has designed novel class of peptide-histidinal conjugates of compound of formula (I) that is potent and selective inhibitors of malarial cysteine protease such as falcipain-2 (FP- 2) and falcipain-3 (FP-3). In an embodiment, the present invention relates to a peptide histidinal conjugate of compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: wherein:

L is direct bond, CH(R¹), (CH(R¹))nNR⁴CHR⁵, (CH(R¹))nCONR²CHR³, (CH(R¹))nSO2NR²CHR³, or (CH(R¹))nNR⁴CHR⁵CONR⁶CHR⁷, wherein n is 0 or 1; R is aryl, heterocyclyl, alkyl, NH-aryl, SO₂-aryl, or aryl-heterocyclyl, wherein the aryl, heterocyclyl, alkyl is substituted or unsubstituted; R¹ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R² is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R³ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁴ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁵ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁶ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; and R⁷ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted. X is CF3COO-, or Cl-. In another embodiment of the present invention, R is selected from the group consisting of:

In another compound of formula (I) is selected from the group consisting of: (S)-5-(2-(2-methylbenzamido)-3-oxopropyl)-1H-imidazol-1-ium (4a); (S)-5-(2-(1-hydroxy-2-naphthamido)-3-oxopropyl)-1H-imidazol-1-ium (4b); (S)-5-(2-(3-hydroxy-2-naphthamido)-3-oxopropyl)-1H-imidazol-1-ium (4c); (S)-5-(2-(benzo[b]thiophene-2-carboxamido)-3-oxopropyl)-1H-imidazol-1-ium (4d); 5-((S)-2-((S)-2-(6-methoxynaphthalen-2-yl) propanamido)-3-oxopropyl)-1H-imidazol-1-ium (4e); (S)-5-(3-oxo-2-(2-propylpentanamido) propyl)-1H-imidazol-1-ium (4f); (S)-5-(2-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetamido)-3-oxopropyl)-1H-imidazol-1-ium (4g); (S)-5-(2-(4'-((1, 7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d] imidazol]-3'-yl) methyl)-[1, 1'- biphenyl]- 2-carboxamido)-3-oxopropyl)-1H-imidazol-1-ium (4h); 5-((S)-2-((S)-4-methyl-2-(2-methylbenzamido) pentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8a); 5-((S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8b); 5-((S)-2-((S)-2-(1-hydroxy-2-naphthamido)-4-methylpentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8c); 5-((S)-2-((S)-2-(3-hydroxy-2-naphthamido)-4-methylpentanamido)-3-oxopropyl)- 1H-imidazol-1-ium (8d); 5-((S)-2-((S)-2-(benzo[b]thiophene-2-carboxamido)-4-methylpentanamido)-3-oxopropyl) -1H- imidazol-1-ium (8e); 5-((S)-2-((S)-2-((S)-2- (6-methoxynaphthalen-2-yl) propanamido)-4-methylpentan amido)-3- oxopropyl)-1H-imidazol-1-ium (8f); 5-((S)-2-((S)-4-methyl-2-(2-propylpentanamido) pentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8g); 5-((S)-2-((S)-2-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetamido)-4-methylpentan amido)-3- oxopropyl)-1H-imidazol-1-ium (8h); 5-((S)-2-((S)-2-(4'-((1, 7'-dimethyl-2'-propyl-1H,3'H-[2, 5'-bibenzo[d]imidazol]-3'-yl) methyl)- [1, 1'- biphenyl]-2-carboxamido)-4-methylpentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8i); 5-((S)-2-((S)-2-((5-(dimethylamino) naphthalene)-1-sulfonamido)-4-methylpentanamido)-3- oxopropyl)-1H-imidazol-1-ium (8j); 5-((S)-2-((S)-4-methyl-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl) pentanamido) pentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8k); (S)-2-((7-chloroquinolin-4-yl) amino)-3-(1H-imidazol-5-yl) propanal (12); 5-((S)-2-((S)-2-((7-chloroquinolin-4-yl) amino)-4-methylpentanamido)-3-oxopropyl)-1H-imidazol-1- ium (15); and 5-((S)-2-((S)-2-((S)-2-((7-chloroquinolin-4-yl)amino)propanamido)-4-methylpentan amido)-3- oxopropyl)-1H-imidazol-1-ium (18). In another embodiment, the compounds of present invention are in the form of trifluoroacetate or chloride salt. Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein and the appended claims. These definitions should not be interpreted in the literal sense as they are not intended to be general definitions and are relevant only for this application. The term “L as direct bond” used herein means that the L group without being present (or as absent), making direct bond between R- group and -CO- group. The term, “alkyl”, as used herein, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups having eight or fewer carbon atoms in its backbone, for instance, C1- C8alkyl for straight chain and C3-C8 for branched chain. As used herein, C1-C8alkyl refers to an alkyl group having from 1 to 8 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and 3-methylbutyl. Furthermore, unless stated otherwise, the alkyl group can be unsubstituted or substituted with one or more substituents, for example, from one to four substituents, independently selected from the group consisting of tetrahydro-1H-thieno[3,4-d] imidazol-2(3H)-one, alkoxy, halogen, hydroxy, cyano, nitro and amino. Examples of substituted alkyl include, but are not limited to hydroxymethyl, 2-chlorobutyl, trifluoromethyl and aminoethyl. The term, "halogen" as used herein refers to chlorine, fluorine, bromine or iodine atom. The term, “alkoxy" refers to a (C1-C8) alkyl having an oxygen radical attached thereto. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n- butoxy, isobutoxy and tert-butoxy. Furthermore, unless stated otherwise, the alkoxy groups can be unsubstituted or substituted with one or more groups. A substituted alkoxy refers to alkoxy substituted with one or more groups, particularly one to four groups independently selected from the groups indicated above as the substituents for the alkyl group. The term “aryl" as used herein refers to monocyclic, bicyclic or tricyclic hydrocarbon groups having 6 to 14 ring carbon atoms, wherein at least one carbocyclic ring is having a π electron system. Examples of aryl ring systems include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl and phenanthrenyl. Unless indicated otherwise, aryl group can be unsubstituted or substituted with one or more substituents, for example 1 -4 substituents independently selected from the group consisting of halogen, alkyl, alkoxy, acetyl, 9H-carbazol-9-yl, (1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d] imidazol]-3'-yl) methyl, hydroxy, phenyl, cyano, nitro, -COOH and NR^a R^b; wherein R^a and R^b is hydrogen, substituted or unsubstituted aryl or heteroaryl. As used herein, the terms "heterocyclyl" or "heterocyclic" whether used alone is a 3-12 membered saturated or partially unsaturated, monocyclic or bicyclic ring system, including spiro ring systems, containing one to four heteroatoms independently selected from the group consisting of O, N and S. Representative examples of heterocyclyls include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyrazinyl, piperazinyl, oxazolyl, oxadiazolyl, isoxazolyl, triaziolyl, thiazolyl, tetrazolyl, furyl, thienyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, piperidyl, benzoxazolyl, benzothiazolyl, benzofuranyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, isoindolyl, isothiazolyl, isoquinolyl, isoquinolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-1, 1-dioxide, quinoxalinyl, quinolinyl and thiophenyl. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Heterocyclyl having an aromatic ring containing heteroatoms are herein referred to by the customary term "heteroaryl". Within the context of the present invention and as used herein, the term "heteroaryl" refers to a 5-12 membered aromatic monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from: nitrogen, sulphur and oxygen. Representative examples of heteroaryls include, but are not limited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine) and tetrazole. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. A heterocyclyl or heteroaryl group can be unsubstituted or substituted with one or more groups independently selected from group consisting of halogen, hydroxy, oxo, cyano, (C1-C8)-alkyl, halo(C1- C₈)-alkyl, (C₁-C₈)-alkoxy, halo(C₁-C₈)-alkoxy, (C₃-C₁₂)-cycloalkyl, hydroxy, cyano, nitro, amine, and COOH. The substituents can be present on either ring carbon or ring nitrogen atom(s). The substituents can be present at one or more positions provided that stable molecule results. In another aspect, the present invention relates to a process for synthesis of peptide-histidinal conjugate compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof;

wherein the process comprising the steps of: a) coupling Fmoc-His (Trt)-OH with N, O-dialkyllhydroxylamine in the presence of coupling reagents in solvent to obtain precursor 1; b) deprotecting Fmoc of 1 by tert-butylamine in solvent; c) coupling the intermediate obtained in step (i) with carboxylic acids in the presence of coupling reagents in solvent to furnish compounds 2a-h; d) reducing the compounds obtained in step (iii) using lithium aluminium hydride (LiAlH4) in dry THF at -20°C to obtain the compounds 3a-h; e) deprotecting compounds obtained in step (iv) using 60% TFA in DCM at temperature in the range of room temperature to 40^oC for the time period in the range of 1 to 2 hours to produce histidinal-based trifluoroacetate salt compounds 4a-h; wherein said carboxylic acids are selected from (1a-h) 2-methylbenzoic acid (a), 1-hydroxy-2- naphthoic acid (b), 3-hydroxy-2-naphthoic acid (c), benzo[b]thiophene-2-carboxylic acid(d), (S)-2-(6- methoxynaphthalen-2-yl) propanoic acid (e), 2-propylpentanoic acid(f), 2-(2-((2,6-dichlorophenyl) amino) phenyl) acetic acid (g), and 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-[1,1'-biphenyl]-2-carboxylic acid (h). The process is depicted in Figure 1 Scheme 3. According to process, Fmoc-His (Trt)-OH was coupled with N, O-dimethylhydroxylamine in the presence of coupling agents to obtain precursor 1, a common intermediate for scaffolds 4a-h. Further removing Fmoc of 1 by tert-butylamine followed by coupling with different carboxylic acids in presence of HBTU/HOBt/EDC.HCl and DIPEA in DMF to obtain compounds 2a-h. Hydride reduction of compounds 2a-h using lithium aluminium hydride (LiAlH₄) in dry THF at -20°C to get the compounds 3a-h, followed by the deprotection of the trityl protecting group with 60% TFA in DCM at room temperature for 2 hours to produce the heteroaryl/aliphatic histidinal trifluoroacetate salt 4a-h. In yet another embodiment, the present invention provides a process for synthesis of peptide-histidinal conjugate compound of formula (I) comprising the steps of; i. deprotecting precursor 1by tert-butylamine in solvent; ii. coupling Fmoc-Leu-OH with precursor 1 obtained in step (i) in the presence of coupling reagents in solvent to obtain intermediate 5; iii. deprotecting Fmoc by tert-butylamine in solvent; iv. coupling the intermediate obtained in step (i) with carboxylic acids in the presence of coupling reagents in solvent to furnish compounds 6a-k; v. reducing the compounds obtained in step (iii) using lithium aluminium hydride (LiAlH4) in dry THF at -20°C to obtain the compounds 7a-k, and vi. deprotecting compounds obtained in step (iv) using 60% TFA in DCM at temperature in the range of room temperature to 40°C for the time period in the range of 2 to 3 hours to produce histidinal-based trifluoroacetate salt compounds 8a-k; wherein said carboxylic acids are selected from (a-k), 2-methylbenzoic acid (a), 1H-indole-2- carboxylic acid (b), 1-hydroxy-2-naphthoic acid (c), 3-hydroxy-2-naphthoic acid(d), benzo[b]thiophene-2-carboxylic acid (e), (S)-2-(6-methoxynaphthalen-2-yl) propanoic acid (f), 2- propylpentanoic acid (g), 2-(2-((2,6-dichlorophenyl) amino) phenyl) acetic acid(h), 4'-((1,7'-dimethyl- 2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-[1,1'-biphenyl]-2-carboxylic acid (i), 5- (dimethylamino) naphthalene-1-sulfonic acid (j), and 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4- d] imidazol-4-yl) pentanoic acid (k) The process is depicted in Figure 2 Scheme 4. According to the process, precursor 1 was first deprotected using tert-butylamine, then coupling with Fmoc-Leu-OH to obtain a common intermediate 5. Deprotection of 5 followed by coupling with different carboxylic acids afforded compounds 6a-k. Hydride reduction of compounds 6a-k by using LiAlH4 in dry THF under inert conditions followed by deprotecting aldehydes 7a-k with 60% TFA in dichloromethane at temperature in the range of room temperature to 40 ^{^}C for the time period in the range of 2 to 3 hours remove their trityl protecting groups to obtain histidinal-based scaffold 8a-k as trifluoroacetate salts. In still another embodiment, the present invention provides process for the synthesis of peptide- histidinal conjugate compound of formula (I) comprising the steps of: i) reacting 4, 7-dichloroquinoline 9 with the amino acids, at temperature in the range of 140 to 150°C for the time period of 1-6h to obtain compounds 10 a-c as reported in literature.¹ ii) coupling Compound 10c with N, O-dimethylhydroxylamine to obtain compound 11; iii) reacting compound 10b with precursor 1 in presence of coupling reagents to afford compound 13 iv) reacting compound 10a with intermediate 5 in presence of coupling reagents to afford compound 16 v) deducing the compounds obtained in step (i), (ii), (iii) using lithium aluminium hydride (LiAlH4) in dry THF at -20°C to obtain the compounds 12, 14, 17; vi) deprotecting compounds obtained in step (iv) using 60% TFA in DCM at temperature in the range room temperature to 40 ^{^}C for the time period in the range of 2 to 3 hours to produce histidinal-based trifluoroacetate salt compounds 15 and 18; wherein said amino acids are selected from a-c L-alanine (a), L-leucine (b) and L-histidine (c). The process is depicted in Figure 3 Scheme 5. According to the process 4, 7-dichloroquinoline 9 (commercially available) was first reacted with the amino acids at temperature in the range of 140°C to150°C for 1-6h to obtain compounds 10 a-c, following literature protocols.¹ Coupling 10c with N, O- dimethylhydroxylamine to obtain compound 11 followed by hydride reduction to furnish compound 12. Reacting compound 10b with the free amine of compound 1 in presence of coupling reagents followed reduction with LiAlH₄ at -20℃ in dry THF to get compound 14. Deprotecting trityl by using 60% TFA in solvent at temperature in the range of room temperature to 40^oC for the time period in the range of 1 to 2 hours to furnish compound 15. Reacting compound 10a with the free amine of compound 5 in the presence of coupling reagents followed by reduction with LiAlH4 at -20°C in dry THF to furnish compound 17. Deprotecting trityl group using 60% TFA in solvent at temperature in the range of room temperature to 40^oC for the time period in the range of 1 to 2 hours to yield compound 18. The solvent for the process is selected from polar or non-polar, protic or aprotic solvent such as lower alcohols, nitriles, ketones, halogenated hydrocarbons, TFA or combinations thereof. The base for the reaction is selected from organic base such as ethylamine, triethylamine, DIPEA, pyridine or from inorganic base such as sodium hydroxide, alkali or alkaline earth metal carbonates and bicarbonates or combination thereof. The coupling agent for reaction is selected from HBTU, EDC.HCl, or HOBt. In yet another preferred embodiment, the peptide-histidinal conjugate compounds of formula (I) are useful for inhibition of cysteine and aspartic acid proteases. Peptide-histidinal conjugate compounds of formula (I) tested to determine whether they could inhibit blood cells infected with P. falciparum. Inventor observed that the majority of molecules were found to be active against P. falciparum strains. Further the inhibitory potency (EC₅₀) of compounds of present invention is within the micromolar range, between 8.1 ^M to 0.01 ^ ^M. Importantly, it was noted that histidinal-containing leucine and aromatic/aliphatic compounds are having good antimalarial activity. Particularly, the compounds 8g (EC50 of 0.018 μΜ), 8h (EC50 of 0.06 μΜ), and 15 (EC50 of 0.02 μΜ) were found to have nanomolar inhibition potency against the parasites. EXAMPLES Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention. [A] Synthesis of compounds of formula I Example 1: (9H-fluoren-9-yl) methyl (S)-(1-(methoxy (methyl)amino)-1-oxo-3-(1-trityl-1H- imidazol-4-yl) propan-2-yl) carbamate (1): A mixture of Fmoc-His (Trt)-OH (1g, 1.61 mmol, 1 equiv.), HBTU (0.73 g, 1.93 mmol, 1.2 equiv), and HOBt (0.21g, 1.61 mmol,1 equiv) were dissolved in DMF at ice temperature and N, N-diisopropylethylamine was added (0.82 mL, 4.84 mmol, 3 equiv.) and stirred for 20 min. Then N O-dimethylhydroxylamine hydrochloride (0.31g, 3.23 mmol, 2 equiv.) was added and stirred for 5 h at room temperature. The reaction mixture was diluted with ice-cold water (20 mL), and the resulting solid precipitate was filtered under vacuum, and the solid residue was dissolved in ethyl acetate (30 mL) and washed with dilute citric acid, NaHCO3 solution, and brine solution, and dried over Na2SO4. The product obtained after evaporating solvent was pure enough and carried forward for next reactions. Yield: 0.9g, (84%); mp: 70-75℃; Rf = 0.5 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D = -3.55 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ 7.75 - 7.74 (d, J = 7.5 Hz, 2 H), 7.38 (t, J = 6.9 Hz, 2 H), 7.38 -7.32 (m, 3 H), 7.31 - 7.30 (m, 11 H), 7.13 - 7.11 (m, 7 H), 6.60 (s, 1 H), 6.11 (d, J = 7.6 Hz, 1 H), 4.98 - 4.95 (d, J = 5.4 Hz, 1 H), 4.31 - 4.23 (m, 2 H), 4.17(d, J = 7.5 Hz, 1 H), 3.77 (s, 3 H), 3.16 - 3.09 (s, 3 H), 2.98 - 2.96 (m, 2H); Calcd m/z: [M+H]⁺ for; C42H39N4O4; 663.2966; Found 663.2953. Example 2: (S)-N-(1-(methoxy(methyl) amino)-1-oxo-3-(1-trityl-1H- imidazol-4-yl) propan-2-yl)- 2-methylbenzamide (2a): Fmoc deprotection was done first, as follows. Fmoc compound 1 (0.678g, 1 mmol, 1equiv.) was taken in 50% solution of tert-butylamine in DCM (30mL) and stirred at room temperature for 45 min, and the reaction mixture was concentrated under vacuum. The resulting semisolid residue was washed with diethyl ether (3 x 5 mL). The free amine of 1 (0.440g, 1 mmol, 1 equiv.) was added to a reaction mixture containing O-toluic acid (0.136 g, 1 mmol, 1 equiv.), HBTU (0.456g, 1.2 mmol, 1.2 equiv), HOBt (0.135g, 1 mmol, 1 equiv) and N, N-diisopropylethylamine (0.347 mL, 2 mmol, 2 equiv.) in DMF (12mL). The solution was stirred at room temperature for overnight. Then, the reaction mixture was diluted with ice cold water (20 mL), and extracted with ethyl acetate (2 x 30 mL). It was successively washed with dilute aqueous citric acid solution, NaHCO₃ solution, and brine solution, dried over Na₂SO₄ and concentrated under vacuum, then purified with neutral allumimium oxide packed column chromatography. The mobile phase starting from pet-ether and gradually increasing polarity with dichloromethane and then 3% methanol/DCM afforded 2a as white solid. Yield: 0.4g, (70%); mp: 75 - 80℃; Rf = 0.45 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D = -10.64 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ 7.30 (d, J = 7.5 Hz, 1 H), 7.29 (s, 1 H), 7.29 (d, J = 5.3 Hz, 10 H), 7.28 (d, J = 8.1 Hz, 2 H), 7.12 - 7.09 (m, 8 H), 6.57 (s, 1 H), 5.33 - 5.32 (d, J = 19.0 Hz, 1 H), 3.83 (s, 3 H), 3.17 (s, 3 H), 3.10 - 3.03 (dd, J = 5.6, 9.1 Hz, 2 H), 2.42 (s, 3 H); Calcd m/z: [M+H]⁺ for C35H35N4O3; 559.2704; Found 559.2701. Example 3: (S)-1-hydroxy-N-(1-(methoxy(methyl) amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-2-naphthamide (2b): Using 1-hydroxy-2-naphthoic acid, 2b was synthesized following the analogous procedure of 2a White solid (note: in place of HBTU, we used EDC.HCl as a coupling agent); Yield: 0.56g, (75%); mp: 85-90℃; Rf = 0.6 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D = 26.42 (c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ 13.67 (bs, 1H), 8.38 (d, J = 8.1 Hz, 1 H), 8.36 (d, J = 7.3 Hz, 1 H), 7.72 (bs., 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.50 (m, 3 H), 7.46 - 7.28 (m, 11 H), 7.26 (d, J = 6.1 Hz, 6 H), 7.58 (s, 1 H), 5.33 (m, 1 H), 3.86 (s., 3 H), 3.19 - 3.13 (m, 3 H), 3.11 - 3.109 (m, 3H); Calcd m/z: [M+H]⁺ for C38H35N4O4; 611.2653; Found 611.2648. Example 4: (S)-3-hydroxy-N-(1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-2-naphthamide (2c): Using 2-hydroxy-3-naphthoic acid, 2c was synthesized following the analogous procedure of 2a. White solid (note: in place of HBTU, we used EDC.HCl as a coupling agent); Yield: 0.38g (62%); [α]²⁷D = 22.42 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ 13.62 (bs, 1H), 8.33 (m, 2 H), 8.30 (m, 1H); 7.74 (bs., 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.54 - 7.46 (m, 2 H), 7.47 - 7.36 (m, 1 H), 7.27 - 7.22 (m, 10 H), 7.20 (d, J = 8.8 Hz, 1 H), 7.03 - 7.02 (m, 6 H), 6.76 (s, 1 H), 5.42 (m, 1 H), 3.89 (bs., 3 H), 3.31 (m, 2 H), 3.26 - 3.121; Calcd m/z: [M+H]⁺ for C38H35N4O4; 611.2653; Found 611.2640. Example 5: (S)-N-(1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) benzo [b] thiophene-2-carboxamide (2d): Using benzo[b]thiophene-2-carboxylic acid, 2d was synthesized following the analogous procedure of 2a. 2d was obtained as a white solid: Yield: 0.35g, (58%); mp:80-84℃; R_f = 0.55 (silica gel TLC, 2% MeOH in DCM); [α]²⁷ _D = -13.60 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ 7.83 (bs., 1 H), 7.81-7.78 (m, 2 H), 7.42 (m, 1 H), 7.31 - 7.30 (m, 12 H), 7.13 - 7.11 (m, 7 H), 6.59 (s, 1 H), 5.30 (d, J = 5.9 Hz, 1 H), 3.86 (s, 3 H), 3.19 (m, 3 H), 3.12 - 3.08 (m, 2 H); Calcd m/z: [M+H]⁺ for C₃₆H₃₃N₄O₃; 601.2268; Found 601.2266. Example 6: (S)-N-methoxy -2-((S)-2-(6-methoxynaphthalen-2-yl) propanamido)-N-methyl-3-(1- trityl-1H-imidazol-4-yl) propanamide (2e): Using (S)-(+)-2-(6-methoxy-2-naphthyl) propionic acid, 2e was synthesized following the analogous procedure of 2a. 2e was obtained as a white solid. Yield: 0.4g, (61%); [α]²⁷D = -73.21 ^(c = 0.1, MeOH); mp: 60-65℃; Rf = 0.65 (silica gel TLC, 2% MeOH in DCM); ¹H NMR (400MHz, CDCl₃) ^ ^7.61 - 7.60 (m, 3 H), 7.34 (d, J = 1.8 Hz, 1 H), 7.33 - 7.28 (m, 10 H), 7.08 - 7.03 (m, 9 H), 6.91 (d, J = 2.4 Hz, 1 H), 6.91 (bs., 1 H), 6.44 (s, 1 H), 5.07-5.02 (m, 1 H), 3.88 (s, 3 H), 3.74 (s, 3 H), 3.65 (q, J = 7.2 Hz, 1 H), 3.09 (s, 3 H), 2.89 (dq, J = 5.4, 14.6 Hz, 2 H), 1.54 (d, J = 7.3 Hz, 3 H); Calcd m/z: [M+H]⁺ for C₄₁H₄₁N₄O₄; 653.3122; Found 653.3104. Example 7: (S)-N-(1-(methoxy(methyl) amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)- 2-propyl pentanamide (2f): Using 2-propylpentanoic acid, 2f was synthesized following the analogous procedure of 2a. 2f was obtained as a white solid. Yield: 0.28g, (50%); mp: 65-70℃; Rf = 0.6 (silica gel TLC, 2% MeOH in DCM); [α]²⁷ _D = -8.80 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ 7.34 - 7.32 (m, 10 H), 7.13 - 7.12 (m, 6 H), 6.80 (bs., 1 H), 6.55 (s, 1 H), 5.12 (d, J = 6.9 Hz, 1 H), 3.77 (s, 3 H), 3.13 (s, 3 H), 2.96 - 2.95 (d, J = 5.5 Hz, 2 H), 2.08 - 2.07 (d, J = 4.5 Hz, 1 H), 1.56 - 1.26 (m, 2 H), 1.38 - 1.14 (m, 7 H), 0.87 - 0.78 (m, 6 H); Calcd m/z: [M+H]⁺ for C₃₅H₄₃N₄O₃; 567.3330, Found 567.3332. Example 8: (S)-2-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetamido)-N-methoxy-N-methyl-3- (1-trityl-1H-imidazol-4-yl) propanamide (2g): Using 2-(2,6-dichloroanilino) phenylacetic Acid, 2g was synthesized following the analogous procedure of 2a. 2g was obtained as a white solid: Yield: 0.287g, (59%): mp:95-99℃; Rf = 0.55 (silica gel TLC, 2% MeOH in DCM); [α]²⁷ _D =-29.33 ^ (c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^ ^7.80 (s, 1 H), 7.33 - 7.31 (m, 12 H), 7.18 (d, J = 6.5 Hz, 1 H), 7.13 - 7.11 (m, 6 H), 7.05 - 7.03 (m, 2 H), 6.95 (t, J = 8.1 Hz, 1 H), 6.79 (t, J = 7.4 Hz, 1 H), 6.52 - 6.50 (m, 2 H), 5.14 - 5.10 (d, J = 6.3 Hz, 1 H), 3.76 (s, 3 H), 3.71 - 3.59 (m, 2 H), 3.14 (s, 3 H), 2.99 – 2.98 (d, J = 5.4 Hz, 2 H); Calcd m/z: [M+H]⁺ for C₄₁H₃₈N₅O₃; 718.2346; Found 718.2345. Example 9: (S)-4'-((1, 7'-dimethyl-2'-propyl-1H, 3'H-[2, 5'-bibenzo[d] imidazol]-3'-yl)methyl)-N- (1-(methoxy(methyl) amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) -[1, 1'-biphenyl]-2- carboxamide (2h): Using 4'-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H- benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid, 2h was synthesized following the analogous procedure of 2a. 2h was obtained as a white solid. Yield: 0.13g, (71%); mp. 105 -108℃; [α]²⁵D = - 6.90 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ 7.80 - 7.78 (dd, J = 2.8, 6.3 Hz, 1 H), 7.54 (d, J = 7.5 Hz, 1 H), 7.45 - 7.40 (m, 3 H), 7.32 - 7.30 (m, 4 H), 7.29 - 7.25 (m, 16 H), 7.09 (m, 6 H), 7.08 (d, J = 8.1 Hz, 2 H), 6.89 (bs., 1 H), 6.44 (s, 1 H), 5.39 (s, 2 H), 5.12 (bs., 1 H), 3.76 (s, 3 H), 3.62 (s, 3 H), 3.02 (s, 3 H), 2.93 - 2.89 (m, 2 H), 2.81 - 2.79 (m, 5 H), 1.87 - 1.85 (m, 2 H), 1.03-1.01 (t, J = 7.3 Hz, 3 H); Calcd m/z: [M+H]⁺ for C₆₀H₅₇N₈O₃; 937.4548; Found 937.4568. Example 10: (S)-2-methyl-N-(1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) benzamide (3a): The compound 2a (0.30g, 0.536 mmol, 1 equiv.) was dissolved in dry THF under nitrogen atmosphere and cooled to -20^oC, added LiAlH4 (0.039g, 1 mmol, 2 equiv.), stirred for 1hour and the reaction progress was monitored by TLC. The resulting reaction mixture was quenched with dilute solution of citric acid (0.1 - 0.2mL), followed by the addition of ethyl acetate (30 mL). Afterwards, the combined organic layer was washed with dilute citric acid solution and NaHCO3 and brine solutions, dried over Na2SO4 and then the organic solvent was concentrated under vacuum. The crude product was purified by Al₂O₃ packed column chromatography. The mobile phase was pet ether to dichloromethane. The compound 3a was precipitated in 50% diethyl ether and hexane to yield a white solid.Yield: 0.22g, (82%); mp: 80 - 85℃; Rf = 0.5 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D = -14.92 ^(c = 0.1, MeOH); ¹H NMR (500 MHz, CDCl3) ^ 9.72 (s, 1 H), 7.52 (d, J = 6.6 Hz, 1 H), 7.42 (d, J = 7.6 Hz, 1 H), 7.32 - 7.26 (m, 12 H), 7.24 - 7.17 (m, 2 H), 7.13 - 7.06 (m, 6 H), 6.64 (s, 1 H), 4.84 (d, J = 6.2 Hz, 1 H), 3.24 (dd, J = 5.1, 15.0 Hz, 1 H), 3.15 (dd, J = 5.3, 15.1 Hz, 1 H), 2.45 (s, 3 H); Calcd m/z: [M+H]⁺ for C₃₃H₃₀N₃O₂; 500.2333; Found 500.2320. Example 11: (S)-1-hydroxy-N-(1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-2-naphthamide (3b): The synthetic method of 3a was adopted to synthesize 3b. White solid; Yield: 0.155g, (56%); mp:80-85℃; Rf = 0.5 (silica gel TLC, 70% ethyl acetate in pet. ether); [α]²⁷D =- 9.24 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^ ^13.66 (bs, 1H); 9.66 (s, 1 H), 9.07 (d, J = 5.9 Hz, 1 H), 8.41 (d, J = 8.3 Hz, 1 H), 7.74 (d, J = 7.9 Hz, 1 H), 7.55 (m, 3 H), 7.45 - 7.32 (d, J = 1.1 Hz, 1 H), 7.32 - 7.26 (m, 10 H), 7.25 (s, 1 H), 7.10 - 7.09 (m, 6 H), 6.66 (s, 1 H), 4.79 (d, J = 5.5 Hz, 1 H), 3.24 (dd, J = 5.4, 15.0 Hz, 1 H), 3.12 (dd, J = 5.1, 15.0 Hz, 1 H); Calcd m/z: [M+H]⁺ for C36H30N3O3; 552.2882; Found 552.2880. Example 12: (S)-3-hydroxy-N-(1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-2-naphthamide (3c): The synthetic method 3a was used to synthesize 3c. White solid; Yield: 0.140g, (50%); mp:83-86℃; Rf = 0.45 (silica gel TLC, 3% MeOH in DCM); [α]²⁷D =-9.10 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ ^11.81 (bs, 1H) 9.69 (s, 1 H), 9.22 - 9.21 (d, J = 5.8 Hz, 1 H), 8.21 (s, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.46 - 7.43 (m, 2 H), 7.32 (m, 11 H), 7.11 - 7.08 (m, 7 H), 6.68 (s, 1 H), 4.83 - 4.80 (m, 1 H), 3.28 - 3.12 (m, 2 H); Calcd m/z: [M+H]⁺ for C₃₆H₃₀N₃O₃; 522.5282; Found 522.5280. Example 13: (S)-N-(1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) benzo[b]thiophene-2- carboxamide (3d): The synthetic method 3a was used to synthesize 3d. White solid; Yield: 0.25g, (85%); mp: 75-80℃; R_f = 0.25 (silica gel TLC, 2% MeOH in DCM); [α]²⁷ _D = -17.28 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^9.70 (s, 1 H), 8.56 (d, J = 5.8 Hz, 1 H), 7.86 - 7.85 (m, 2 H), 7.44 - 7.33 (m, 2 H), 7.32 (m, 8 H), 7.31 (m, 2 H), 711. - 7.09 (m, 8 H), 6.66 (s, 1 H), 4.82 - 4.78 (d, J = 5.6 Hz, 1 H), 3.27 - 3.22 (s, 1 H), 3.14 - 3.09 - (d, J = 5.0 Hz, 1 H); Calcd m/z: [M+H]⁺ for C34H28N3O2S; 542.1897; Found 542.1893. Example 15: (S)-2-(6-methoxynaphthalen-2-yl)-N-((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) propanamide (3e): The synthetic method of 3a was adopted to synthesize 3e. White solid. Yield: 0.23g, (84%); Rf = 0.5 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D =-5.32 ^(c = 0.1, MeOH); mp: 80-84℃; ¹H NMR (400MHz, CDCl3) ^ 9.52 - 9.41 (s, 1 H), 7.69 - 7.61 (m, 4 H), 7.32 - 7.29 (m, 13 H), 6.99 (td, J = 2.2, 8.9 Hz, 2 H), 6.98 - 6.97 (m, 7 H), 6.97 (dd, J = 1.3, 4.0 Hz, 1 H), 6.45 (d, J = 9.5 Hz, 1 H), 4.50 (d, J = 5.8 Hz, 1 H), 3.88 (s, 3 H), 2.98 (s, 2 H), 1.61-1.58 (dd, J = 3.5, 7.1 Hz, 3 H); Calcd m/z: [M+H]⁺ for C₃₉H₃₆N₃O₃; 594.2751; Found 594.2339. Example 16: (S)-N-(1-oxo-3-(1-trityl- 1H-imidazol-4-yl) propan-2-yl)-2-propylpentanamide (3f): The synthetic method of 3a was adopted to synthesize 3f. White solid. Yield: 0.2g (74%); R_f = 0.5 (silica gel TLC, 30% ethyl acetate in pet. ether); [α]²⁵D = 27.66 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ ^9.59 (s, 1 H), 7.34 - 7.32 (m, 10 H), 7.10 - 7.07 (m, 6 H), 6.61 (s, 1 H), 4.61 - 4.57 (q, J = 5.8 Hz, 1 H), 3.14 (dd, J = 5.9, 15.0 Hz, 1 H), 2.96 (dd, J = 5.3, 15.0 Hz, 1 H), 2.17 (dt, J = 4.7, 9.3 Hz, 1 H), 1.64 (m, 4 H), 1.27 (m, 4 H), 0.98 - 0.76 (m, 6 H); Calcd m/z: [M+H]⁺ for C33H37N3O2; 508.2959; Found 508.2957. Example 17: (S)-2-(2-((2, 6-dichlorophenyl) amino) phenyl)-N-(1-oxo-3-(1-trityl-1H-imidazol-4- yl) propan-2-yl) acetamide (3g): The synthetic method of 3a was adopted to synthesize 3g. White solid; Yield: 0.16g, (58%); Rf = 0.4 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D = -12.80 ^(c = 0.1, MeOH); mp: 70-75℃; ¹H NMR (400MHz, CDCl3) ^ 9.57 (s, 1 H), 7.73 (d, J = 6.6 Hz, 1 H), 7.55 (s, 1 H), 7.38 - 7.30 (m, 15 H), 7.15 - 7.03 (m, 10 H), 6.97 (t, J = 8.1 Hz, 2 H), 6.84 (t, J = 7.4 Hz, 1 H), 6.58 (s, 1 H), 6.51 (d, J = 8.0 Hz, 1 H), 4.77 - 4.49 (m, 1 H), 3.51 - 3.45 (m, 1 H), 3.12 (dd, J = 5.3, 15.0 Hz, 1 H), 2.98 (dd, J = 5.1, 15.1 Hz, 1 H); Calcd m/z: [M+H]⁺ for C₃₉H₃₃N₄O₂Cl₂; 659.1975; Found 659.1971. Example 18: (S)-4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-N- (1-oxo -3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-[1,1'-biphenyl]-2-carboxamide (3h): The synthetic method of 3a was adopted to synthesize 3h. White solid; Yield: 0.07g, (74%); Rf = 0.36 (silica gel TLC, 2% MeOH in DCM); mp: 95-105℃; [α]²⁷D = -6.80 ^(c = 0.1, MeOH); ¹H NMR (500MHz, CDCl3) ^ ^9.42 (s, 1 H), 7.87 - 7.68 (m, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.46 (d, J = 1.1 Hz, 1 H), 7.43 (s, 2 H), 7.39 - 7.32 (m, 3 H), 7.32 - 7.22 (m, 17 H), 7.17 (d, J = 6.8 Hz, 1 H), 7.14 - 7.06 (m, 1 H), 7.06 - 6.96 (m, 7 H), 6.48 (s, 1 H), 5.39 (s, 2 H), 4.55 (d, J = 6.5 Hz, 1 H), 3.82 - 3.64 (m, 3 H), 3.56 - 3.36 (m, 2 H), 3.04 - 2.81 (m, 3 H), 2.81 - 2.61 (m, 4 H), 1.97 - 1.79 (m, 2 H), 1.40 - 1.15 (m, 8 H), 1.15 - 0.95 (m, 3 H), 0.88 (t, J = 6.8 Hz, 3 H); Calcd m/z: [M+H]⁺ for C58H51N7O2; 878.4182; Found 878.4160. Example 19: (S)-5-(2-(2-methylbenzamido)-3-oxopropyl)-1H-imidazol-1-ium (4a): The compound 3a (0.25g, 0.5 mmol, 1 equiv.) was dissolved in a solution of 60% TFA in DCM and stirred at room temperature for 3-4 h and the complete deprotection was monitored by TLC. The resultant yellow solution was concentrated under the vacuum and the residual TFA was stripped off using co-evaporation with DCM (2 x 10 mL), and the solid residue was washed (3 x 5 mL) with diethyl ether to yield compound 4a as white solid; Yield: 0.15g, (81%); R_f = 0.2 (silica gel TLC, 3% MeOH in DCM); mp: 70-75℃; [α]²⁵ _D = 30.30 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD₃OD) ^ ^ ^8.78 (s, 1 H), 7.34 - 7.27 (m, 3 H), 7.21- 7.12 (m, 3 H), 4.70 - 4.40 (m, 2 H), 3.29 (d, J = 15.5 Hz, 1 H), 2.95 (bs., 1 H), 2.23 (s, 3 H); Calcd m/z: [M+H] ⁺ for C14H16N3O2; 258.1237; Found 258.1234. Example 20: (S)-5-(2-(1-hydroxy-2-naphthamido)-3-oxopropyl)-1H-imidazol-1-ium (4b): The synthetic method of 4a was adopted to synthesize 4b. White solid; Yield: 0.06 g (78%); R_f = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁷D = -17.28 ^(c = 0.1, MeOH); mp: 65-70℃; ¹H NMR (400MHz, CD3OD) ^ ^8.74 (s, 1 H), 8.31-8.29 (d, J = 8.3 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.69 - 7.68 (m, 2 H), 7.58 (s, 2 H), 7.49 (d, J = 7.4 Hz, 1 H), 7.32 (s, 1 H), 7.30 - 7.25 (m, 3 H), 4.79 -4.57 (bs., 2 H), 3.50 (d, J = 7.0 Hz, 1 H), 3.23 - 3.10 (t, J = 7.0 Hz, 2 H); Calcd m/z: [M+H]⁺ for C₁₇H₁₆N₃O₃; 310.1186; Found 310.1182. Example 21: (S)-5-(2-(3-hydroxy-2-naphthamido)-3-oxopropyl)-1H-imidazol-1-ium (4c): The synthetic method of 4a was adopted to synthesize 4c. White solid; Yield: 0.072g, (75%); R_f = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁵ _D = 7.90 ^(c = 0.1, MeOH); mp: 80 - 85℃; ¹H NMR (400MHz, CD₃OD) ^ 8.74 – 8.73 (m, 1 H), 8.44 - 8.38 (d, J = 4.8 Hz, 1 H), 7.82 - 7.79 (d, J = 8.1 Hz, 1 H), 7.66 - 7.64 (d, J = 8.3 Hz, 1 H), 7.46 (dt, J = 1.1, 7.6 Hz, 1 H), 7.33 - 7.28 (m, 2 H), 7.22 (s, 1 H),4.77 - 4.76 (m,1H), 4.59-4.53 (m, 1 H); 3.05 (s, 2 H); Calcd m/z: [M+H] ⁺ Calcd for C17H16N3O3; 310.1186; Found 310.1179. Calcd m/z: [M+H]⁺ Calcd for C17H16N3O3; 310.1186; Found 310.1179. Example 22: (S)-5-(2-(benzo[b]thiophene-2-carboxamido)-3-oxopropyl)-1H-imidazol-1-ium (4d): The synthetic method of 4a was adopted to synthesize 4d. White solid; Yield: 0.11g, (72%); Rf = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁷D = -17.28 ^(c = 0.1, MeOH); mp: 80-85℃; ¹H NMR (400MHz CD3OD) ^ 8.73 (bs., 1 H), 7.97 (s, 1 H), 7.89 ( ^^, J = 7.1 Hz, 2 H), 7.44 - 7.41 (m, 2 H), 7.28 (s, 1 H), 4.76 - 4.73 (m, 1 H), 4.44 (bs., 2 H), 3.76 - 3.65 (m, 2 H), 3.51 - 3.42 (m, 1 H), 3.28 - 3.13 (m, 1 H), 3.13 - 2.95 (m, 1 H); Calcd m/z: [M+H]+ for C15H14N3O2S; 300.0801; Found 300.0793. Example 23: 5-((S)-2-((S)-2-(6-methoxynaphthalen-2-yl)propanamido)-3-oxopropyl) -1H- imidazol-1-ium (4e): The synthetic method of 4a was adopted to synthesize 4e. White solid; Yield: 0.12g, (85%); R_f = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁵ _D = 36.18 ^ (c = 0.1, MeOH); mp: 100-105℃; ¹H NMR (400MHz, CD3OD) ^ ^ ^8.70 (bs., 1 H), 8.24 (s, 1 H), 7.70 - 7.66 (m, 4 H), 7.58 (s, 1 H), 7.38 (d, J = 8.5 Hz, 1 H), 7.25 - 7.18 (m, 3 H), 7.12 (t, J = 9.7 Hz, 2 H), 6.75 (m, 1 H), 4.62 - 4.61 (dd, J = 3.4, 7.2 Hz, 1 H), 4.46 (dd, J = 3.6, 10.1 Hz, 1 H), 4.26 - 4.12 (m, 2 H), 3.90 (s, 3 H), 3.77 - 3.68 (m, 3 H), 3.09 (d, J = 15.5 Hz, 1 H), 2.98 (d, J = 14.0 Hz, 1 H), 2.77 (m, 2 H), 1.46 -1.39 (dd, J = 7.0, 18.9 Hz, 5 H), 1.16-1.10 (d, J = 6.1 Hz, 6 H): Calcd m/z: [M+H]⁺ for C20H22N3O3; 352.1656; Found 352.1656. Example 24: (S)-5-(3-oxo-2-(2-propylpentanamido) propyl)-1H-imidazol-1-ium (4f): The synthetic method of 4a was adopted to synthesize 4f. White solid; Yield: 0.12g (80%); [α]²⁷D = 3.80 ^(c = 0.1, MeOH); mp: 60 - 65℃; ¹H NMR (400MHz, CD₃OD) ^ ^8.78 (d, J = 1.3 Hz, 1 H), 7.44 - 7.27 (m, 2 H), 4.31- 4.28 (tdd, J = 3.9, 5.5, 11.3 Hz, 1 H), 3.32 (m, 1 H), 2.88 (ddd, J = 3.9, 11.4, 15.4 Hz, 2 H), 2.19 (m, 1 H), 1.29 – 1.25 (m, 8 H), 0.91 - 0.80 (m, 6 H); Calcd m/z: [M+H]⁺ for C14H24N3O2; 352.1656; Found 352.1656. Example 25: (S)-5-(2-(2-(2-((2, 6-dichlorophenyl) amino)phenyl)acetamido)-3-oxopropyl)-1H- imidazol-1-ium (4g): The synthetic method of 4a was adopted to synthesize 4g. White solid; Yield: 0.12g, (74%); mp: 75-80℃; R_f = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁷ _D = 25.80 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD₃OD) ^ ^ 8.41 - 8.39 (m, 1 H), 7.30 - 7.28 (m, 3 H), 7.25 - 7.11 (m, 2 H), 7.08 - 7.06 (m, 1 H), 6.98 (t, J = 8.2 Hz, 2 H), 6.83 - 6.78 (m, 2 H), 6.27 - 6.25 (d, J = 8.0 Hz, 1 H), 4.54 – 4.52 (t, J = 4.4 Hz, 1 H), 4.16 (t, J = 11.8 Hz, 1 H), 3.57 (dd, J = 3.8, 13.4 Hz, 1 H), 3.49 - 3.45 (d, J = 13.4 Hz, 1 H), 3.38 - 3.35 (m, 1 H), 2.99 (dt, J = 3.5, 15.4 Hz, 1 H), 2.75 (m, 1 H); Calcd m/z: [M+H]⁺ for C20H19N4O2Cl2; 417.0880; Found 417.0882. Example 26: (S)-5-(2-(4'-((1, 7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d] imidazol]-3'-yl) methyl)-[1, 1'-biphenyl]- 2-carboxamido)-3-oxopropyl)-1H-imidazol-1-ium (4h): A synthetic method of 4a was used to synthesize 4h. White solid; Yield: 0.123g, (69%); [α]²⁷D = -6.80 ^(c = 0.1, MeOH); mp: 80-85℃; ¹H NMR (400MHz, CD3OD) ^ 8.78 - 8.77 (t, J = 1.6 Hz, 1 H), 7.92 - 7.87 (m, 2 H), 7.70 - 7.76 (m, 1 H), 7.71 (s, 1 H), 7.69 - 7.61 (m, 2 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.45 - 7.65 (m, 1 H), 7.42 - 7.40 (m, 4 H), 7.26 - 7.24 (m, 4 H), 5.76 (s, 2 H), 4.39 (m, 1H),4.38 (m, 1H), 4.01 (s, 3 H), 3.33 - 3.29 (m, 3 H), 3.19 (t, J = 7.4 Hz, 2 H), 2.79 (s, 3 H), 1.90 (dd, J = 2.2, 7.7 Hz, 2 H), 1.29 - 1.16 (m, 2 H) 1.14 - 1.01 (m, 3 H); Calcd m/z: [M+H]⁺ for C39H38N7O2; 636.3081; Found 636.3081. Example 27: (9H-fluoren-9-yl) methyl ((S)-1-(((S)-1-(methoxy(methyl) amino)-1-oxo-3-(1-trityl- 1H-imidazol-4-yl) propan-2-yl) amino)-4-methyl-1-oxopentan-2-yl) carbamate (5): The synthetic method of 2 was adopted to synthesize compound 5. White solid. Yield: 0.45g, (58 %); mp:85-90℃; Rf = 0.65 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D = 0.76 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ 7.74 (d, J = 7.4 Hz, 2 H), 7.57 - 7.51 (m, 2 H), 7.37 (t, J = 7.5 Hz, 3 H), 7.31 - 7.25 (m, 12 H), 7.10 - 7.08 (m, 6 H), 6.52 (s, 1 H), 5.58 (d, J = 8.3 Hz, 1 H), 5.06 (bs., 1 H), 4.40 (bs., 1 H), 4.38 - 4.31 (m, 2 H), 4.28 - 4.16 (d, J = 7.0 Hz, 1 H), 3.76 (s, 3 H), 3.12 (s, 3 H), 2.97 (d, J = 5.3 Hz, 2 H), 2.09 (s, 3 H), 1.69 - 1.67 (m, 2 H), 1.47 (bs, 1H), 0.93 – 0.87 (t, J = 5.8 Hz, 6 H); Calcd m/z: [M+H]⁺ Calcd for C₄₈H₅₀N₅O₅; 776.3806; Found 776.3815. Example 28: N-((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino)-4-methyl-1-oxopentan-2-yl)-2-methylbenzamide (6a): Fmoc deprotection was done first, as follows. Fmoc compound 5 (0.675g, 1 mmol, 1equiv.) was taken in 50% solution of tert- butylamine in DCM (30mL) and stirred at room temperature for 45 min, and the reaction mixture was concentrated under vacuum. The resulting semisolid residue was washed with pet-ether (3 x 5 mL). The free amine of 1 (0.4g, 0.72 mmol, 1 equiv.) was added to a reaction mixture containing O-toluic acid (0.1 g, 0.73 mmol, 1.02 equiv.), HBTU (0.456 g, 1.2 mmol, 1.2 equiv), HOBt (0.135g, 1 mmol, 1 equiv) and N, N-diisopropylethylamine (0.347 mL, 2 mmol, 2 equiv.) in DMF (12mL). The solution was stirred at room temperature for overnight. Then, the reaction mixture was diluted with ice cold water (20 mL), and extracted with ethyl acetate (2 x 30 mL). It was successively washed with dilute aqueous citric acid solution, NaHCO₃ solution, and brine solution, dried over Na₂SO₄ and concentrated under vacuum., then purified with neutral allumimium oxide packed column chromatography. The mobile phase starting from pet-ether and gradually increasing polarity with dichloromethane and then 3% methanol/DCM afforded 2a as white solid. Yield: (0.34g), 70%; mp: 72-77℃; R_f = 0.45 (silica gel TLC, 2% MeOH in DCM); [α]²⁴D = -2.4 ^(c = 0.1, MeOH); ¹H NMR (500MHz, CDCl3) ^ ^7.47 (d, J = 7.0 Hz, 1 H), 7.44 - 7.35 (m, 1 H), 7.34 (m, 9 H), 7.29 - 7.26 (m, 2 H), 7.12 (d, J = 7.9 Hz, 1 H), 7.11- 7.10 (m, 7 H), 6.71 - 6.70 (d, J = 7.9 Hz, 1 H), 6.55 (s, 1 H), 5.14 – 5.12 (d, J = 7.0 Hz, 1 H), 4.78 - 4.76 (m, 1 H), 3.77 (s, 3 H), 3.13 (s, 3 H), 3.01 - 2.99 (m, 2 H), 2.44 (s, 3 H), 1.82 - 1.80 (m, 2 H), 1.62 - 1.60 (m, 1 H), 1.28 - 1.23 (m, 3 H), 1.01 - 0.98 (m, 6 H); Calcd m/z: [M+H]⁺ for C41H46N5O4; 772.3544; Found 772.3522. Example 29: N-((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide(6b): Using 1H-indole- 2-carboxylic acid, 6b was synthesized following the analogous procedure of 2a. 6b was obtained as a white solid. Yield: 0.45g, (58 %); mp: 80-85℃; Rf = 0.45 (silica gel TLC, 2% MeOH in DCM); [α]²⁴D = -3.4 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^9.42 (bs., 1 H), 7.60 (bs., 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.30 - 7.22 (m, 14 H), 7.08 (m, 2 H), 7.07 (m, 4 H), 6.89 (s, 1 H), 6.53 (s, 1 H), 5.17 - 5.15(m, 1 H), 4.87- 4.83 (m, 1 H), 3.77 (s, 3 H), 3.14 (s, 3 H), 2.99 - 2.95 (m, 2 H), 1.87 - 1.65 (m, 3 H), 1.26 (m, 1H), 0.97 - 0.74 (m, 6 H); Calcd m/z: [M+H]⁺ Calcd for C42H45N6O4; 697.3497; Found 697.3479. Example 30: 1-hydroxy-N-((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol- 4-yl) propan-2-yl) amino)-4-methyl-1-oxopentan-2-yl)-2-naphthamide (6c): Using 1-hydroxy-2- naphthoic acid, 6c was synthesized following the analogous procedure of 2a. 6c was obtained as a white solid. (Note: EDC.HCl was used in place of HBTU). Yield: 0.45g, (62%); mp: 80-85℃; R_f = 0.45 (silica gel TLC, 2% MeOH in DCM); [α]²⁴D = 2.80 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ ^13.89 (bs., 1 H), 8.83 (bs, 1H), 8.35 (bs, 1H), 7.98, (s,1H), 7.72 (bs., 1 H), 7.61 - 7.51 (m, 1 H), 7.40 - 7.38 (m, 9 H), 7.04 (m, 6 H), 6.74 (s, 1 H), 5.19-5.17 (bs., 1 H), 4.94 (t, J = 8.5 Hz, 1 H), 3.72 (s, 3 H), 3.15 (d, J = 6.0 Hz, 2 H), 3.72 (s, 3 H), 2.05 - 1.02 (m, 1 H), 1.81 - 1.74 (m, 2 H), 0.94 - 0.93 (m, 6 H); Calcd m/z: [M+H]⁺ for C₄₄H₄₆N₅O_, 724.3493 Found, 724.3475. Example 31: 3-hydroxy-N-((S)-1-(((S)-1-(methoxy (methyl) amino)-1-oxo-3-(1-trityl-1H-imidazol- 4-yl) propan-2-yl) amino)-4-methyl-1-oxopentan-2-yl)-2-naphthamide (6d): Using 3-hydroxy-2- naphthoic acid, 6d was synthesized following the analogous procedure of 2a. 6d was obtained as a white solid. (Note: in place of HBTU we used EDC.HCl). Yield: 0.4g, (55 %); [α]²⁴D = -2.43 ^(c = 0.1, MeOH); mp: 85-90℃; ¹H NMR (400MHz, CDCl3) ^ ^11.74 (bs., 1 H), 9.04 (bs., 1 H), 8.90 (bs., 1 H), 8.00 - 7.95 (m, 2 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.38 - 7.33 (m, 9 H), 7.06 - 7.04 (dd, J = 2.0, 7.4 Hz, 5 H), 6.73 (s, 1 H), 5.17 (bs., 1 H), 4.92 - 4.90 (t, J = 8.1 Hz, 1 H), 3.71 - 3.66 (m, 3 H), 3.15 - 3.14 (m, 2 H), 3.010 - 3.06 (m, 3 H), 1.99 (t, J = 10.3 Hz, 1 H), 1.78 - 1.74 (m, 2 H), 1.29 - 1.21 (m, 2 H), 0.95 - 0.87 (m, 6 H); Calcd m/z: [M+H]⁺ Calcd for C₄₄H₄₆N₅O₅ Exact Mass: 724.3493 found, 724.3475. Example 32: N-((S)-1-(((S)-1-(methoxy (methyl) amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino)-4-methyl-1-oxopentan-2-yl) benzo[b]thiophene-2-carboxamide(6e): Using benzo[b] thiophene-2-carboxylic, 6e was synthesized following the analogous procedure of 2a. 6e was obtained as a white solid. Yield: 0.454g, (64%); mp: 70-75℃; Rf = 0.35 (silica gel TLC, 2% MeOH in DCM); [α]²⁴ _D = -2.50 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ 7.81 - 7.78 (m, 3 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.44 (d, J = 7.1 Hz, 1 H), 7.40 - 7.38 (m, 2 H), 7.30 - 7.27 (m, 9 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.09 - 7.04 (m, 6 H), 6.54 (s, 1 H), 5.11 - 5.9 (d, J = 5.5 Hz, 1 H), 4.79 - 4.76 (m, 1 H), 3.76 (s, 3 H), 3.12 (s, 3 H), 2.99 - 2.95 (m, 2 H), 1.81 - 1.76 (m, 2 H), 1.66 - 1.62 (m, 1 H), 0.98 - 0.93 (dd, J = 6.1, 15.4 Hz, 6 H); Calcd m/z: [M+H] ⁺ Calcd for C42H43N5O4S Exact Mass: 714.3109, Found, 714.3112. Example 33: (S)-N-((S)-1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2- yl)-2-((S)-2-(6-methoxynaphthalen-2-yl) propanamido)-4-methylpentan amide (6f): Using (S)-2- (6-methoxynaphthalen-2-yl) propanoic acid, 6f was synthesized following the analogous procedure of 6a.6f was obtained as a white solid. Yield: 0.55g ,(71%); mp: 96-100℃; Rf = 0.45 (silica gel TLC, 3% MeOH in DCM); [α]²⁴D = -2.4 ^(c = 0.1, MeOH; ¹H NMR (500 MHz, CDCl3) ^ ^7.69 (t, J = 7.7 Hz, 3 H), 7.68 (s, 1 H), 7.32 - 7.30 (m, 10 H), 7.10 – 7.09 (m, 9 H), 6.46 (s, 1 H), 6.13-6.11 (bs., 1 H), 5.00 (m, 1 H), 4.50 – 4.49 (m, 3 H), 3.73 - 3.70 (m, 3 H), 2.89 - 2.82 (m, 2 H), 1.61-1.55 (d, J = 7.3 Hz, 4 H), 1.37 - 1.33 (s, 4 H), 1.28 (m, 1 H), 0.88 -0.87(d, J = 12.9 Hz, 2 H), 0.84 - 0.83 (m, 6 H); Calcd m/z: [M+H]⁺ for C₄₇H₅₂N₅O₅ Exact Mass: 766.3963 found, 766.3445. Example 34: (S)-N-((S)-1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2- yl)-4-methyl-2-(2-propylpentanamido) pentanamide (6g): Using 2-propylpentanoic acid, 6g was synthesized following the analogous procedure of 6a. 6g was obtained as a white solid (Note: EDC.HCl was used in place of HBTU). Yield: (0.3g), 73%; [α]²⁴D = -97.18 ^(c = 0.1, MeOH); mp: 70- 75℃; Rf = 0.4 (silica gel TLC, 2% MeOH in DCM); ¹H NMR (400MHz, CDCl3) ^ 7.35 - 7.34 (m, 9 H), 7.33 - 7.13 (m, 1 H), 7.12 - 7.10 (m, 7 H), 7.29, (bs, 1H), 6.53, (s, 1H), 6.29 (d, J = 8.4 Hz, 1 H), 5.09 -5.07, (d, J = 7.0 Hz, 1 H), 3.74 (s, 3 H), 3.10 (s, 3 H), 2.96 - 2.94 (d, J = 5.6 Hz, 2 H), 2.07 (bs, 1H), 1.82 (m, 1 H), 1.65 (m, 3 H), 1.65 - 1.59 (m, 3 H), 1.26 - 1.21 (m, 3 H), 0.93 - 0.87 (m, 7 H), 0.88 - 0.80 (m, 6 H); Calcd m/z: [M+H]⁺ Calcd for C41H54N5O4; 680.4170; Found 680.4139. Example 35: (S)-2-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetamido)-N-((S)-1- (methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl)propan-2-yl)-4-methylpentanamide (6h): Using 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetic acid, 6h was synthesized following the analogous procedure of 6a.6h was obtained as a white solid. Yield: 0.45g, (54%); mp: 90 - 95℃; Rf = 0.5 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D=-2.96 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ 7.61 (s, 1 H), 7.33 - 7.30 (m, 13 H), 7.12 - 7.10 (m, 8 H), 7.08 - 7.01 (m, 1 H), 6.96 (t, J = 8.1 Hz, 1 H), 6.90 - 6.81 (m, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 6.50 - 6.48 (m, 1 H), 5.04 -5.02 (d, J = 7.1 Hz, 1 H), 4.56 - 4.54 (d, J = 5.3 Hz, 1 H), 3.73 (s, 3 H), 3.67 (s, 2 H), 3.10 (s, 3 H), 2.89 – 2.88 (d, J = 4.9 Hz, 1 H), 1.92 (s, 3 H), 1.66 - 1.59 (m, 2 H), 1.44 (m, 1 H), 1.27 (m, 2 H), 0.90 - 0.83 (m, 7 H); Calcd m/z: [M+H]⁺ for C₄₇H₄₉N₆O₄Cl₂; 831.3187; Found 831.3327. Example 36: 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-N-((S)- 1-(((S)-1-(methoxy (methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino)-4- methyl-1-oxopentan-2-yl)-[1,1'-biphenyl]-2-carboxamide (6i): Using 24'-((1,7'-dimethyl-2'-propyl- 1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, 6i was synthesized following the analogous procedure of 6a.6i was obtained as a white solid. Yield: 0.23g (56%); mp: 85-90℃; R_f = 0.50 (silica gel TLC, 3% MeOH in DCM); [α]²⁷ _D=12.96 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ 7.79 (dd, J = 2.7, 6.2 Hz, 1 H), 7.56 (d, J = 7.3 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.37 - 7.31 (m, 6 H), 7.28 (d, J = 1.8 Hz, 7 H), 7.24 - 7.18 (m, 2 H), 7.15 - 7.07 (m, 4 H), 7.07 - 7.01 (m, 5 H), 6.60 - 6.51 (m, 1 H), 6.46 (s, 1 H), 5.45 - 5.36 (m, 2 H), 5.03 (d, J = 7.3 Hz, 1 H), 4.59 - 4.45 (m, 1 H), 3.74 (s, 3 H), 3.72 - 3.66 (m, 3 H), 3.07 - 3.01 (m, 3 H), 2.94 - 2.89 (m, 2 H), 2.76 (s, 3 H), 1.94 - 1.79 (m, 3 H), 1.54 (ddd, J = 5.2, 8.6, 13.5 Hz, 1 H), 1.48 - 1.34 (m, 1 H), 1.34 - 1.20 (m, 3 H), 1.12 - 0.97 (m, 3 H), 0.97 - 0.83 (m, 3 H), 0.80 - 0.76 (m, 6 H); Calcd m/z: [M+H]⁺ for C66H67N9O4;1050.5389; Found 1050.5416. Example 37: (S)-2-((5-(dimethylamino)naphthalene)-1-sulfonamido)-N-((S)-1- (methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl)propan-2-yl)-4-methylpentanamide (6j): The dansyl chloride (269 mg, 1 mmol, 1 equiv.) was dissolved in DMF and cooled at ice temperature then DIPEA (0.521 mL, 3 mmol, 3 equiv.) was added and stirred for 5 min then free amine of compound 3, (0.633g, 1.14 mmol, 1.2 equiv.) was added and stirred for 5 h at room temperature. The reaction mixture was diluted with cold water and product was extracted with ethyl acetate. (2x20mL) The combined organic layer was subsequently washed with cold water, dilute citric acid, saturated solution of NaHCO₃ and brine solution respectively, dried over Na₂SO₄, the organic layer was concentrated under vacuum and resultant residue purified by column chromatography, on neutral Al2O3 using pet-ether to DCM to 5% methanol as mobile phase to get compound 6j as white solid. Yield: 0.4g (51%); [α]²⁴ _D=-42.00 ^(c = 0.1, MeOH); mp: 110-115℃; ¹H NMR (400MHz, CDCl₃) ^ ^8.48 (d, J = 8.5 Hz, 1 H), 8.46 (d, J = 8.8 Hz, 1 H), 8.31 (dd, J = 1.1, 7.3 Hz, 1 H), 7.53 (m, 2 H), 7.36 - 7.33 (m, 11 H), 7.16 - 7.12 (m, 8 H), 6.48 (s, 1 H), 5.71 - 5.69 (d, J = 7.5 Hz, 1 H), 4.72 - 4.68 (m, 1 H), 3.63 (s, 4 H), 3.06 (s, 3 H), 2.84 (s, 8 H), 1.40 (bs., 2 H), 0.66 (d, J = 6.3 Hz, 3 H), 0.49 (d, J = 6.0 Hz, 3 H); Calcd m/z: [M+H]⁺ for C45H51N6O5; 787.3636; Found 787.3617. Example 38: (S)-N-((S)-1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-5-yl) propan-2- yl)-4-methyl-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl) pentanamido) pentanamide (6k): Using 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl) pentanoic acid (biotin), 6k was synthesized following the analogous procedure of 6a.6k was obtained as a white solid. Yield: 0.46g (59%); mp: 80-85℃; [α]²⁴D=-3.12 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ 7.51 (d, J = 8.3 Hz, 1 H), 7.36 - 7.33 (m, 10 H), 7.12 - 7.09 (m, 6 H), 6.76 (bs., 1 H), 6.55 (s, 1 H), 5.96 (bs., 1 H), 5.13 (d, J = 6.8 Hz, 1 H), 4.56 (m, 1 H), 4.50 - 4.48 (m, 1 H), 4.31 - 4.28 (m, 1 H), 3.72 (s, 3 H), 3.21 - 3.14 (m, 1 H), 3.11 (s, 3 H), 2.94 - 2.92 (m, 3 H), 2.67 (d, J = 12.8 Hz, 1 H), 2.29 - 2.11 (m, 2 H), 1.74 (td, J = 7.2, 14.2 Hz, 2 H), 1.66 - 1.60 (m, 4 H), 1.55 - 1.45 (m, 1 H), 1.41 - 1.32 (m, 2 H), 0.88 (d, J = 5.9 Hz, 6 H); Calcd m/z: [M+H]⁺ for C43H53N7O5; 780.3902; Found 780.3893. Example 39: 2-methyl-N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan- 2-yl) amino) pentan-2-yl) benzamide (7a): The synthetic method of 3a was adopted to synthesize 7a. White solid. Yield: 0.2g, (73%); mp: 70 - 75℃; Rf = 0.4 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D=- 2.96 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ ^ ^9.57 (d, J = 3.5 Hz, 1 H), 8.16 (m, 1 H), 7.43 (t, J = 8.4 Hz, 1 H), 7.34 - 7.32 (m, 9 H), 7.20 - 7.13 (m, 1 H), 7.07 - 7.05 (m, 7 H), 6.61 (s, 1 H), 6.28 (m, 1 H), 4.79 - 4.77 (td, J = 4.3, 8.5 Hz, 1 H), 4.59 (dd, J = 6.6, 11.9 Hz, 1 H), 3.13 - 3.12 (m, 1 H), 2.99 - 2.95 (m, 1 H), 2.42 - 2.40 (d, J = 8.4 Hz, 3 H), 1.85 - 1.76 (m, 2 H), 1.70 - 1.54 (m, 2 H), 1.01 - 0.94 (m, 6 H); Calcd m/z: [M+H]⁺ for C39H40N4O2; 613.3173; Found 613.3158. Example 40: N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino) pentan-2-yl)-1H-indole-2-carboxamide(7b): The synthetic method of 3a was adopted to synthesize 7b. Light yellow solid; Yield: 0.2 g, (73%); mp: 70-75℃; Rf = 0.43 (silica gel TLC, 2% MeOH in DCM); [α]²⁴D=5.50 ^(c = 0.1, MeOH); [α]²⁷D = -12.80 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ 9.55 (d, J = 7.5 Hz, 1 H), 9.46 (m, 1 H), 8.33 (m, 1 H), 7.57 (dd, J = 5.5, 7.8 Hz, 1 H), 7.31 - 7.26 (m, 12 H), 7.20 - 7.04 (m, 3 H), 7.07 - 6.85 (m, 6 H), 6.61 - 6.58 (d, J = 11.1 Hz, 1 H), 4.88 - 4.84 (m, 1 H), 4.62 - 4.54 (m, 1 H), 3.08 - 2.98 (m, 2 H), 1.86 - 1.69 (m, 1 H), 1.37 - 1.26 (m, 2 H), 0.97 - 0.88 (m, 6 H); Calcd m/z: [M+H]⁺ for C₄₀H₄₀N₅O₃; 638.3126; Found 638.3099. Example 41: 1-hydroxy-N-((S)-4 -methyl-1-oxo-1-(((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino) pentan-2-yl)-2-naphthamide (7c): The synthetic method of 3a was adopted to synthesize 7c. White solid. Yield: 0.2g, (72%); mp: 65-70℃; [α]²⁵ _D= 36.41 ^(c = 0.1, MeOH); ¹H NMR (400MHz,CDCl₃) ^ 13.58 (bs, 1 H), 9.55 – 9.53 (d, J = 6.8 Hz, 1 H), 8.36 (d, J = 8.3 Hz, 1 H), 8.20 (m, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.63 - 7.53 (m, 1 H), 7.53 - 7.47 (m, 1 H), 7.44 (t, J = 9.1 Hz, 1 H), 7.30 - 7.27 (m, 11 H), 7.01 - 7.12 (m, 2 H), 7.01 (m, 1 H), 7.00 (m, 6 H), 6.58 (m, 1 H), 4.86 - 4.84 (m, 1 H), 4.63 - 4.62 (m, 1 H), 3.10 (ddd, J = 2.9, 5.3, 14.9 Hz, 1 H), 3.09 - 2.98 (m, 1 H), 1.74 - 1.73 (m, 2 H), 1.22 (m, 1H), 1.01 - 0.95 (m, 6 H); Calcd m/z: [M+H]⁺ for C₄₂H₄₁N₄O₄; 665.3122; Found 638.3094. Example 42: 3-hydroxy-N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan- 2-yl) amino) pentan-2-yl)-2-naphthamide (7d): The synthetic method of 3a was adopted to synthesize 7d. White solid; Yield: 0.195g (70%); mp: 68-73℃; [α]²⁴D 11.31 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ 9.55 - 9.51(m, 1 H), 8.20 (s, 1 H), 8.11 (d, J = 6.9 Hz, 1 H), 7.63 (d, J = 8.3 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.30 - 7.29 (m, 11 H), 7.26 - 7.18 (m, 2 H), 7.18 - 7.11 (m, 2 H), 7.06 – 7.02 (m, 6 H), 6.58 (m, 1 H), 4.87 (d, J = 5.3 Hz, 1 H), 4.63 - 4.62 (d, J = 6.9 Hz, 1 H), 3.10 (d, J = 5.0 Hz, 1 H), 3.09 - 2.99 (m, 1 H), 1.89 (s, 1 H), 1.80 - 1.26 (m, 3 H), 0.98 (td, J = 3.1, 6.1 Hz, 6 H); Calcd m/z: [M+H]⁺ for C₄₂H₄₁N₄O₄; 665.3122; Found 665.3098. Example 43: N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino) pentan-2-yl) benzo[b]thiophene-2-carboxamide(7e): The synthetic method of 3a was adopted to synthesize 7e. White solid; Yield: 0.22g (79%); mp: 82-87℃; [α]²⁷D=-2.99 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl3) ^ ^ ^9.55 – 9.53 (d, J = 7.5 Hz, 1 H), 8.29 - 8.28 (m, 1 H), 7.81 - 7.79 (dd, J = 2.7, 7.4 Hz, 1 H), 7.46 - 7.35 (m, 2 H), 7.32 - 7.28 (m, 10 H), 7.26 (d, J = 6.9 Hz, 1 H), 7.04 (m, 7 H), 7.00 (d, J = 8.1 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.60 - 6.59 (d, J = 3.5 Hz, 1 H), 4.81 - 4.80 (m, 1 H), 4.62 - 4.60 (m, 1 H), 3.13 - 3.08 (m, 1 H), 3.00 - 2.99 (td, J = 5.6, 15.0 Hz, 1 H), 1.83 - 1.73 (m, 4 H), 1.29- 1.20 (m, 3 H), 1.00 - 0.94 (m, 6 H); Calcd m/z: [M+H]⁺ for C₄₂H₄₁N₄O₄; 655.2737; Found 655.2737. Example 44: (S)-2-((S)-2-(6-methoxynaphthalen-2-yl) propanamido)-4-methyl-N-((S)-1-oxo-3-(1- trityl-1H-imidazol-4-yl) propan-2-yl) pentanamide(7f): The synthetic method of 3a was adopted to synthesize 7f. White solid; Yield: 0.2g (72%); mp: 80-85℃; [α]²⁷D=14.04 ^(c = 0.1, MeOH; ¹H NMR (400MHz, CDCl3) ^ ^9.53 - 9.46 (d, J = 2.1 Hz, 1 H), 7.69 (m, 4 H), 7.41 - 7.31 (m, 11 H), 7.10 - 7.08 (m, 8 H), 6.58 - 6.56 (m, 1 H), 5.94 - 5.92 (d, J = 6.3 Hz, 1 H), 4.54 - 4.48 (m, 2 H), 3.92 - 3.90 (m, 3 H), 3.74 - 3.71 (m, 1 H), 3.49 - 3.47 (dd, J = 5.4, 15.1 Hz, 1 H), 2.89 - 2.86 (m, 2 H), 1.60 - 1.46 (m, 4 H), 1.46 - 1.35 (m, 1 H), 1.26 (s, 1 H), 0.89 - 0.83 (m, 6 H); Calcd m/z: [M+H]⁺ for C₄₅H₄₇N₄O₄; 707.3592; Found 707.3563. Example 45: (S)-4-methyl-N-((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-2-(2- propylpentan amidopentanamide (7g): The synthetic method of 3a was adopted to synthesize 7g. White solid; Yield: 0.75g (82%); mp: 70-75℃; [α]²⁷D=0.96 ^(c = 0.1, MeOH); mp: 60-65℃; Rf = 0.5 (silica gel TLC, 70% ethyl acetate in pet. ether); ¹H NMR (400MHz, CDCl3) ^ 9.54 (d, J = 2.9 Hz, 1 H), 7.92 - 7.90 (m, 1 H), 7.36 - 7.33 (m, 10 H), 7.11 - 7.08 (m, 6 H), 6.63 (d, J = 3.1 Hz, 1 H), 6.07- 6.05 (d, J = 8.3 Hz, 1 H), 4.62 - 4.54 (m, 2 H), 3.14 - 3.09 (m, 1 H), 2.96 (m, 1 H), 2.10 (m, 1H), 1.65 - 1.58 (m, 5 H), 1.26 - 1.25 (m, 7 H), 0.94 - 0.82 (m, 12 H); Calcd m/z: [M+H]⁺ for C₃₉H₄₉N₃O₄; 621.3799; Found 621.3785. Example 46: (S)-2-(2-(2-((2,6-dichlorophenyl) amino) phenyl) acetamido)-4-methyl-N-((S)-1-oxo- 3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) pentanamide (7h): The synthetic method of 4a was adopted to synthesize 7h. White solid; Yield: 0.15g (53%); mp: 86-90℃; R_f = 0.5 (silica gel TLC, 70% ethyl acetate in pet. ether); [α]²⁷D = 14.46 ^(c = 0.1, MeOH); ¹H NMR (500MHz, CDCl3) ^ ^ ^9.47 (s, 1 H), 7.89 (d, J = 6.9 Hz, 1 H), 7.59 - 7.44 (m, 1 H), 7.36 - 7.28 (m, 12 H), 7.15 (d, J = 7.4 Hz, 1 H), 7.13 - 7.03 (m, 7 H), 6.99 (t, J = 8.1 Hz, 1 H), 6.91 - 6.82 (m, 1 H), 6.62 - 6.57 (m, 1 H), 6.46 (d, J = 8.0 Hz, 2 H), 4.61 - 4.56 (m, 1 H), 4.53 - 4.52 (d, J = 6.4 Hz, 1 H), 3.72 - 3.66 (m, 2 H), 3.02 (dd, J = 5.3, 15.0 Hz, 1 H), 2.83 (dd, J = 5.0, 15.0 Hz, 1 H), 1.77 - 1.72 (m, 5 H), 1.62 - 1.40 (m, 3 H), 1.26 (bs., 2 H), 0.89 - 0.83 (m, 6 H), Calcd m/z: [M+H]⁺ for C45H43N5O3Cl2; 771.2743; Found 772.2811. Example 47: 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-N-((S)- 4-methyl-1-oxo-1-(((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) amino) pentan-2-yl)-[1,1'- biphenyl]-2-carboxamide (7i): The synthetic method of 4a was adopted to synthesize 7i. White solid; Yield: 0.07g, (73%); mp: 75-80℃; R_f = 0.5 (silica gel TLC, 2% MeOH in DCM); [α]²⁷ _D = -12.04 ^ (c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^ 9.44 - 943 (d, J = 4.5 Hz, 1 H), 7.91 (d, J = 6.8 Hz, 1 H), 7.80 - 7.67 (m, 1 H), 7.60 (dd, J = 7.3, 15.2 Hz, 1 H), 7.49 - 7.40 (m, 3 H), 7.39 - 7.27 (m, 18 H), 7.26 - 7.20 (m, 4 H), 7.16 - 7.01 (m, 12 H), 6.56 (d, J = 3.5 Hz, 2 H), 6.12 (s, 1 H), 6.05 (d, J = 8.1 Hz, 1 H), 5.43 (s, 3 H), 4.60 - 4.34 (m, 3 H), 3.87 - 3.66 (m, 4 H), 3.47 (s, 1 H), 3.13 - 2.85 (m, 5 H), 2.76 (s, 4 H), 2.09 - 1.96 (m, 4 H), 1.89 (qd, J = 7.4, 15.1 Hz, 3 H), 1.33 - 1.20 (m, 4 H), 1.12 - 0.99 (m, 4 H), 0.92 - 0.82 (m, 4 H), 0.76 (q, J = 6.2 Hz, 6 H); Calcd m/z: [M+H]⁺ for C₆₄H₆₃N₈O₃; 991.5018; Found 991.4998 Example 48: (S)-2-((5-(dimethylamino) naphthalene)-1-sulfonamido)-4-methyl-N-((S)-1-oxo-3-(1- trityl-1H-imidazol-4-yl) propan-2-yl) pentanamide (7j): The synthetic method of 4a was adopted to synthesize 7j. White solid; Yield: 0.08g (72%); mp: 90-95℃; [α]²⁷D=-37.62 ^(c = 0.1, MeOH); ¹H NMR (400MHz,CDCl3) ^ ^ ^9.08 (s, 1 H), 8.51 (d, J = 8.5 Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1 H), 8.20 (d, J = 7.3 Hz, 1 H), 7.77 (d, J = 6.0 Hz, 1 H), 7.77 (t, J = 8.1 Hz, 2 H), 7.45 - 7.39 (m, 2 H), 7.38 - 7.28 (m, 9 H), 7.11 - 7.09 (m, 7 H), 6.57 (s, 1 H), 4.25 (d, J = 5.5 Hz, 1 H), 3.72 (bs., 1 H), 2.89 - 2.83 (m, 6 H), 2.82 - 2.66 (m, 2 H), 1.41 - 1.31 (m, 3 H), 0.67 (d, J = 5.6 Hz, 3 H), 0.43 (d, J = 5.0 Hz, 3 H); Calcd m/z: [M+H]⁺ for C43H46N5O4S; 728.3265; Found 728.3251. Example 49: (S)-4-methyl-N-((S)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-2-(5 - ((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl) pentanamido) pentanamide (7k): The synthetic method of 4a was adopted to synthesize 7k. White solid; Yield: 0.3g, (63%); mp: 70- 75℃; [α]²⁴ _D= 17.07 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^9.53 - 9.49 (m, 1 H), 7.99-7.98 (d, J = 6.6 Hz, 1 H), 7.59 (m, 13 H), 7.34-7.33 (s, 3 H), 7.11 - 7.09 (m, 8 H), 6.80 (bs., 1 H), 6.62 - 6.57 (m, 1 H), 6.17 (bs., 1 H), 4.56 - 4.53 (m, 2 H), 4.48 - 4.46 (m, 2 H), 4.30 (d, J = 4.1 Hz, 2 H), 3.11 (m, 2 H), 2.87 (d, J = 5.9 Hz, 1 H), 2.27 - 2.20 (m, 3 H), 1.66, (d, J = 12.6 Hz, 2 H), 1.42 (m, 3 H), 1.29 - 1.22 (m, 8 H), 1.22- 1.21 (m, 3 H), 1.35 - 1.24 (m, 6 H), 1.24 - 1.18 (m, 2 H), 0.91 - 0.87 (m, 9 H), 0.80 (d, J = 5.4 Hz, 2 H); Calcd m/z: [M+H]⁺ for C₆₄H₆₂N₈O₃; 721.0713; Found 721.3541. Example 50: 5-((S)-2-((S)-4-methyl-2-(2-methylbenzamido)pentanamido)-3-oxopropyl)-1H- imidazol-1-ium (8a): The synthetic method of 4a was adopted to synthesize 8a. White solid; Yield :0.06g (82%); Rf = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁵ _D = 12.89 ^(c = 0.1, MeOH); mp: 70- 75℃; ¹H NMR (400MHz, CD₃OD) ^ 8.78 - 8.73 (bs., 1 H), 7.33 - 7.23 (m, 6 H), 4.67 - 4.66 (dd, J = 1.9, 3.4 Hz, 1 H), 4.56 - 4.22 (m, 1 H), 4.47 (m, 1 H), 4.22 (m, 1 H), 3.29 (m, 1 H), 3.14 - 2.94 (m, 1 H), 2.37 - 2.35 (m, 3 H), 1.82 - 1.70 (m, 1 H), 1.70 - 1.60 (m, 1 H), 1.60 - 1.36 (m, 2 H), 1.08 - 0.86 (m, 6 H); Calcd m/z: [M+H]⁺ for ;C20H27N4O3; 371.2078; Found 371.2071. Example 51: 5-((S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-oxopropyl)-1H- imidazol-1-ium (8b): The synthetic method of 4a was adopted to synthesize 8b. Light yellow solid; Yield: 0.1g (84%); mp: 72-76℃; R_f = 0.2 (silica gel TLC, 4% MeOH in DCM); [α]²⁴ _D=-27.0 ^(c = 0.1, MeOH); ¹H NMR (500MHz, CD3OD) ^ 8.92 (s, 1 H), 7. (d, J = 7.9 Hz, 1 H), 7.48 - 7.46 (m, 2 H), 7.45 - 7.28 (m, 2 H), 7.24 - 7.11 (m, 3 H), 7.09 (m, 2 H), 6.99 (s, 1 H), 6.52 (s, 1 H), 5.12 (bs., 1 H), 3.78 – 3.69(d, J = 4.4 Hz, 1 H), 1.66 - 1.56 (m, 1 H), 1.55 (dd, J = 6.6, 13.9 Hz, 1 H), 1.40 (dd, J = 6.9, 13.2 Hz, 1 H), 1.11 (bs., 1 H), 1.00 - 0.93 (m, 6 H); Calcd m/z: [M+H]⁺ for C₂₁H₂₆N₅O₃; 396.2030; Found 396.2016. Example 52: 5-((S)-2-((S)-2-(1-hydroxy-2-naphthamido)-4-methylpentanamido)-3-oxopropyl)- 1H-imidazol-1-ium (8c): The synthetic method of 4a was adopted to synthesize 8c. White solid; Yield: 0.6g (74%) [α]²⁷D=-21.00 ^(c = 0.1, MeOH); mp: 80-85℃; Rf = 0.2 (silica gel TLC, 4% MeOH in DCM); ¹H NMR (400MHz, CD₃OD) ^8.83-8.13 (m, 1H), 7.82 - 7.77 (m, 1 H), 7.77 - 7.72 (m, 3 H), 7.57 - 7.51 (m, 3H), 7.30 - 6.70 (m, 1H), 5.93 - 5.91(m, 1H), 5.79 (m, 1H), 5.20 (m, 1H), 4.67 (s, 2H), 3.40 (m, 2H), 3.90 (m, 2H), 1.84-1.69 (m, 2H), 0.98 - 0.80 (m, 6H); Calcd m/z: [M+H]⁺ for C₂₃H₂₇N₄O₄; 423.2027; Found 423.2013. Example 53: 5-((S)-2-((S)-2-(3-hydroxy-2-naphthamido)-4-methylpentanamido)-3-oxopropyl)- 1H-imidazol-1-ium (8d): The synthetic method of 4a was adopted to synthesize 8d. Brown solid; Yield: 0.13g, (80%); mp: 83-87℃; Rf = 0.3 (silica gel TLC, 4% MeOH in DCM); [α]²⁵ _D=38.40 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD₃OD) ^ ^8.92 - 8.88 (s, 1 H), 8.54 - 8.51 (m, 2 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.77 (s, 1 H), 7.59 (bs., 2 H), 7.48 - 7.43 (m, 3 H), 7.32 (s, 2 H), 7.25 (s, 1 H), 7.05 (s, 1 H), 5.73 - 5.71 (d, J = 9.0 Hz, 1 H), 5.36 - 5.33 (d, J = 11.1 Hz, 1 H), 4.58 (m, 1 H), 4.21-419 (m, 1 H), 3.31-3.15 (s, 2 H), 1.94 - 1.77 (m, 1 H), 1.13 (d, J = 6.1 Hz, 2 H), 1.06 – 1.00 (m, 6 H); Calcd m/z: [M+H]⁺ for C23H27N4O4; 423.2027; Found 423.2013. Example 54: 5-((S)-2-((S)-2-(benzo[b]thiophene-2-carboxamido)-4-methylpentanamido)-3- oxopropyl) -1H-imidazol-1-ium (8e): The synthetic method of 4a was adopted to synthesize 8e. White solid. Yield: 0.12g, (78%); mp: 70-75C; Rf = 0.25 (silica gel TLC, 3% MeOH in DCM); [α]²⁵ _D=32.52 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD₃OD) ^ ^ ^8.77 - 8.67 (t, J = 1.1 Hz, 1 H), 8.05 (m, 1 H), 7.89 - 7.88 (m, 2 H), 7.45 - 7.41 (m, 2 H), 7.30 (m, 1 H), 4.64-4.55 (m, 2 H), 4.48 (ddd, J = 3.9, 7.1, 10.5 Hz, 1 H), 4.19 (m, 2H), 3.31 - 3.29 (m, 1 H), 3.11 - 2.91 (m, 1 H), 1.75 - 1.64 (m, 1 H), 1.62 (m, 2 H), 0.97 - 0.91 (m, 6 H); Calcd m/z: [M+H]⁺ for C21H25N4O3; 413.1642; Found 413.1633. Example 55: 5-((S)-2-((S)-2-((S)-2- (6-methoxynaphthalen-2-yl) propanamido)-4-methylpentan amido)-3-oxopropyl)-1H-imidazol-1-ium (8f): The synthetic method of 4a was adopted to synthesize 8f. White solid.Yield: 0.1g, (81%); mp: 93-98C; Rf = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁷ _D=10.9 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD₃OD) ^ ^ ^8.55 (m, 1 H), 8.06 (m, 1 H), 7.67 - 7.59 (m, 3 H), 7.55 - 7.33 (m, 2 H), 7.09 (m, 1 H), 7.03 - 6.80 (m, 3 H), 4.79 - 4.32 (m, 2 H), 4.15 (m, 1 H), 3.82 - 3.76 (m, 4 H), 3.19 (d, J = 7.0 Hz, 1 H), 2.80-2.60 (m,1H), 2.50-2.30 (m, 1H), 3.03 - 2.74 (m, 1 H), 1.46 - 1.39 (m, 6 H), 0.99 - 0.77 (m, 6 H); Calcd m/z: [M+H] ⁺ for C26H33N4O4; 424.2493; Found 424.2496. Example 56: 5-((S)-2-((S)-4-methyl-2-(2-propylpentanamido)pentanamido)-3-oxopropyl)-1H- imidazol-1-ium (8g): The synthetic method of 4a was adopted to synthesize 8g. White solid; Yield: 0.5g, (63%); mp: 70 – 75C; R_f = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁷ _D=-2.88 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD₃OD) ^ ^8.78 - 8.73 (m, 1 H), 7.43-7.30 (m, 1 H), 7.29-7.24 (bs., 1 H), 4.60 - 4.48 (m, 1 H), 4.28 - 4.25 (m, 1 H), 4.20 (m, 1 H), 3.21 - 2.98 (m, 1 H), 2.98 - 2.77 (m, 1 H), 2.30 (tt, J = 4.7, 9.5 Hz, 1 H), 1.78 - 1.61 (m, 1 H), 1.61 - 1.43 (m, 4 H), 1.30 - 1.26 (m, 4 H), 0.95 - 0.84 (m, 14 H); Calcd m/z: [M+H]⁺ for C20H35N4O3; 379.2704; Found 379.2695. Example 57: 5-((S)-2-((S)-2-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetamido)-4- methylpentan amido)-3-oxopropyl)-1H-imidazol-1-ium (8h): The synthetic method of 4a was adopted to synthesize 8h. White solid; Yield: 0.16g, (66%); mp: 88-93C; Rf = 0.2 (silica gel TLC, 4% MeOH in DCM); [α]²⁷D= -48.00 ^(c = 0.1, MeOH); ¹H NMR (500MHz, CD3OD) ^ ^ ^8.85 - 8.71 (m, 1H ), 8.24 (m, 1H), 7.41 (d, J = 7.9 Hz, 3 H), 7.39 - 7.19 (m, 4 H), 7.09-7.06 (t, J = 7.4 Hz, 2 H), 6.91 (m, 1 H), 6.42 (d, J = 7.6 Hz, 1 H), 4.51 (d, J = 3.5 Hz, 1 H), 4.37 - 4.30 (m, 1 H), 4.12 (bs., 1 H), 3.74 - 3.73 (m, 2 H), 3.24 - 3.00 (m, 1 H), 2.83 - 2.82 (m, 1 H), 1.65 (bs., 1 H), 1.65 - 1.57 (m, 1 H), 1.46 (d, J = 7.9 Hz, 1 H), 1.17 - 0.95 (m, 6 H); Calcd m/z: [M+H]⁺ for C26H30N5O3Cl2; 530.1711. Example 58: 5-((S)-2-((S)-2-(4'-((1, 7'-dimethyl-2'-propyl-1H,3'H-[2, 5'-bibenzo[d]imidazol]-3'-yl) methyl)- [1, 1'-biphenyl]-2-carboxamido)-4-methyl pentanamido)-3-oxopropyl)-1H-imidazol-1- ium (8i): The synthetic method of 4a was adopted to synthesize 8i. White solid; Yield: 0.2g (83%); mp: 75-80C; [α]²⁷ _D=-2.9 ^(c = 0.1, MeOH); R_f = 0.5 (silica gel TLC, 4% MeOH in DCM). ¹H NMR (500MHz, CD₃OD) ^ 8.52 (m 1 H), 8.05 (m, 1H), 7.80 (, J = 7.4 Hz, 1 H), 7.79 - 7.76 (m, 2 H), 7.63 - 7.62 (m, 2 H), 7.42 - 7.40 (m, 4 H), 7.32 - 7.30 (m, 3 H), 7.28 - 7.20 (m, 1 H), 7.15 (bs., 1 H), 5.84 - 5.76 (m, 2 H), 4.44 (bs,1H), 3.96 - 3.95 (m, 2 H), 3.64 (s, 1 H), 2.75 (s, 3 H), 1.88 - 1.84 (m, 2 H), 1.33 (bs., 2 H), 1.22 (bs., 1 H), 1.05 – 1.03 (m, 6 H), 0.77 - 0.67 (m, 4 H); Calcd m/z: [M+H]⁺ for C45H49N8O3; 749.3922; Found 749.3893. Example 59: 5-((S)-2-((S)-2-((5-(dimethylamino) naphthalene)-1-sulfonamido)-4- methylpentanamido)-3-oxopropyl)-1H-imidazol-1-ium(8j): The synthetic method of 4a was adopted to synthesize 8j. Light green solid; Yield: 0.12g, (81%); mp: 90-95C; [α]²⁵ _D =3.6 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD3OD) ^ ^ ^8.71 (d, J = 4.0 Hz, 1 H), 8.53 (d, J = 8.8 Hz, 1 H), 8.51 - 8.32 (m, 1 H), 8.17 - 8.18 (dd, J = 1.3, 7.4 Hz, 1 H), 7.57 - 7.52 (m, 2 H), 7.25 - 7.23 (m, 2 H), 4.49 - 4.30 (t, J = 4.0 Hz, 1 H), 3.40 - 3.35 (m, 3 H), 3.20 (m, 1H), 2.83 - 2.65 (m, 8 H), 1.24 (bs., 2 H), 1.20 - 1.07 (m, 1 H), 0.85 - 0.83 (m, 3 H), 0.49 - 0.48 (m, 3 H); Calcd m/z: [M+H] ⁺ for C₂₄H₃₂N₅O₄S; 486.2170; Found 486.2154. Example 60: 5-((S)-2-((S)-4-methyl-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl) pentanamido) pentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8k): The synthetic method of 4a was adopted to synthesize 8k. White solid: Yield: 0.09g (68%); mp: 70 – 75°C; Rf = 0.3 (silica gel TLC, 3% MeOH in DCM); [α]²⁴D = 40.00 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CD3OD) ^ 8.77 - 8.72 (d, J = 19.5 Hz, 1 H), 7.41 - 7.23 (m, 2 H), 5.06 (d, J = 5.4 Hz, 1 H), 4.51 - 4.50 (m, 2 H), 4.29 - 4.24 (m, 2 H), 4.16 - 3.78 (m, 1 H), 3.43 - 3.39 (m, 2 H), 3.19 - 2.91 (m, 2 H), 2.71 (m, 1 H), 2.26 - 2.24 (d, J = 12.6 Hz, 1 H), 1.67 - 1.41 (m, 9 H), 1.07 - 0.80 (m, 6 H); Calcd m/z: [M+H]⁺ for C22H35N6O4S; 479.2435; Found 479.2435. Example 61: (S)-2-((7-chloroquinolin-4-yl) amino)-3-(1H-imidazol-4-yl)-N-methoxy-N- methylpropanamide (11): Using compound 10c, 11 was synthesized following the analogous procedure of compound 1 as white solid: Yield: 0.13g, (57%); mp: 85 – 89C; Rf = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁷ _D = -17.28 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^ ^8.35 - 8.34 (d, J = 5.4 Hz, 1 H), 7.84 – 7.81 (m, 2 H), 7.54 (s, 1 H), 7.28 - 7.26 (dd, J = 2.0, 8.9 Hz, 1 H), 6.87 (bs, 1H), 6.76 (s, 2 H), 6.23 - 6.22 (d, J = 5.4 Hz, 1 H), 4.90 (bs, 1H), 3.38 (s, 3 H), 3.29 – 2.80 (m, 5 H); Calcd m/z: [M+H]⁺ for C17H18N2O5Cl; 360.1222, found 360.1217. Example 62: (S)-2-((7-chloroquinolin-4-yl) amino)-3-(1H-imidazol-4-yl) propanal (12): The synthetic method of compound 2a was adopted to synthesize 12. Yellow solid: Yield: 0.16g, (63%); [α]²⁷D=-9.75 ^(c = 0.1, MeOH); mp: 68-73C; ¹H NMR (400MHz, CD3OD) ^ ^8.35 (dd, J = 1.9, 6.0 Hz, 1 H), 8.26 - 8.24 (m, 1 H), 8.21 - 8.15 (m, 1 H), 7.75 (m, 1 H), 7.54 (s, 1 H), 7.45 – 7.42 (m, 1 H), 6.80 (s, 1 H), 6.58 - 6.56 (m, 1 H), 4.16 – 4.12 (qd, J = 4.1, 8.5 Hz, 1 H), 3.13 (dd, J = 3.8, 14.8 Hz, 1 H), 2.98 (td, J = 9.0, 14.9 Hz, 1 H); Calcd m/z: [M+H]⁺ for C₁₅H₁₄N₄O₁Cl; 301.0851; Found 301.0855. Example 63: (S)-2-((7-chloroquinolin-4-yl)amino)-N-((S)-1-(methoxy(methyl) amino)-1-oxo-3-(1- trityl-1H-imidazol-4-yl)propan-2-yl)-4-methylpentanamide (13): Using compound 10b, 13 was synthesized following the analogous procedure of 2a. White solid. Yield: 0.51g, (70%); [α]²⁷ _D=- 2.28 ^(c = 0.1, MeOH), 80-85C; ¹H NMR (400MHz, CDCl3) ^ ^8.46 - 8.44 (dd, J = 5.4, 11.3 Hz, 1 H), 8.06 (bs, 1H), 7.89 - 7.81 (m, 2 H), 7.33 - 7.30 (m, 10 H), 7.01 - 6.99 (m, 5 H), 6.86 (s, 1 H), 6.46 (d, J = 5.5 Hz, 2 H), 6.41 (s, 1 H), 5.70 - 5.69 (d, J = 6.5 Hz, 1 H), 5.02 – 4.97 (m, 1 H), 4.12 (d, J = 2.8 Hz, 1 H), 3.80 - 3.76 (d, J = 12.4 Hz, 3 H), 3.14 (s, 1 H), 3.06 (s, 2 H), 2.95 – 3.94 (d, J = 5.0 Hz, 1 H), 2.84 - 2.83 (t, J = 5.4 Hz, 1 H), 1.94 (dd, J = 5.7, 13.7 Hz, 1 H), 1.87 - 1.79 (m, 3 H), 1.27 (m, 1H), 1.00 - 0.99 (d, J = 6.3 Hz, 3 H), 0.92 - 0.90 (m, 3 H); Calcd m/z: [M+H]⁺ for C42H44N6O3Cl; 715.3158; Found 715.3133. Example 64: (S)-2-((7-chloroquinolin-4-yl)amino)-4-methyl-N-((S)-1-oxo-3-(1-trityl-1H-imidazol- 4-yl) propan-2-yl)pentanamide (14): The synthetic method of compound 2a was adopted to synthesize 14. White solid; Yield: 0.5g, (76%); [α]²⁷ _D=-0.67 ^(c = 0.1, MeOH); mp: 70 – 75C; ¹H NMR (400MHz, CDCl₃) ^ 9.52 - 9.31 (dd, 1H) 8.78 - 8.75 (m, 1H), 8.50 - 8.45 (dd, J = 5.3, 14.6 Hz, 1 H), 7.85 - 7.83 (m, 2 H), 7.35 - 7.30 (m, 12 H), 7.10 - 7.14 (m, 2H), 6.93 - 6.87 (m, 5 H), 6.45 - 6.44 (m, 1 H), 5.61 (m, 1 H), 4.54 - 4.53 (m, 1 H), 4.15 - 4.14 (m, 1H), 3.04 - 2.92 (m, 2 H), 2.05 – 2.01 (m, 1 H), 1.87 (dd, J = 6.3, 11.0 Hz, 2 H), 1.44 - 1.15 (m, 3 H), 1.03 - 0.94 (m, 3 H); Calcd m/z: [M+H]⁺ for C40H39N5O2Cl; 656.2787; Found 656.2755. Example 65: (S)-2-((S)-2-((7-chloroquinolin-4-yl) amino) propanamido)-N-((S)-1-(methoxy (methyl) amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl) propan-2-yl)-4-methylpentanamide (16): Using compound 10a, 16 was synthesized following the analogous procedure of 6a. White solid: Yield: 0.645g (82%); Rf = 0.4 (silica gel TLC, 2% MeOH in DCM); [α]²⁷D = -28.62 ^(c = 0.1, MeOH); mp: 80 – 85C; ¹H NMR (400 MHz, CDCl₃) ^ ^8.52 - 8.50 (d, J = 5.4 Hz, 1 H), 7.94 (dd, J = 1.9, 8.4 Hz, 1 H), 7.78 - 7.76 (dd, J = 6.3, 8.9 Hz, 1 H), 7.34 - 7.31 (m, 11 H), 7.30 (d, J = 1.1 Hz, 1 H), 7.09 - 7.00 (m, 6 H), 6.53 (d, J = 6.5 Hz, 1 H), 6.33 (t, J = 5.4 Hz, 1 H), 5.04 (bs., 1 H), 4.59 (d, J = 2.3 Hz, 1 H), 4.17 - 4.16 (d, J = 6.4 Hz, 1 H), 3.73 - 371 (d, J = 6.9 Hz, 3 H), 3.09 - 3.08 (d, J = 6.1 Hz, 3 H), 2.96 - 2.91 (m, 2 H), 2.04 (bs, 1 H), 1.61 - 1.59 (m, 6 H), 1.33 - 1.29 (m, 3 H), 0.92 - 0.86 (m, 6 H); Calcd m/z: [M+H]⁺ for C45H49N7O4Cl; 786.3529; Found 786.3526. Example 66: (S)- 2-( (S)-2-((7-chloroquinolin-4-yl) amino) propanamido)-4-methyl-N-((S)-1-oxo- 3-(1-trityl-1H-imidazol-4-yl) propan-2-yl) pentanamide (17): The synthetic method of compound 3a was adopted to synthesize 17. Light yellow solid; Yield: 0.2g, (72%); [α]²⁷D=-2.90 ^(c = 0.1, MeOH); mp: 80-85C; ¹H NMR (500MHz, CDCl3) ^ ^9.54 - 9.50 (m, 1 H), 8.46 (bs., 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.75 (dd, J = 5.4, 8.6 Hz, 1 H), 7.33 (m, 11 H), 7.18 - 7.07 (m, 6 H), 6.62 (s, 1 H), 6.36 - 6.29 (m, 1 H), 5.87 (m, 1 H), 4.64 - 4.54 (m, 2 H), 4.19 - 4.16 (m, 1 H), 3.09 (bs., 1 H), 2.96-2.93 (dd, J = 5.1, 14.6 Hz, 2 H), 1.67 - 1.56 (m, 5H), 1.40 - 1.21 (m, 3 H), 0.92 - 0.80 (m, 6 H); Calcd m/z: [M+H]⁺ for C43H44N6O3Cl 727.3158, found 727.3157. Example 67: (S)-2-((7-chloroquinolin-4-yl) amino)-3-(1H-imidazol-4-yl)-N-methoxy-N- methylpropanamide (11): Using compound 10c, 11 was synthesized following the analogous procedure of compound 1 as white solid: Yield: 0.13g, (57%); mp: 85 – 89C; Rf = 0.2 (silica gel TLC, 3% MeOH in DCM); [α]²⁷ _D = -17.28 ^(c = 0.1, MeOH); ¹H NMR (400MHz, CDCl₃) ^ ^ ^8.35 - 8.34 (d, J = 5.4 Hz, 1 H), 7.84 – 7.81 (m, 2 H), 7.54 (s, 1 H), 7.28 - 7.26 (dd, J = 2.0, 8.9 Hz, 1 H), 6.87 (bs, 1H), 6.76 (s, 2 H), 6.23 - 6.22 (d, J = 5.4 Hz, 1 H), 4.90 (bs, 1H), 3.38 (s, 3 H), 3.29 – 2.80 (m, 5 H); Calcd m/z: [M+H]⁺ for C17H18N2O5Cl; 360.1222, found 360.1217. Example 68: (S)-2-((7-chloroquinolin-4-yl) amino)-3-(1H-imidazol-4-yl) propanal (12): The synthetic method of compound 2a was adopted to synthesize 12. Yellow solid: Yield: 0.16g, (63%); [α]²⁷D=-9.75 ^(c = 0.1, MeOH); mp: 68-73C; ¹H NMR (400MHz, CD3OD) ^ ^8.35 (dd, J = 1.9, 6.0 Hz, 1 H), 8.26 - 8.24 (m, 1 H), 8.21 - 8.15 (m, 1 H), 7.75 (m, 1 H), 7.54 (s, 1 H), 7.45 – 7.42 (m, 1 H), 6.80 (s, 1 H), 6.58 - 6.56 (m, 1 H), 4.16 – 4.12 (qd, J = 4.1, 8.5 Hz, 1 H), 3.13 (dd, J = 3.8, 14.8 Hz, 1 H), 2.98 (td, J = 9.0, 14.9 Hz, 1 H); Calcd m/z: [M+H]⁺ for C₁₅H₁₄N₄O₁Cl; 301.0851; Found 301.0855. Example 69: 5-((S)-2-((S)-2-((7-chloroquinolin-4-yl) amino)-4-methylpentanamido)-3-oxopropyl)- 1H-imidazol-1-ium (15): The synthetic method of compound 4a was adopted to synthesize 15. light yellow solid; Yield: 0.35g, (87%); [α]²⁷ _D=0.67 ^(c = 0.1, MeOH); mp: 98 -102C; ¹H NMR (400MHz, CD₃OD) ^ 8.79 - 8.69 (dd, 1 H), 8.55 (m, 1 H), 8.46 (m, 1 H), 7.93 - 7.92 (m, 1 H), 7.88 - 7.70 (m, 1 H), 7.42 - 7.24(m, 4 H), 6.81 - 6.64 (m, 1 H), 4.64 - 4.61 (m, 1 H), 4.57-4.29 (bs., 1 H), 4.03 (t, J = 11.2 Hz, 1 H), 2.93-2.91 (d, J = 14.6 Hz, 1 H), 2.86 - 2.70 (m, 1 H), 1.76 (m, 1 H), 1.03 – 0.97(m, 2 H), 0.95- 0.91 (m, 6 H); Calcd m/z: [M+H]⁺ for C21H25N5O2Cl; 414.1691; Found 414.1678. Example 70: 5-((S)-2-((S)-2-((S)-2-((7-chloroquinolin-4-yl) amino) propanamido)-4-methylpentan amido)-3-oxopropyl)-1H-imidazol-1-ium (18): The synthetic method of compound 4a was adopted to synthesize 18. Light yellow solid; Yield: 0.150g, (86%); [α]²⁷D=-12.90 ^(c = 0.1, MeOH); mp: 90-95C; ¹H NMR (400MHz, CD3OD) ^ ^8.78 (d, J = 7.3 Hz, 1 H), 8.58 - 8.48 (m, 1 H), 8.45 (m, 1 H), 7.93- 7.91 (m, 1 H), 7.71 (m, 1 H), 7.53 - 7.34 (m, 1 H), 7.27 - 7.24 (m, 2 H), 6.69 - 6.67 (m, 1 H), 4.61 - 4.53 (m, 2 H), 4.34 - 4.33 (m, 1 H), 4.26 - 4.04 (m, 1 H), 3.11 (m, 1 H), 2.89 (m, 1 H), 1.71 - 1.68 (m, 3 H), 1.65 - 1.35 (m, 3 H), 1.34 - 1.26 (m, 1 H), 1.03 - 0.87 (m, 7 H); Calcd m/z: [M+H]⁺ for C₂₄H₃₀N₆O₃Cl; 485.2062, found 485.2050. [B] Assay protocol and results Example 71: Protocol for laboratory culturing and developmental stage synchronization of the human malaria parasite P. falciparum: Asexual blood-stage P. falciparum (strain 3D7) parasites were cultured under optimal conditions of 37°C and 5% CO2. These parasites are adapted to normoxic conditions and so the microaerophilic condition was not required. The culture medium consisted of 2% hematocrit with O+ human erythrocytes in RPMI1640 containing 25 mM HEPES, 50µg/ml Gentamicin sulfate, 2mM GlutaMAX 10 mg/L hypoxanthine, 2g/L sodium bicarbonate (Sigma-Aldrich), and 2.5g/L AlbuMAX II (Thermo Fisher Scientific). Parasites were synchronized using 5% sorbitol (Sigma-Aldrich) for enrichment of ring-stage parasites.² For synchronization, P. falciparum cultures were collected by centrifugation at 500 g for 5 min at 25°C and the parasitized RBC pellet was re- suspended in 5% sorbitol, followed by incubation at 37°C for 10 min. Following incubation, the cells were pelleted and washed with complete RPMI medium, before placing parasites back into culture flasks at 2% parasitaemia under optimal conditions. Example 72: Preparation of stock solutions of inhibitor molecules: Working stocks (1mM) for inhibitor molecules were prepared using cell culture grade DMSO (Sigma Aldrich, USA). Chloroquine and Atovaquone were used as standard positive controls in inhibition assays. These two drugs were dissolved in water and DMSO to make 1µM working stocks. Example 73: Determining percentage growth inhibition and EC₅₀ values for inhibitor compounds against blood-stage malaria parasites: All the peptide-histidine conjugates (Series 1-3) were screened against P. falciparum for both their ability to parasite growth of inhibition and inhibitory potency EC₅₀. The compounds were used at a fixed concentration of 10 µM in the inhibition assays and all assays were carried out in a 96-well plate format under optimal growth conditions. Chloroquine (1µM) was used as a positive control for parasite killing in the assays. Complete RPMI medium was added into the wells of each 96-well plate pre- seeded with inhibitor molecules, followed by the addition of an infected RBCs culture. The final culture volume was 200 µl, the assays were set up in triplicates and the treated cultures were incubated for 60 h under optimal conditions for P. falciparum growth. After incubation, the cultures were lysed with 0.05% triton X and stained with Sybr Green I nucleic acid stain (Invitrogen) to estimate the relative growth of parasites in presence of inhibitor molecule.³ Fluorescence scan readings were obtained using the GloMax plate reader (Promega). Data were processed using Microsoft Excel to determine the percentage growth inhibition for the inhibitors tested and EC50 value was determined for those found to have >80% inhibition of growth at 10 µM. For determining the EC50value a two-fold dilution series of the inhibitor starting at 10 µM as the highest concentration and ending at sub- nanomolar concentration was used. The EC50value of the compounds of present invention is given in the table below. Table 1: Inhibition of p. falciparum 3D7 (EC₅₀) growth in vitro The (±) values indicate standard deviation of replicate samples (n-3). S.No. Compound No. EC50 (µM) 1 4a 8.19 ± 1.132 2 4b 6.74 ±0.919 3 4c 5.78 ± 1.654 4 4d 7.92 ± 0.384 5 4e 3.92 ± 1.762 6 4f >10 7 4g 2.11 ± 0.035 8 4h 0.44 ± 0.039 9 8a >10 10 8b >10 11 8c 7.8 ± 0.22 12 8d 7.4 ±0.98 13 8e 0.432 ± 0.22 14 8f 8.7 ± 0.88 15 8g 0.018 ± 0.001 16 8h 0.069 ± 0.001 17 8i 2.43 ±1.365 19 8j >10 20 8k 0.447 ± 0.2 21 12 0.1 ± 0.035 22 15 0.02 ± 0.002 23 18 0.31 ± 0.057 24 Chloroquine 0.018±0.003 Example 74: Phenotypic studies: Late ring stage parasites (6-10 hours after 5% sorbitol synchronization) were treated with 25 µM of compounds E64, 8e, 8g and 8j and incubated for 24 h and 36 h from the time of synchronization. At these time points, thin smears of the parasite culture were made on glass slides, stained with Giemsa stain and visualized by light microscopy using 100X oil immersion objective. The falcipains are involved in hemoglobin breakdown. This was tested using the cysteine protease inhibitor E64 as a reference inhibitor (refer, figure 4). It was observed that compound 8g, and its biotinylated version 8j showed specific morphological changes in the food vacuole consistent with inhibition of hemoglobin digestion. Thus, 8g is a potent novel inhibitor of parasite falcipain-2/3 proteases capable of disrupting the food vacuole function and arresting parasite growth. ADVANTAGES OF THE INVENTION ^ Compounds can be claimed to be active in any parasite that uses cysteine protease, enzymes specifically found in falciparum ^ Recently, malaria treatment failures have been reported for ACTs. Thus, aldehyde-based scaffolds might be useful against resistant strain. ^ Modified chloroquine compounds might be able to access the target site, which is the food vacuole of the parasites.

Claims

We Claim: 1. A histidinal peptide conjugate compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate thereof of formula I, represented by:

wherein L is direct bond either present or absent, wherein L is selected from CH(R¹), (CH(R¹))nNR⁴CHR⁵, (CH(R¹))nCONR²CHR³, (CH(R¹))nSO2NR²CHR³, or (CH(R¹))nNR⁴CHR⁵CONR⁶CHR⁷, wherein n is 0 or 1; R is aryl, heterocyclyl, alkyl, NH-aryl, SO₂-aryl, or aryl-heterocyclyl, wherein the aryl, heterocyclyl, alkyl is substituted or unsubstituted; R¹ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R² is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R³ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁴ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁵ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; R⁶ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted; and R⁷ is hydrogen, alkyl, or aryl; wherein the alkyl, aryl is substituted or unsubstituted. X is CF3COO-, or Cl-.

2. The histidinal peptide conjugate compound of formula (I) as claimed in claim 1, wherein R is selected from:

. 3. The histidi p p g p m 1, wherein the compound is selected from the group consisting of: i. (S)-5-(2-(2-methylbenzamido)-3-oxopropyl)-1H-imidazol-1-ium (4a); ii. (S)-5-(2-(1-hydroxy-2-naphthamido)-3-oxopropyl)-1H-imidazol-1-ium (4b); iii. (S)-5-(2-(3-hydroxy-2-naphthamido)-3-oxopropyl)-1H-imidazol-1-ium (4c); iv. (S)-5-(2-(benzo[b]thiophene-2-carboxamido)-3-oxopropyl)-1H-imidazol-1-ium (4d); v. 5-((S)-2-((S)-2-(6-methoxynaphthalen-2-yl) propanamido)-3-oxopropyl)-1H-imidazol-1-ium (4e); vi. (S)-5-(3-oxo-2-(2-propylpentanamido) propyl)-1H-imidazol-1-ium (4f); vii. (S)-5-(2-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetamido)-3-oxopropyl)-1H-imidazol-1- ium (4g); viii. (S)-5-(2-(4'-((1, 7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d] imidazol]-3'-yl) methyl)-[1, 1'- biphenyl]- 2-carboxamido)-3-oxopropyl)-1H-imidazol-1-ium (4h); ix. 5-((S)-2-((S)-4-methyl-2-(2-methylbenzamido) pentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8a); x. 5-((S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-oxopropyl)-1H-imidazol- 1-ium (8b); xi. 5-((S)-2-((S)-2-(1-hydroxy-2-naphthamido)-4-methylpentanamido)-3-oxopropyl)-1H-imidazol- 1-ium (8c); xii. 5-((S)-2-((S)-2-(3-hydroxy-2-naphthamido)-4-methylpentanamido)-3-oxopropyl)- 1H-imidazol- 1-ium (8d); xiii. 5-((S)-2-((S)-2-(benzo[b]thiophene-2-carboxamido)-4-methylpentanamido)-3-oxopropyl) -1H- imidazol-1-ium (8e); xiv. 5-((S)-2-((S)-2-((S)-2- (6-methoxynaphthalen-2-yl) propanamido)-4-methylpentan amido)-3- oxopropyl)-1H-imidazol-1-ium (8f); xv. 5-((S)-2-((S)-4-methyl-2-(2-propylpentanamido) pentanamido)-3-oxopropyl)-1H-imidazol-1- ium (8g); xvi. 5-((S)-2-((S)-2-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetamido)-4-methylpentan amido)-3-oxopropyl)-1H-imidazol-1-ium (8h); xvii. 5-((S)-2-((S)-2-(4'-((1, 7'-dimethyl-2'-propyl-1H,

3'H-[2, 5'-bibenzo[d]imidazol]-3'-yl) methyl)- [1, 1'-biphenyl]-2-carboxamido)-4-methylpentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8i); xviii. 5-((S)-2-((S)-2-((5-(dimethylamino) naphthalene)-1-sulfonamido)-4-methylpentanamido)-3- oxopropyl)-1H-imidazol-1-ium (8j); xix. 5-((S)-2-((S)-4-methyl-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl) pentanamido) pentanamido)-3-oxopropyl)-1H-imidazol-1-ium (8k); xx. (S)-2-((7-chloroquinolin-4-yl) amino)-3-(1H-imidazol-5-yl) propanal (12); xxi. 5-((S)-2-((S)-2-((7-chloroquinolin-4-yl) amino)-4-methylpentanamido)-3-oxopropyl)-1H- imidazol-1-ium (15); and xxii. 5-((S)-2-((S)-2-((S)-2-((7-chloroquinolin-4-yl)amino)propanamido)-4-methylpentan amido)-3- oxopropyl)-1H-imidazol-1-ium (18).

4. The histidinal peptide conjugate compound of formula (I) as claimed in claim 1, wherein the pharmaceutically acceptable salt form of the compound is selected from trifluoroacetate salt or chloride salt.

5. A process for the preparation of histidinal peptide conjugate compounds of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate thereof as claimed in claim 1, wherein the process comprising the steps of: a) coupling N ^{^}-(((9H-fluoren-9-yl) methoxy) carbonyl)-N ^{^}-trityl-L-histidine with aminating agent or base in the presence of coupling reagent(s) in solvent to obtain precursor 1

Precursor 1; b) deprotecting Fmoc of precursor 1 of step a) by treating the precursor 1 in presence of tert- butylamine in a solvent at temperature in the range of 25-35 ºC for time period in the range of 3 to 5 hrs to obtain an intermediate

c) coupling the intermediate obtained in step (b) with R-carboxylic acid in the presence of coupling reagent(s) in solvent to furnish compound selected from formula 2a-h

d) reducing the compound obtained in step (c) using lithium aluminium hydride (LiAlH₄) in solvent at temperature in the range of 0 to -20 °C for time period of 45 to 120 minutes to obtain the compound selected from Formula 3a-h

Formula 3a-h; e) deprotecting compound obtained in step (d) using salt precursor trifluoroacetic acid (TFA) in solvent at temperature in the range of 25 to 40^oC for the time period in the range of 1 to 2 hours to obtain the histidinal peptide conjugate compound of formula (I) with salt form selected from compounds 4a-h;.

Formula I wherein X is trifluoroacetate salt, and HCl salt, and R is the same as defined in claim 1, and wherein the compounds 4a-h recite X as trifluoroacetate salt form. 6. The process as claimed in claim 5, wherein said R-carboxylic acid (1a-h) is selected from 2- methylbenzoic acid (a), 1-hydroxy-2-naphthoic acid (b), 3-hydroxy-2-naphthoic acid (c), benzo[b]thiophene-2-carboxylic acid (d), (S)-2-(6-methoxynaphthalen-2-yl) propanoic acid (e), 2- propylpentanoic acid (f), 2-(2-((2,

6-dichlorophenyl) amino) phenyl) acetic acid (g), and 4'-((1,7'- dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-[1,1'-biphenyl]-2-carboxylic acid (h).

7. A process for the preparation of peptide-histidinal conjugate compounds of formula (I) as claimed in claim 1, wherein the process comprising the steps of: (i) coupling N ^{^}-(((9H-fluoren-9-yl) methoxy) carbonyl)-N ^{^}-trityl-L-histidine with aminating agent or base in the presence of coupling reagent(s) in solvent to obtain precursor 1

Precursor 1; (ii) deprotecting precursor 1 by treating the precursor 1 in presence of tert-butylamine in a solvent at temperature in the range of 25-35 ºC for time period in the range of 3 to 5 hrs to obtain an intermediate

(iii)coupling Fmoc-Leu-OH with the precursor 1 as obtained in step (i) in the presence of coupling reagent(s) in solvent to obtain intermediate 5 5; (iv) deprotecting Fmoc of the intermediate 5 of step (ii) by treating the intermediate 5 in presence of tert-butylamine in a solvent at temperature in the range of 25-35 ºC for time period in the range of 3 to 5 hrs to obtain an intermediate; (v) coupling the intermediate obtained in step (iii) with R-carboxylic acid in the presence of coupling reagent(s) in solvent to furnish compound selected from compounds of formula 6a-k;

Formula 6a-k (vi) reducing the compound obtained in step (iv) using lithium aluminium hydride (LiAlH₄) in solvent at 0 to -20°C to obtain the compound selected from compounds of formula 7a-k

Formula 7a-k (vii) deprotecting compound obtained in step (v) using salt precursor TFA in solvent at temperature in the range of 25 to 40°C for the time period in the range of 2 to 3 hours to obtain the histidinal peptide conjugate compound of formula (I) with trifluoroacetate salt form selected from compounds 8a-k; Formula I wherein X is trifluoroacetate salt a is the same as defined in claim 1, and wherein the compounds 8a-k recite X as trifluoroacetate salt form.

8. The process as claimed in claim 7, wherein said R-carboxylic acids are selected from (a-k) 2- methylbenzoic acid (a), 1H-indole-2-carboxylic acid (b), 1-hydroxy-2-naphthoic acid (c), 3-hydroxy-2- naphthoic acid (d), benzo[b]thiophene-2-carboxylic acid (e), (S)-2-(6-methoxynaphthalen-2-yl) propanoic acid (f), 2-propylpentanoic acid (g), 2-(2-((2,6-dichlorophenyl) amino) phenyl) acetic acid (h), 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl) methyl)-[1,1'-biphenyl]-2- carboxylic acid (i), 5-(dimethylamino) naphthalene-1-sulfonic acid (j), and 5-((3aS,4S,6aR)-2- oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl) pentanoic acid (k).

9. A process for the preparation of peptide-histidinal conjugate compounds of formula (I) as claimed in claim 1, wherein the process comprising the steps of: (i) reacting 4, 7-dichloroquinoline 9 with the amino acids, at temperature in the range of 140 to 150°C for the time period of 1-6h to obtain compounds 10 a-c wherein the amino acids are selected from a-c L-alanine (a), L-leucine (b) and L-histidine (c). (ii) coupling the compound 10c with N, O-dimethylhydroxylamine to obtain compound 11, ;

(iii) reacting compound 10b with precursor 1, wherein the precursor 1 is represented by in presence of coupling reagent(s) to afford compound 13,

(iv)reacting compound 10a with intermediate 5 wherein intermediate 5 is represented by in presence of coupling reagent(s) to afford compound 16

16 (v)deducing the compounds obtained in step (ii), (iii), (iv) using lithium aluminium hydride (LiAlH4) in dry THF at -20°C to obtain the compounds 12, 14, 17 (vi) deprotecting the compounds 12, 14 or 17 obtained in step (v) using trifluororacetic acid in solvent at temperature in the range of 25 to 40 ^{^}C for the time period in the range of 2 to 3 hours to produce histidinal-based trifluoroacetate salt compounds 15 and 18

10. The process as claimed in claim 5, 7 or 9, wherein the coupling agent used in step a) is selected from HBTU, HOBt and EDC·HCl or mixtures thereof.

11. The process as claimed in claim 5, 7 or 9, wherein the aminating agent is selected from DIPEA, DMF, and N, O-dimethyl hydroxylamine. HCl.

12. The process as claimed in claim 5, 7 or 9, wherein the precursor salt is selected from trifluororacetic acid and 4M HCl in 1,4-Dioxane.

13. The process as claimed in claim 5, 7 or 9, wherein the solvent is selected from polar or non-polar solvent, and protic or aprotic solvent.

14. The process as claimed in claim 5, 7 or 9, wherein the base is selected from organic base and inorganic base.

15. The process as claimed in claim 13, wherein the solvent is selected from DMF, THF, lower (C1- C5) alcohol, nitrile, ketone, halogenated hydrocarbon, TFA or combinations thereof; 16. The process as claimed in claim 14, wherein the wherein the organic base is selected from ethylamine, triethylamine, DIPEA, and pyridine; and wherein the inorganic base is selected from sodium hydroxide, alkali or alkaline earth metal carbonate and bicarbonate or combination thereof. 17. A pharmaceutical composition comprising the compound of formula I as claimed in claim 1 and a pharmaceutically acceptable excipient(s). 18. A method of treating malaria wherein, the method comprising administering therapeutically effective amount of the compound of Formula I as claimed in claim 1 or the pharmaceutical composition as claimed in claim 17 to reduce the malarial infection. 19. A method of inhibition of malaria cysteine proteases by contacting plasmodium with the compound of formula I as claimed in claim 1 or the pharmaceutical composition as claimed in claim 17.