Send Orders for Reprints to [email protected] Mini-Reviews in Medicinal Chemistry, 2013, 13, 1421-1447 1421
Novel Research Strategies of Benzimidazole Derivatives: A Review
Kuldipsinh P. Barot1, Stoyanka Nikolova2, Illiyan Ivanov2 and Manjunath D. Ghate*,1
1Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad-382481, Gujarat, India; 2Faculty of Chemistry, University of Plovdiv, 24 "Tsar Asen" str., 4000 Plovdiv, Bulgaria
Abstract: Benzimidazole plays an important role in the medicinal chemistry and drug discovery with many pharmacological activities which have made an indispensable anchor for discovery of novel therapeutic agents. Substitution of benzimidazole nucleus is an important synthetic strategy in the drug discovery process. Therapeutic properties of the benzimidazole related drugs have encouraged the medicinal chemists to synthesize novel therapeutic agents. Therefore, it is required to couple the latest information with the earliest information to understand the current status of benzimidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for the development of SAR on benzimidazoles for each activity. This article aims to review the work reported, chemistry and pharmacological activities of benzimidazole derivatives during past years.
Keywords: Benzimidazoles, early rationality, chemistry, pharmacological activities.
1. INTRODUCTION
Benzimidazoles are the benzo derivatives of imidazole which contains imidazole heterocycle. It is accepted name for the parent compound in the series and numbering which follows the accepted pattern for heterocyclic compounds [1]. Azapyrrole moiety is involved in imidazole or iminazoline heterocycles in which nitrogen atom is separated by one carbon atom. It was earlier also called as glyoxalin as first prepared in 1958 from glyoxal and ammonia. Benzimidazole is also known as 1H-benzimidazole or 1,3-benzodiazole [2]. Five-membered nitrogen-containing heterocyclic ring is present in the structures of various biologically active synthetic compounds [3]. Structural frameworks have been described as privileged structures and in particular, N-containing polycyclic structures have been reported to be associated with a wide range of biological activity. The high therapeutic properties of the benzimidazole related drugs have encouraged the medicinal chemists to synthesize a large number of novel chemotherapeutic agents [4-6].
Woolley et al. [7] have described that therapeutic potential of benzimidazole nucleus is traced back to 1944 when benzimidazole can act as similar to purines to elicit some optimum biological responses. Five years later, Brink
*Address correspondence to this author at the Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad-382481, Gujarat, India; Tel: +91-2717-241900 to 04; Fax: +91-2717-241916; E-mail: [email protected]
et al. [8] has identified 5, 6-dimethylbenzimidaozle as the degradation product of vitamin B12 and subsequently found some of its derivatives having vitamin B12 like activity. These initial reports sparked active research to explore the nucleus for varied activities [7, 9]. Over the years of active research, benzimidazole has evolved as an important heterocyclic system due to its presence in a wide range of bioactive compounds like antiparasitics, anticonvulsants, analgesics, antihistaminics, antiulcers, antihypertensives, antiviral, anticancers, antifungals, anti-inflammatory agents, proton pump inhibitors and anticoagulants [10-16].
Benzimidazole drugs are widely used for the prevention and treatment of parasitic infections. Omeprazole 1,rabeprazole 2, lansoprazole 3, pantoprazole 4 and esomeprazole 5 are well known discovered benzimidazole drugs. Thiabendazole (TBZ) 6 was the first benzimidazole to be marked over 40 years ago. After its introduction, many benzimidazoles offering similar activity came to the market, such as parbendazole (PAR) 10, cambendazole (CAM) 11,mebendazole (MBZ) 7 and oxibendazole 13 (OXI) [17]. Benzimidazole possessing sulphide and sulphoxide functional groups were subsequently introduced which offers a wide spectrum of activity and improved efficacy. Albendazole (ABZ) 8, fenbendazole (FBZ) 12 and oxfendazole (OFZ) 14were the first benzimidazoles to be successfully used in the treatment of all growth stages of gastrointestinal nematodes [18]. Tricyclabendazole (TCB) 9 was later introduced as an antihelmenthic agent for the treatment of all stages of liver flukes, but is ineffective against nematodes. Luxabendazole (LUX) 5 is another benzimidazole sulphide used in the treatment of food-producing animal but is not licensed for use in the EU. Netobimin and febantel are the pro-drugs of albendazole and fenbendazole respectively. Similar, probenzimidazoles have found widespread use as fungicidal agents, including benomyl (BEN) and thiophanate-methyl
1422 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
(TM), which are precursors of carbendazim (MBC) (Fig. 1)[19].
2. CHEMISTRY
Benzimidazoles are the well known heterocyclic compounds which have common and characteristic features of a variety of medicinal agents. It is soluble in water and other polar solvents [20]. It exists in two equivalent tautomeric forms because the hydrogen atom can be located on either of the two nitrogen atoms. It is also highly polar compound, as evidenced by a calculated dipole of 3.61D, and entirely soluble in water [21]. It is classified as aromatic due to the presence of a sextet of �-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring. It can function as both an acid and as a base. As an acid, the pKa of benzimidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. As a base, the pKa of the conjugate acid is approximately 7, making benzimidazole approximately sixty times more basic than pyridine [22, 23].
Great concerns have been made since long time to generate libraries of benzimidazole derivatives due to its various activities and immense synthetic importance. The literature review on chemistry of benzimidazole derivatives states that Hoebrecker et al. have synthesized first benzimidazole 16 and 17 in 1872 through the reduction of 2-nitro-4-methylacetanilide (Fig. 2) [37]. After several years later, Ladenburg et al. have synthesized the same compound by refluxing 3,4-diamino toluene with acetic acid.
Benzimidazoles 18 were also known as benziminazoles or benzoglyoxalines which are also named as derivatives of o-phenylenediamine. For example, methenyl-o-phenylenediamine and 2-methylbenzimidazole 19 are also known as ethenyl-o-phenylenediamine. They are also known as derivatives of groups containing imidazole portion of ring, for example, benzimidazole has also been called as o-phenyleneformamidine. 2(3H)-Benzimidazolone 20 and 2(3H)-benzimidazolethione 21 are also known as o-phenylurea and o-phenylenethiourea, respectively [24, 37]. Hydrogen atom attached to N-1 of the nucleus readily tautomerises (Fig. 3) which is responsible for isomerisation in the derived compounds [37]. Two numbers or sets of numbers are usually given to designate the position of the substituent group (or groups) and the second number or groups of numbers being placed in parenthesis for the designating such tautomeric compounds. According to this convention above compounds are named as 5(or 6)-methylbenzimidazole [24, 37].
3. BIOLOGICAL ACTIVITIES
Literature survey states that various derivatives of benzimidazole have been synthesized for their biological and pharmacological activities. Some of the already discovered compounds from the above mentioned field have found very strong application in medicinal field [25]. The activity against bacteria, fungi and helminthes results their mode of action, which resulted in the blockage of microtubule in various nematode, trematode and cystode [26].
Benzimidazole is the core in medicinal chemistry which acts at different targets to predict various pharmacological
NH
NH3COS
ON
H3C OCH3
CH3
NH
NS
ON
H3C OCH2CH2CH2OCH3
CH3
NH
NS
ON
H3C OCH2CF3
NH
NS
ON
H3CO OCH3
FH2CO
NH
NS
ON
H3CO CH3
OCH3H3C
NH
N
N
S
NH
N
NH
OO
O
CH3
NH
N
SH3C
NH
OO
CH3
NH
N
O
Cl
ClCl
SCH3
NH
N
C4H9
HN O
OCH3
NH
N
S
NHNO
O NH
NNH
OO CH3
S
NH
NNH
OO CH3
OC3H7
NH
NNH
OO CH3
SO
NH
NNH
OO CH3
S
F
1 2 3
45
6
7 8 9
10 1112
13 14 15
Fig. (1). Early rationality of discovered benzimidazole drugs.
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1423
activities (Fig. 4) [37]. All the positions in benzimidazle nucleus can be substituted by various chemical entities, but most of the biologically active benzimidazole based compounds has functional groups at 1-, 2- and/or 5-(or 6-) positions. Compounds may be mono-, di- or tri- substituted derivatives of the nucleus. In the present review, various benzimidazole derivatives have been categorized on the basis of their pharmacological activities [37]. Various literature survey states that benzimidazole derivatives show various pharmacological activities such as antimicrobial [27], antifungal [28], anti-inflammatory [29], antianalgesic [30], antitubercular [31], antidepressant [32], anticancer [33], antiviral [34], antileishmanial [35], antiulcer [36] etc.
3.1. Antimicrobial Activity
Many research activities on the development of antimicrobials from benzimidazole nucleus have been taken up after the year 2000. Antimicrobial agents contain different
chemical entities which can acts against various microbes including bacteria, protozoa, helminths (worms), fungi and viruses. Many different research groups have evaluated antibacterial, antiprotozoal, anthelmintic and/or antifungal activities concomitantly while evaluation of antiviral compounds remains solitary [37].
Shingalapur et al. [22] have synthesized a series of novel 5-(nitro/bromo)-styryl-2-benzimidazole derivatives 22 and tested for the antibacterial activity against Staphylococcus aureus, Escherichia coli, Enterococcus faecalis and Klebsiella pneumoniae and antifungal activity against Candida albicans and Aspergillus fumigates which are comparable with ciprofloxacin. Olender et al. [38] have synthesized nitroimidazole derivatives and tested for their antifungal activity using the standard nutrient method against Sclerophoma pityophila and compound 23 showed more potent fungistatic activity. Ansari et al. [39] have synthesized novel azetidine-2-one derivatives 24 and evaluated their antibacterial activity against Bacillus subtilis, Escherichia coli, Candida albicans, Aspergillus niger and Aspergilus flavus. The tested compounds are more effective against Gram positive bacteria. The strong lipophilic character of molecule plays major role in the development of antimicrobial effects. Some derivatives of benzimidazole were synthesized by nucleophilic substitution of substituted benzimidazole 2-substituted-1-[{(5-substituted-alkyl/aryl)-1,3,4-oxadziazolyl-2-yl}] 25 and were evaluated for antimicrobial activities toward Gram positive and Gram negative bacteria. Some of the synthesized compounds showed moderate activity against tested fungi [40].
Gupta et al. [41] have synthesized 2-thiohalogenonitrophenyl benzimidazole by the condensation of halogenonitrobenzenes and sodium salt of 2-mercaptobenzimidazole 26 and was tested for their antifungal activity against Helmithosporium sativum, A. niger and Fusarium oxysporum by spore germination method and percentage inhibition of the spores at 10 ppm was recorded. Mane et al. [42] have synthesized various benzimidazoles 27 and evaluated against Alternaria brassicicola, Fusarium, Staphylococcus (Gram +ve) and E.coli (Gram –ve) using filter paper disc method at 500 ppm concentration using 5 mm size filter paper. It was found that the compound having NO2 and chloro substituent showed good activity against fungi as well as bacteria. Khalafallh etal. [43] have synthesized a series of fused and spiropyrazolones 28, isoxazolines 29, pyrimidines 30, �-lactam 31 and thiazolidinones 32 incorporating 2-cyanomethyl benzimidazole. Synthesized compounds are tested against some bacterial and fungal strains using the filter paper disc method and 3-cyano-2,3-dihydropyrolo[1,2-a]benzimidazole-1(H)-one is more potent against bacteria and fungi than pyrazolines and pyrimidines.
Mavrova et al. [44] have synthesized 1[H]-benzimidazole-2-yl thioacetylpiperazine derivatives 33, 34, 35 and evaluated for their in vitro activity against T. spiralis as well as their in vivo antinematode activity against S. obvelata. In vitro activity showed that most of the tested compounds exhibited higher activity than albendazole against T. spiralis and comparable to that of ivermectin. Some of the compounds demonstrated 96.0%, 98.2% and 100% activities at a dose of 200 �g/mL after 48 h. Some of
H3C NO2
NHCOCH3
HCl
H3C NH2
NHCOCH3
FeCH3OH
-H2O
N
HNH3C
CH3
2,6-dimethyl-1H-benzo[d]imidazole
16
NH2
NH2
CH3COOH -H2O
NH2
NHCOCH3
-H2O
H3C
H3C
N
HN
CH3H3C
2,5-dimethyl-1H-benzo[d]imidazole17
Fig. (2). Early discovered 2, 5- and 2, 6- disubstituted benzimidazole derivatives [37].
NH
NY
12
34
56
718
Tauto-merism
N
HNY
3
2
176
54
NH
NCH3
19
NH
HN
O
NH
HN
S
20
21 Fig. (3). Tautomerism in benzimidazole nucleus [37].
1424 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
the compounds were found most active with 76.0%, 73.0% and 77.0% against S. obvelata (Fig. 5).
3.2. Antiviral Activity
Different benzimidazole derivatives are evaluated using different virus strains for the antiviral properties such as human cytomegalovirus (HCMV), human herpes simplex virus (HSV-1), human immunodeficiency virus (HIV) and hepatitis B and C virus (HBV and HCV). 5,6-Dichloro-l-(�-D-ribofuranosyl) benzimidazole (DRB 36) was synthesized during 1950-1990s as selective inhibitors of HCMV. It inhibits viral RNA synthesis by blocking RNA polymerase II [45, 46]. Incorporation of chloro and bromo group at 2-position of DRB provided TCRB 37 and BDCRB 38respectively having dramatically improved therapeutic index. A ribosyl moiety at 1st position is proved to be very important for the activity [47]. Non-nucleoside derivatives of DRB were synthesized by replacing �-D-ribofuranosyl with a benzyl and phenylethyl group. They were found inferior in the activity against HCMV but active against HIV-1. Enviradine 39 and enviroxime 40 are the non-nucleoside analogs and potent broad spectrum inhibitors of RNA viruses [48].
Garuti et al. [49] have synthesized some 2-substituted benzimidazole-N-carbamates as potent antiviral compounds amongst which isopropylcarboxamide group at 2nd position 41 leds to highly potent activity. Dehydroabietic acid derivatives of benzimidazoles exemplified by 42 and 43 inhibit both varicella-zoster virus (VZV) and cytomegalovirus (CMV) replication at concentrations much lower than their cytotoxic concentrations [50]. Various fluorinated pyrido
[1,2-a]benzimidazoles have exhibited no antiviral properties except compound 44 inhibited the growth of variolovaccine and monkeypox viruses [51].
Amongst a series of benzimidazole derivatives having amidino group at 5-position and various hetero nuclie such as pyridine, N-methyl-pyrrole or imidazole, the compounds with pyridine ring at 2-position 45 showed potent antiviral activity against RNA replicating enteroviruses. Optimum activity against other types of viruses especially adenovirus was observed by pyrrole substituted compound 46 [52]. SAR study of 2-naphthyl benzimidazoles with different substituents at 5,6-positions of benzimidazole ring and 4-position of naphthyl ring 47 suggests that electron releasing groups on benzimidazole nucleus enhance antiviral activity. Potent antiviral compound is obtained by substitution of an amino group on naphthalene ring and replacement of amino with nitro and acetyl groups decreases the activity significantly [53]. 2-Biphenyl derivatives of benzimidazoles are developed by taking 2-aryl benzimidazole as a lead, but most of the compounds except 48 and 49 showed no activities against all viruses tested [54]. 1[H]-Benzimidazole-4-carboxamide derivatives having furyl at 2-postion and aryl moiety at carboxamide nitrogen possess good inhibitory activity [55, 56]. Barreca et al. synthesized 1-benzyl 1,3-dihydro-2H-benzimidazol-2-ones as potential non-nucleoside reverse transcriptase inhibitors (NNRTIs) active against HIV-1 [57]. 6-Chloro-1-(2,6-difluorobenzyl)-substituted derivative 50 was found to possess significant activity against HIV-1. Subsequently molecular modeling studies on 50 leds to the rational discovery of N1-arylsulfonyl-1,3-dihydro-2H-benzimidazol-2 one 51 as a novel template for
NH
NNH
OO
O
Mebendazole(Antimicrobial)
N
NNH2
SOO
Enviradine(Antiviral)
N
N
N
N
H3C
H3C
COOH
Telmisartan(Antihypertensive)
N
NNN
F
F N
NN
N
GABA Modulator
N
NNH
NH
F
Norastemizole(Antihistaminic)
NH
N
NNH3C
HNO
FNH2
Dovitinib(Anticancer)
N
NH3CCH3
O
Benoxaprofen analogue
NH
N
(Anti-inflamatory)
OF
FS
O
N
O O
Pentoprazole (Antiulcer)
Fig. (4). Pharmacological activities of benzimidazole derivatives [37].
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1425
design of new NNRTIs active against wild-type and mutant strains of HIV-1 [58].
Hirashima et al. have synthesized JTK-109 52 as a potent inhibitor of HCV NS5B RNA-dependent RNA polymerase [59]. Biphenyl moiety was replaced with a 2-morpholinophenyl and pyrrolidone group yielded potent compounds 53 and 54 [60]. SAR studies on a series of hybrid molecules containing benzimidazole and coumarin with a methylenethio linker and the corresponding N-glucosides has revealed 55 as lead anti HCV compound [61]. Beaulieu et al. have developed some benzimidazole-based allosteric inhibitors of HCV NS5B which binds to Thumb Pocket I of the HCV NS5B polymerase which are known as ‘finger-loop inhibitors’ [62].
A common binding mode of benzimidazole molecules to the enzyme allosteric site is suggested by the SAR around three benzimidazole sub-series of NS5B inhibitors containing 5-carboxybenzimidazole scaffold. A hypothetical pharmacophore model (Fig. 7) and further optimization of these molecules leds to the development of potent diamide derivative [63].
Respiratory Syncytial Virus (RSV) is mostly observed in the children below 5 years of age which is the most common viral cause of death. Identification of potent and selective inhibitors of RSV has attracted considerable attention. A research group from Bristol-Myers Squibb Pharmaceutical Research Institute initiated the development of RSV inhibitors with a series of benzotriazole-substituted
NH
N
Br
OH
NH
N
Br
OCH3
OCH3
22 23
N
NH3C
S
N N
N
Ar
ClO
24
R = C6H5, 4-BrC6H5, 2-ClC6H4, 4-C6H4,2-OCH3C6H4, 4-OCH3C6H4, 2-OHC6H4, 4-OHC6H4
N
N R
O
NN
R1
25R = H or CH3R1= CH3, C2H5, CH2Cl, C6H5, 2-ClC6H4, 4-ClC6H4, 2-OHC6H4, 4-OHC6H4, 2-OCH3C6H4, 4-OCH3C6H4
Fig. (5). Novel benzimidazole derivatives as antimicrobial agents.
1426 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
benzimidazoles [64]. Replacement of benztriazole with benzimidazol-2-one yielded better RSV inhibitors with a broader tolerance for substituent size at 1-position [65]. Structural modifications improve solubility properties for invivo evaluation and compounds 56 and 57 exhibited optimum potency following oral administration [66]. The continual efforts of the group led to 6-aza benzimidazolone derivative BMS-433771 58 which have demonstrated good oral bioavailability and antiviral activity [67]. Attempts to further increase the activity aculminated in 5-aminomethyl analog exhibiting potent antiviral activity towards wild type RSV and excellent inhibitory activity towards a BMS-433771 resistant viral strain [68]. Benzimidazole-2-one moiety is replaced with benzoxazole, oxindole, quinoline-2-
one, quinazolin-2,4-dione and benzothiazine revealed that intrinsic potency of 6,6-fused ring systems is generally less than that of 5,6-fused heterocycles (Fig. 6) [69].
N
N OHN
O
Hydrophobic pocket
ScaffoldSpacer
HO
O
H-bond to proteinImproves potency
Fig. (7). Hepatitic C viral inhibition by hypothetical pharmacophore receptor model.
N
N
OO
O
HNCH3
CH3
H3CN
HN
R2
R1
COOCH3
41 42 R1, R2 = H43 R1 = CH3, R2 = Br
N
HNF
F
CN
CH3
CHOO44
N
N
Cl
Cl
X
O
ROOR
OR
36 X = H37 X = Cl38 X = Br
N
N
X
NH2
SOO
39 X= CHCH340 X = N-OH
N
HN
NH
H2N
N
N
HN
NH
H2N
NH3C
N
HNH3C
H3CR
H3C
45 46 47
N
HNR1
R2
HN
N
48 R1 = COCH3, R2 = NO249 R1 = CH3, R2 = NHCOCH3
Cl
O
XF
F50 X = CH251 X = SO2
N
N
COOH
O
F
Cl
NO
52
NN
COOH
O
F
N
N
O
O N N
HOOC
O
F
NO
NH
OH3C
CH3
O N
OAcAcO OAc
AcO
N
S
OO
Br
53 54
55
NN
O
R
ON
N
NH3CCH3
56 R = OCH3
57 R = N(CH3)2)
NN
HO
NN
N
O
58
Fig. (6). Novel benzimidazole derivatives as antiviral agents.
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1427
3.3. Antiulcer Activity
Many benzimidazole derivatives have been proved to have antiulcer activity and as potential inhibitors of H+/K+-ATPase [70]. Clinical significance of these drugs in the treatment of peptic ulcer and associated gastrointestinal diseases encouraged the development of novel more potent and significant compounds which makes benzimidazole more specific for proton pump inhibitors [71]. In 1991, benzimidazole derivatives were synthesized by derivatization at N-H of benzimidazole by electron donating group and substitution with long chain of propyl acetamido-thio, thiazole-amino, tetramethyl piperidine on pyridine resulting in good antiulcer activity [72].
Omeprazole (racemic mixture) 59, lansoprazole 60,rabeprazole 61, pantoprazole 62 and esomeprazole (absolute (S) configuration) 63 (Fig. 8) are the well-known antiulcer agents having benzimidazole nucleus. Kosaka et al. [73] have synthesized compounds with substitution of dimethyl imidazopyridine at 6-position of benzimidazole showing strong antisecretory activity. Kohl et al. [74] have synthesized pantoprazole and explained role of methoxy group of pyridine for maximum biological activity. Introduction of rigid ring with benzimidazole and their conversion to biological active sulfonamide in acidic media has been verified by Yamada et al. [75] in 1994. Yamada S et al. [76]have substituted pyridine by triazole 3-yl, 1,3-dithiane and reported promising results when biologically evaluated against H. pylori. Other approach was also applied to reduce the basicity of ring nitrogen of pyridine and to reduce the irreversibility of compound with enzyme by using pyrimidine as ring substituent by Hiroshi et al. [77] in 1995. Ung et al. [78] have reported the synthesis of leminiprazole by replacing pyridine with phenylisobutylmethylamine in 1996 which shows potent proton pump inhibitory activity. Elof et al. [79] have replaced pyridine by 2,2-dimethyl pyrranopyridine ring. Jain et al. [80] have synthesized 2-dimethylaminothiazo cyclobenzene benzimidazole showed good proton pump inhibitory activity. Kaun et al. [81] have replaced pyridine with pyrrolobenzimidazolyl moiety, which showed proton pump inhibitory activity. Yong et al. [82]have synthesized esomeprazole by asymmetric oxidation of prochiral sulfide of omeprazole which showed potent antiulcer activity.
Nicole et al. [83] have synthesized 2-(thiopropyne)-5-(imidazole-1-yl) benzimidazole 64 which exhibited moderate
antiulcer activity against ulcer induced by anti-inflammatory agents in rats orally. Uchida et al. [84] synthesized N-allyl-1-ethyl-8-((5-fluoro-6-methoxy-1H-benzo [d] imidazol-2-ylsulfinyl) methyl)-N-methyl-1,2,3,4-tetrahydroquinolin-4-amine 65 and showed potent antiulcer activity. It appears from these results that the presence of basic amino group may be an important contributing factor in activity of the molecule. Kovalev et al. [85] have synthesized 9-(diethyl amino ethylene)-2–phenyl imidazo [1,2-a] benzimidazole 66which was found to be more potent than omeprazole for antiulcer activity.
It was found that many omeprazole like compounds undergo decomposition by rapid purple coloration in aqueous solution, limited shelf life and tends to colorize during storage. Omeprazole is effectively used in enteric coated capsule otherwise the drug will be destroyed in acidic compartment of stomach. The chemical instability and biological activity of omeprazole appears to be associated with behavior of N-H substituent of benzimidazole ring and its transformation to sulfonamide. It was observed that derivatization at N-H position would render omeprazole more chemically stable for storage, handling and formulation for oral and parentral formulation and could make more bioavailable. Many N-H substituted derivatives were synthesized such as N-hydroxy methyl and N-hydroxy ethyl ester, N-carbalkoxy, N-carbaryloxy and N-carbobenzyloxy ester showed greater chemical stability and good in vivo antisecretory, gastroprotective and proton pump inhibitory activity than parent N-H compound. Sih et al. [86] have synthesized 1-(1-ethoxyethyl)-2-(pyridin-2-ylmethylsulfinyl)-1H-benzo[d]imidazole 67 which showed potent antiulcer activity.
Grassi et al. [87] have reported that 2-(2'-benzimidazolyl)-amino-4-methyl-thiazol 68 showed good gastroprotective and antisecretory effect than other standard drugs in many experimental ulcer models. It was thought that the sulphur in thiazole ring may be implicated in gastroprotective action. Kiyoaki et al. [88] have reported the synthesis of 5-methoxy-2-(2-(2,2,6,6-tetramethylpiperidin-1-yl)ethylthio)-1H-benzo[d]imidazole 69 which showed moderate antiulcer activity. Lindberg et al. [89] have reported the synthesis 2-((3,4-dimethoxypyridin-2-yl) methylsulfinyl)-5-methoxy-6-methyl-1H-benzo[d]imidazole 70 which showed potent antiulcer activity and also inhibited gastric acid secretion in dogs. 2-((4-(Difluoromethoxy)-3-methylpyridin-
NH
NS
ON
H3C OCH2CF3
NH
NS
ON
H3C OCH2CH2CH2OCH3
CH3
NH
NS
ON
H3CO OCH3
FH2CO
60 61
62
H3CO
N
NH
SH3C
NCH3
OCH3H3C
OH59
N
CH3H3CO
H3C
SO
NH
N(S)
63
Fig. (8). Well-known antiulcer agents in clinical practice.
1428 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
2-yl) methylsulfinyl)-1H-benzo[d] imidazole 71 inhibited ethanol induced ulcers in rats orally which was studied by Takashi et al. [90].
Lohray et al. [91] have reported the synthesis of 6-fluoro-2-((4-methoxy-3-methylpyridin-2-yl)methylsulfinyl)-5-(piperidin-1-yl)-1H-benzo[d] imidazole 72 showed potent antiulcer activity. Keiji et al. [92] have reported the synthesis of (2-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazol-1-yl)methyl acetate 73 which showed excellent antiulcer, gastric acid secretion inhibitory, mucosa protecting and anti H. pylori effect invivo. This compound also showed low toxicity, high stability to acid, higher absorption rate than enteric preparation and long lasting effect. Carcanague et al. [93] have synthesized 2-(3-((1H-benzo[d]imidazol-2-ylthio)methyl)phenylthio)ethyl phenylcarbamate 74 and 22-(3-((1H-benzo[d]imidazol-2-
ylthio)methyl)phenylthio)ethanol 75 which displayed potent and selective activities against H. pylori. The substitution of hydrogen with sulphur in 3-position of phenyl ring of these structures proved to be beneficial in improving potency. Tolerance was also observed by larger substitution such as isobutyl, -(CH2-CH2-O)3-CH3, -(CH2-CH2-O)5-CH3 and 4-morpholinyl groups.
Michael et al. [94] have 2-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylsulfinyl)-1-(pyridin-3-ylsulfinyl)-1H-benzo[d]imidazole 76 which exhibited proton pump inhibitory activity and was highly effective in treatment of diseases caused by gastric acid secretion. Reddy et al. [95] have synthesized N-(1-(cyclohex-3-enylmethyl) piperidin-4-yl)-6-ethoxy-2-propyl-1H-benzo[d]imidazole-5-carboxamide 77 which exhibited potent antiulcer activity. Shin-ichi et al. have synthesized 9-(1H-benzo[d]imidazol-2-
NH
NN
N
SCH
64
HN
N F
OCH3S
O
NCH3
NH3C
H2C
65
N
NN
N CH3H3C
66
N
NS
ON
O
CH3
H3C
67
S
NHN
HN
N
68
HN
N
OCH3
SN
69
NH
NH3CO
H3CS
ON
H3CO OCH3
70
NH
NS
ON
H3C OCHF2
71
NH
NN
FS
ON
H3C OCH3
72
N
N
SO N
CH3OCH2CF3
O
CH3O
73
NH
N S
S
NH
N SS
OH
OHN
O
74
75
N
N
SO
N
CH3OCH2CF3S
ON
76
NH
N CH3
O
H3C
NH
ON
77
NH
NS
O
H
NO
CH3
78
N
H3CS S N
NN
CH3
SN
NH 79
Fig. (9). Novel benzimidazole derivatives as antiulcer agents.
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1429
ylsulfinyl)-4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 78 which showed potent antiulcer activity and stability on isolated H+/K+-ATPase of rabbit gastric mucosa. Introduction of a rigid ring system was expected to influence a process of chemical transformation in acidic medium to biologically active sulfonamide from parent compound. Kohl et al. [96] have synthesized 2-((3-methyl-4-(3-(4-methyl-4H-1, 2, 4-triazol-3-ylthio) propylthio) pyridin-2-yl) methylthio)-1H-benzo[d]imidazole 79 which showed highly potent antiulcer activity against H. pylori (Fig. 9).
3.4. Anti-inflammatory Activity
Control of the inflammation has significant importance due to its association with many diseased states like Alzheimer’s disease, diabetes mellitus, carcinoma, asthma, atherosclerosis, Crohn’s disease, gout, multiple sclerosis, osteoarthritis, psoriasis, rheumatoid arthritis, bacterial or viral infections, etc. that results in chronic inflammation [97, 98]. Inflammation control includes inflammatory mediators like plasma proteases, serotonin, nitric oxide, interleukins 1–16 (IL-1 to IL-16), tumor necrosis factor-� (TNF-�), chemokines (CXC, CC and C subsets), prostaglandins, leukotrienes, histamine, and colony stimulating factors (CSF) [99-101]. They are produced through various processes involving cyclooxygenases, caspases and kinases like kinase insert domain receptor (KDR), lymphocyte specific kinase (Lck), cyclin dependent kinases (CDK1 and CDK5), interleukin receptor associated kinase 4 (IRAK-4), Janus kinases (JAK1- JAK3 and Tyk2), spleen tyrosin kinase (Syk), mitogen activated protein kinase 38 (MAP38), c-Jun N-terminal kinase (JNK), serine threonine kinases (IKK1 and IKK2), and TNF-� kinase (TNFK) [102, 103].
Inhibition or blockage of the inflammatory process at one or the other stage is occurs mainly by many chemical entities derived from diverse group of heterocyclic nuclei. The discovery of anti-inflammatory compounds derived from benzimidazole nucleus is as old as the age of modern medical chemistry. Various benzimidazole derivatives having well to excellent anti-inflammatory activity is reported by many research groups but no such molecule has made its way to the clinics so far. A number of compounds targeting the kinases are currently undergoing clinical trials related to inflammation and autoimmunity [104].
2-Substituted benzimidazole with different moieties such as (4-isobutyl phenyl) ethyl, (6-methoxy naphthyl ethyl) and (3-benzoylphenyl ethyl) have shown anti-inflammatory activity [105]. It was reported that the non-steroidal anti-inflammatory drugs showed their activity to the inhibition of cyclooxygenase and the consequent reduction in the formation of thromboxane and prostaglandins, little interest was shown in other oxidative pathways [106]. Slow reacting substance of anaphylaxis (SRS-A) as a mixture of the leukotrienes LTC4 and LTE4, LTB4 a potent chemotoxin that focused attention on the 5-lipooxygenase pathway of arachidonic acid metabolism which increase awareness of the arachidonic acid cascade and the enzyme involved. It leads to the development of novel 1H-2-substituted benzimidazole-4-ols with potent 5-lipooxygenase inhibitory activity. In the series of 7-methyl-1H-benzimidazole-4-ols
80, compound 81 having constituent as (R=C6H5) showed potent inhibition of 5- lipooxygenase in vitro [107].
Achar et al. [108] have synthesized a series of 2-methylaminobenzimidazole derivatives N-((6-bromo-1H-benzo[d]imidazol-2-yl)methyl)-4-chlorobenzenamine 82 and N-((1H-benzo[d] imidazol-2-yl)methyl)benzenamine 83.These compounds were screened for analgesic and anti-inflammatory activities which showed potent activity compared with nimesulide. 2-Substituted benzimidazole derivatives 84-87 were synthesized by the condensation of o-phenylenediamine with 2-coumaranonyl acetic acid derivatives and indole 3-acid and evaluated their anti-inflammatory and analgesic activities. They were founded significant anti-inflammatory activity at 50 mg/kg dose [109].
New synthesis and their anti-inflammatory activity of a group of 1H-benzimidazole 88-91 were also synthesized [110]. The compounds were tested on rat adjuvant arthritis screen using indomethacin as standard compound. The result gave 30% or greater reduction in non injected paw volume compared to control together with the result for indomethacin. Mohan et al. [111] have synthesized 1-[2,3-(2-Phenylbenzimidazole)]2-methyl/phenyl-4-(3,4-disubstituted benzylidine)-5-oxoimidazoles derivatives 92 and 93 by condensing 2-(2/3-aminophenyl) benzimidazoles with appropriate 2-methyl/phenyl-4-(3,4-disubstituted) oxazoline-5-ones in dry pyridine and screened anti-inflammatory activity against carrageenan induced oedema. Gaba et al.[112] have synthesized a series of novel 5-substituted-1-(phenylsulphonyl)-2-methylbenzimidazole derivatives 94.These compounds were evaluated for their anti-inflammatory and analgesic activities as well as gastric ulcerogenic effects by carrageenan- induced rat paw edema and acetic acid-induced writhing in mice using indomethacin as standard.
A series of 2-(2-pyridinyl)benzimidazoles were synthesized by Pharmaceutical Research Centre at Kanebo Ltd (Japan) based on the moderate anti-inflammatory and analgesic activities of thiabendazole by the isosteric replacement of thiazole ring in the lead [113-115]. From a series of 55 compounds, 2-(5-ethyl-2-pyridinyl)benzimidazole (KB-1043 95) was found to be potent anti-inflammatory, analgesic and antipyretic activities better than phenylbutazone and tiaramide. It has gastrointestinal irritation slightly less and therapeutic index 2-3 times better than the reference compounds. Hosamani et al. [116] have synthesized novel 2-(substituted phenyl) aminomethyl benzimidazoles and evaluated using carrageenan-induced paw edema model. The compound 96 is the emerged as potent compound (81.0% protection) and the activity is further improved (89.0% inhibition) by placement of bromo group at 6-position 97.
The design of 2-methyl-N-substituted benzimidazole with varied sugar moieties 98 have been reported to have significant anti-inflammatory activity dependent on the kind and the linked-position of the sugar conjugated to the nucleus [117]. Many research groups have developed novel anti-inflammatory drugs by substituting at 2- and 5- positions. Dunwel et al. [118] have synthesized compound 100 by bioisosteric replacement of benzoxazole nucleus with benzimidazole by taking benoxaprofen 99 as lead compound
1430 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
which have not reduced the inflammation in rat paw edema model probably due to lower solubility or altered drug receptor interactions. They have also synthesized an exhaustive series of 72 benzimidazole derivatives and tested on rat adjuvant arthritis screen [119]. Only two compounds (101 and 102) have been found to exhibit activity comparable to indomethacin. VUF6002 104 is the 2,5-disubstituted benzimidazole compound designed by taking JNJ7777120 103 as lead [120]. It exhibits potent anti-inflammatory and antinociceptive effects in paw edema and hyperalgesia models. However, contrary to the importance of amino group at 2-position of the nucleus, another related benzimidazole derivative VUF6007 105 does not show any such activity [121]. Avanir Pharmaceuticals has synthesized AVP 13358 106 having an amide linker as a potent anti-IgE
which is useful in various inflammatory conditions (Fig. 10)[122].
3.5. Anticancer Activity
Cancer is the leading problem affecting a wide majority of world health population. Anticancer agents are also known as antitumor, antiproliferative and antineoplastics which are reported for the treatment of different kinds of cancers acting through different mechanisms. Cytotoxicity is the major side effect associated with different anticancer agents towards normal cells due to the lack of selectivity for the abnormal cells. Benzimidazole is the isostere of purine based nucleic acid and an important scaffold in various biologically active molecules which is widely explored for the development of novel anticancer agents [123].
Fig. (10). Novel benzimidazole derivatives as anti-inflammatory agents.
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1431
Benzimidazole nucleus is mostly studied as an important structure as an anticancer or antineoplastic agent. Importance is only given at the various substitutions at different positions in the moiety. The cyclin-dependent kinase (CDK) families are two groups of serine threonine protein kinases with roles in the coordination of the eukaryotic cell cycle and transcriptional regulation. Because of their critical role in the regulation of the cell cycle and the observed expression/ activity pattern in most human cancers, considerable effort has been focused on the development of small molecule CDK cell cycle inhibitors as potential therapeutic agents [124].
Incorporation of a basic group into CDK imidazole pyrimidine amide inhibitor series offered the best opportunity to achieve the CDK inhibitor properties. Imidazolesulfone AZD5438 107 was investigated further as an orally bioavailable anti-cancer agent. Replacement of the sulfone with piperazine led to a novel series of potent CDK inhibitors 108 with improved physical properties that were also suitable for oral dosing [125]. Many secondary amides, like the 5-fluoro pyrimidine ortho-fluoro amide substitution gives the highest levels of enzyme potency against both CDK1 and CDK2, this highly potent CDK1/2 inhibition resulted in extremely potent inhibition of cellular proliferation in cancer cell lines. The chiral, non-racemic pyrrolidines (both S and R forms) also displayed excellent potency against CDK1 and CDK2, again with potent anti-proliferative activity. In contrast to the piperazine amides, the corresponding homopiperazine 109 gave much improved properties with significant increases in both enzyme and cellular potency. The increased basicity of the homopiperazine also resulted in much improved solubility which altogether proved to be potent in vitro anti-proliferative effects against a range of cancer cell lines [126]
Many indole -imidazole compounds also formed that demonstrated substantial in vitro antiproliferative activities against cancer cell lines including multi-drug resistance (MDR) phenotypes, prolonged treatment of cancer cells with certain drugs can result in an acquired resistance of these cells toward multiple drugs [127]. The in vitro cytotoxic effects have been demonstrated across many tumor types, including hematological and solid tumor cell lines of various origins (e.g., leukemia, breast, colon, and uterine). MDR is also associated with an over expression of ATP binding cassette (ABC) transporters [128]. Other mechanisms believed to be associated with MDR in cancer cells includes increased expression of antiapoptotic genes and decreased expression of proapoptotic genes, [129] over expression of specific tubulin isotypes, [130] decreased expression of topoisomerases [131] and overexpression of major vault protein [132]. Various strategies have been employed to overcome MDR, the most common being inhibition of P-gp and related proteins to effectively block the efflux of the drug [133]. Numerous MDR reversal agents have been reported but most have undesirable side effects such as toxicity, but indole -imidazole moiety have shown considerable against the cell lines including MDR phenotypes via various substitutions at different positions. Substitution with a 2-pyridyl group in compound 110produces potent anticancer activity. When a conjugated
ketone group is introduced activity is maintained by compound 111. Another compound 112 with methyl ester substitution displayed strong cytotoxicity against the Taxol-resistant HL60/TX1000 cell line. The indolepyridoimidazole compound showed a 10-fold increase in potency compared to any of the indole-imidazole derivatives 110, 111, 112 [134, 135].
The 3,4-methylenedioxy analog was found to be the most potent FTase inhibitor in the series of substituted 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole compounds, consequently having more than 15,000-fold selectivity in favor of FTase inhibition and Ras processing. This analog has oral bioavailability of 11.3% in rat compared with the complete lack of bioavailability observed in the other analogs of the series of 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole. Studying the various analogs, it was observed that analogs having the ether linkage possessed potent inhibitory activities against the FTase enzyme. The highest selectivity for FTase inhibition over GTase-1 was observed in compound 113. This compound is more potent in inhibition of FTase enzyme and possesses better selectivity. It also has reasonable bio-availability [136].
It was observed that a 3, 4, 5-trimethoxyphenyl ring 114was essential for potent antitumor activity. A trimethoxyphenyl group is considered a structural feature typical for inhibitors of tubulin polymerization [137]. Many other amino substituted xantheno[1,2-d]imidazoles derivatives had also been synthesized with cell growth inhibitory activity specifically against breast cancer cell lines, insertion of two basic side chains at 2- and 5- positions in this moiety, exhibited a strong dose-dependent antiproliferative activity [138]. Again some specific moiety like 5-Arylamino-1H-benzo[d]imidazole-4,7-diones were synthesized for their inhibitory activities on the proliferation of human umbilical vein endothelial cells (HUVECs) and the smooth muscle cells (SMCs). Among them, several 1-H benzo[d] imidazole 4, 7-diones exhibited the selective antiproliferative activity on the HUVECs [139].
Gellis et al. [140] have synthesized benzimidazole-4, 7-diones substituted at position-2 via a microwave-assisted reaction using 2-chloromethyl- 1,5,6-trimethyl-1H-benzimidazole-4,7-dione. Anticancer activity has been evaluated on colon, breast and lung cancer cell lines. Among this 2, 20 bis(chloromethyl)-1,10-dimethyl- 5,50-bi(1H-benzimidazole)-4,40,7,70-tetraone 115 was shown to possess very potent cytotoxicity comparable to that of mitomycin C. Sondhi et al. [141] have synthesized various heterocyclic benzimidazole derivatives 116-119 by the condensation of succinic acid, homophthalic acid and 2, 3-pyrazinedicarboxlic acid with various substituted diamines under microwave irradiation. These compounds were evaluated for anticancer activity at 50 mg/ kg po exhibit potent anticancer activity against ovary (IGROV- 1), breast (MCF-7) and CNS (SF-295) human cancer cell lines. Demirayak et al. [142] have synthesized some 1-methylene-2,3-diaryl-1,2-dihydropyrazino [1,2-a]benzimidazoles derivatives 120 and 1-(2-arylvinyl)-3-arylpyrazino[1,2-a]benzimidazole derivatives 121 and their anticancer activity was reported. It can be seen that for all the compounds, log10GI50 values are smaller than -4. Melphalan cis-
1432 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
diaminodichloroplatinum, one of the chemotherapeutic agents, was used as standard compound.
Refaat [143] have synthesized 2- [(4-oxothiazolidin-2-ylidene)-methyl 122, (4-amino-2- thioxothiazol-5-yl) benzimidazoles derivatives 123, 2-[(4-fluorobenzylidene derivatives 124 and cycloalkylidene)-cyanomethyl] benzimidazoles derivatives 125 was carried out. All the synthesized compound were evaluated against three cell lines representing three common forms of human cancer i.e. human hepatocellular carcinoma cell line (HEPG2), human breast adenocarcinoma cell line (MCF7) and colon carcinoma cell line (HCT 116). Shaharyar et al. [144] have synthesized 2-{5-[(substituted) phenyl]-4,5-dihydro-1H-3-pyrazolyl} 1H-benzoimidazole 126 and 2-{5-[(substituted)phenyl]- 1-phenyl-4,5-dihydro-1H-3-pyrazolyl}-1H-benzimidazole 127 (Fig. 11). They were screened at the National Cancer Institute (NCI), USA for anticancer activity at a single high
dose (10 �M) in full NCI 60 cell panel. Among the selected compounds, 2-[5-(3,4-dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-1H benzimidazole was found to be the most active candidate of the series and selected for further evaluation at five dose level screening.
Thimmegowda et al. [145] have synthesized a novel series of trisubstituted benzimidazole and its precursors. The title compounds were evaluated for inhibition against MDA-MB-231 breast cancer cell proliferation. The results stated that the compound 1-(4-fluorobenzyl)-N-(4-cyano-3-(trifluoromethyl) phenyl)-2-(2,4-dichlorophenyl)-1H benzo[d]imidazole-5-carboxamide 128 was the potent inhibitor against breast cancer cells. Yusuf Ozkay et al. [146] have synthesized many novel imidazole-(Benz) azole and imidazole epiperazine derivatives 129-131 in order to determine the anticancer activity. Anticancer activity screening results revealed that these were the most active
Fig. (11). Novel Benzimidazole derivatives as novel anticancer agents.
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1433
compounds in the series. Cisplatin was used as reference drug. Cenzo congiu et al. [147] have synthesized a series of 1, 4-diarylimidazole-2(3H)-one derivatives and their 2-thione analogues. They were evaluated for antitumor activity. Compound 132 was found to be most potent for antitumor activity.
Cleavages of G and A bases and reductive alkylation of DNA is the novel mechanism of pyrrolo[1,2-a] benzimidazoles 133-135 [148-152]. Substituted benzimidazole derivatives 136-138 are reported as cytotoxic against lung and breast cancers [153, 154]. Ramla et al. [155] have synthesized some 2-(substituted quinolinon-3-yl) benzimidazoles as serine/threonine checkpoint kinase (CHK-1) inhibitors for the treatment of cancer. Compound 139 was reported as potent compound with subnanomolar IC50 value. Neff et al.[157] have synthesized another series 140 of CHK-1
inhibitors but all compounds are found to have inhibitory activity significantly less than that of 139 [156]. 2-Aminobenzimidazole derivatives have been synthesized by taking SNS-314 141 as lead which is in clinical trials for anticancer use and compound 142 is found as potent aurora kinase inhibitor [158]. Novel researches on 2-substituted benzimidazoles have stated various heterocycles at 2-position to yield potent anticancer agents active against various carcinoma cell lines. These include pyrimidine derivatives 143 [159], pyrazoline derivatives 144 [160] and thiazole derivatives 145 [161]. 2-Substituted benzimidazoles with chloro or carboxy group at 5-position having 4-amino-thioxothiazole 146, 4-oxothiazolidine 147, 4-fluorobenzylidene 148 and cycloalkylidene are the potent antitumour agents (Fig. 12 I) [143].
N
NCl
Cl
F
NH
ONC
CF3
128
N
N
CH3
NH
O S R
N
N
N
CH3
NN N
N
CH3
N
S
N
H3C129 R = 130 R = 131 R =
N NH
OCl
OCH3
OCH3H3CO
132
X
O
R1
H3C N
NR2
133 X = O, R1 = , R2 = CH3134 X = O, R1 = NHCOCH3, R2 = Ester function135 X = NH, R1 = NHCOCH3, R2 = Ester function
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Hoechst-33342 149 [162, 163] and Hoechst-33258 150[164-166] are the novel compounds exhibited in vitro antitumor as well as DNA topoisomerase I inhibitory activities. Bis-benzimidazole is the novel class of compounds exhibited for discovery of anticancer agent. Natural products UK-1 151[167], AJI9561 152 [168] and subsequent similar derivatives [169, 170] are synthesized based on cytotoxic activities of bis-benoxazole. Huang et al. [171] have synthesized benzimidazole isosteres amongst which 153 is found as the most potent anticancer synthetic precursor of bis(benzimidazoles) against human A-549, BFTC 905, RD, MES-SA and HeLa carcinoma cell lines. Benzimidazolyl-1,2,4-triazino[4,5-a]benzimidazol-1-one 154 is another bis(benzimidazole) analog having significant activity against multidrug-resistant P-glycoprotein expressing cell lines [172]. Two benzimidazole nuclei linked through a thiophene ring have displayed moderate to strong antiproliferative effect toward a panel of eight carcinoma cell lines. The most active compound 155 of the series is reported to enter into live HeLa cells within 30 min, but did not accumulate in nuclei even after 2.5 h [173].
Taking Hoechst-33258 150 (a head-to-tail bis-benzimidazole wherein benzo ring a benzimidazole nucleus is connected to the imidazole ring of the other nucleus through a bond) and a head to- head bis-benzimidazole 156,wherein two benzimidazole nuclei are connected at either their benzo or imidazole rings through a bond as leads, Yang et al. [174] have synthesized series of symmetrical head-to-head bis-benzimidazoles and found 157 to possess good antitumour activity. Singh et al. [175] have modified Hoechst-33258 to synthesize another series of head-to-tail bis-benzimidazole bearing aryl group at 2-position. The derivatives bearing electron withdrawing groups like F 158and Cl on the aryl ring exhibited potent anticancer activity over the compounds having electron releasing groups (Fig. 12 II).
3.6. Antiprotozoal Activity
Mavrova et al. [176] have synthesized Thieno[2,3-d]pyrimidin-4(3H)-ones containing benzimidazol-2-yl-thioethyl- and benzimidazol-2-yl-methanethioethyl moiety in the second position of the pyrimidine ring for the
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1435
antitrichinellosis and antiprotozoal activities. The benzimidazole derivative 2-(2-(1H-benzo[d]imidazol-1-yl)ethyl)-5,6-dibutylthieno[2,3-d]pyrimidin-4(3H)-one 159exhibited potent activity against Trichinella spiralis in vitroin comparison to albendazole. The most potent compound 5, 6-dibutyl-2-(2-(1-nitro-1H-benzo[d]imidazol-2-ylthio) ethyl) thieno [2, 3-d] pyrimidin-4(3H)-one 160 revealed 95% activity at a dosage of 5 mg/kg. The compound 2-{2-[(5(6)-nitro 1H-benzimidazol-2-yl)thio]ethyl}-5,6,7,8-tetrahydro[1]- benzothieno[2,3-d]pyrimidin-4(3H) one exhibited 90% efficacy. Gomez et al. [177] have synthesized novel series of hybrids from pentamide 161 and pentamidine 162 were synthesized. Each compound was tested in vitro against the protozoa Trichomonas vaginalis, Giardialamblia, Entamoeba histolytica, Leishmania Mexicana and Plasmodium bergheiand were compared with metronidazole.
Ismai et al. [178] have synthesized biphenyl benzimidazoles diamidines 163 from their respective diamidoximes through the bis-o-acetoxyamidoxime followed by hydrogenation. The target compounds contain hydroxy and/or methoxy substituted 1, 3-phenyl groups as the central
space between the two amidino bearing aryl groups. These compounds have performed DNA binding studies [�Tmvalues for poly (dA.dT)2] and in vitro evaluation against Trypanosoma b. rhodesiense (T.b.r.) and P. falciparum for the diamidino biphenyl benzimidazoles. Kopanska et al.[179] have synthesized chloro-, bromo- and methyl-analogues of 1H-benzimidazole 164-167, 1H-benzotriazole and their N-alkyl derivatives 168-171 and evaluated in vitroagainst the protozoa Acanthamoe bacastellanii. It was found that 5, 6-dimethyl-1H benzotriazole and 5, 6- dibromo-1H-benzotriazole have higher efficacy than the antiprotozoal agent chlorohexidine. Vazquez et al. have [180] synthesized derivatives of 2-(tri-fluoromethyl)benzimidazole 172substituted at the 1-, 5- and 6- positions and tested in vitroagainst the protozoa G. lamblia, E. histolytica and the helminth T. spiralis. These tested compounds are more active as antiprotozoal agents than albendazole and metronidazole. Compound 173 was found more active as albendazole against T. spiralis. These were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.
Fig. (13). Novel benzimidazole derivatives as antiprotozoal agents.
1436 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
Vazquez et al. [181] have synthesized 2-(trifluoromethyl)-1H-benzimidazole derivatives 174 with various bio-isosteric substitutents (-Cl, -F, -CF3, -CN) and tested in vitro against G. intestinalis and T. vaginalis using albendazole and metronidazole. Some analogues had IC50values <1 �M against both species, which make them more potent than standard drug. Kazimierczuk et al. [182] have synthesized thio-alkylated and thio-arylated derivatives of benzimidazole 175 and evaluated as antiprotozoal activity against nosocomial strains of S. malthophilia using metronidazole as standard. Compounds 4, 6,-dichloro-2-(4-nitrobenzylthio)-benzimidazole showed highly potent antiprotozoal activity (Fig. 13).
3.7. HIV Inhibitors
Tetrahydro-imidazo[4,5,l-jk] [1,4]-benzodiazepin-2(1H)one (TIBO) is a non-competitive and non-nucleotide antiretroviral drug with a specific allosteric binding site of HIV-1 RT. TIBO derivatives are highly potent, selective and specific inhibitors of HIV-1 replication in vitro. Reverse transcriptase (RT) of HIV-1, but not HIV-2, is mostly inhibited by the TIBO compounds. Some compounds other than TIBO are recently been reported to specifically inhibit HIV-1 replication. It was reported that some novel benzimidazole derivatives have been synthesized bearing analogy to TIBO and were evaluated for inhibition of HIV-1. The most active and selective compounds are a series of N-alkoxy-2-alkyl-benzimidazoles having EC50 < 10�� and selectivity ratio of 10–167. The selective benzimidazoles 176-179 showed potent RT inhibition (Fig. 14) [183].
3.8. Anticonvulsant Activity
1,2,5-Trisubstituted benzimidazoles 180-182 are synthesized as potential anticonvulsant agents (Fig. 15). The results of QSAR investigation and the study of various physicochemical properties indicates that the change in linker at position one (R1) does not change the activity of the synthesized compounds and optimum chain length at position two (R2) is responsible for the anticonvulsant activity. The results also showed that the synthesized compounds with electron withdrawing group such as nitro at position five (R3) have been reported to possess potent anticonvulsant activity as predicted by QSAR studies [184].
3.9. Antitubercular Activity
Shingalapur et al. [185] have synthesized series of novel 5-(nitro/bromo)-styryl-2-benzimidazole derivatives 183-186and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. These compounds showed potent antitubercular activities using streptomycin as
reference drug. Gupta et al. [186] have described antimycobacterium tuberculosis activities of ring substituted-1H-imidazole-4-carboxylic acid derivatives and 3-(2-alkyl-1H-imidazole-4-yl)-propionic acid derivatives against durg-sensetive and durg-resistent M. tuberculosis strains. Compounds 187 and 188 are reported as most potent antitubercular agents against M. tuberculosis H37Rv. Jyoti etal. [187] have synthesized a series of imidazole derivatives and compounds were screened against M. tuberculosis. Compound 189 showed potent antitubercular activity (Fig. 16).
N
N
R1
O2NR2
R1 = PicolineR2 = Varying alkyl chain
180
N
NR
N
R = H, CH3, C2H5, C3H7, C4H9,
181
N
NR
N
O2N
182
Fig. (15). Novel benzimidazole derivatives as anticonvulsant agents.
NH
NR R1
183 R = Br, R1 = H184 R = Br, R1 = 3,4-OCH3185 R = Br, R1 = 4-CH3186 R = Br, R1 = 2,4-Cl
NH
N
O
OC2H5
R1
R2
187 R1 = R2 = C5H9188 R1 = R2 = C6H11
N N
NN
C3H7
189
Fig. (16). Novel imidazole derivatives as antitubercular agents.
3.10. Antidepressant Activity
Novel moclobemide analogues were synthesized by replacing moclobemide phenyl ring with substituted imidazole. They were studied for the antidepressant activity using forced swimming test. Compounds 190-192 were found to be more potent than moclobemide (Fig. 17) [188].
N
N
O
HNN O
SR
190 R = CH3191 R = C2H5192 R = CH2-C6H5
Fig. (17). Novel imidazole derivatives as antidepressant agents.
N
N SCH3
N
CH3
CH3
CH3
Ts
176
NN
SH3C
H3CHN
CH2
177
N
N X
O X
X = Vinyl, Aryl
N
N
O CH3
CH3
178 179
Fig. (14). Novel benzimidazole derivatives as HIV inhibitors.
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1437
3.11. Antilishmanial Activity
Bhandari et al. [189] have synthesized a series of substituted aryloxy alkyl and aryloxy aryl alkyl imidazoles 193-198 (Fig. 18). They were evaluated in vitro as antileishmanial against Leshmania donovani. These compounds exhibited 94-100% inhibition.
O
N
N
R3
RR1
R2
R R1 R2 R3
193 C6H5 H CF3 H194 CH3 H CF3 H195 CH3 H NO2 H196 CF3 F NO2 H197 CH3 NO2 H H198 CH3 CH3 NO2 H
Fig. (18). Novel imidazole derivatives as antilishmanial agents.
3.12. Antihypertensive Activity
Bezimidazole derivatives act as antihypertensive agents by intercepting with Renin–Angiotensin System (RAS). Angiotensin II (Ang II) is active pressor produced by RAS cascade. Angiotensinogen is cleaved by rennin to produce a decapeptide, Ang I, which is further acted upon by Angiotensin Converting Enzyme (ACE) to generate Ang II. It significantly acts on angiotensin receptor 1 (AT1) and results in vasoconstriction, Na+ retention and aldosterone release to cause hypertensive action. Therefore, many research and development activities on producing antihypertensives have been targeted towards development of AT1 receptor blockers [190]. One of the first reports discloses 2-butyl benzimidazole-7-carboxylic acid derivative 199 as a potent AT1 receptor antagonist [191]. Biphenyl benzimidazole derivatives are the potent antihypertensive agents as compared to related drugs due to better availability upon the oral administration and 2-position of biphenyl is essential for the antihypertensive activity [192]. 5-Substituted aryl or alkyl caboxamido derivatives have reported to possess Angiotensin-II AT1 receptor antagonistic activities which are the potent antihypertensives agents [193].
CV-11974 200 was synthesized by the lead optimization of the functional groups around the benzimidazole nucleus which reduces blood pressure in dose-dependent manner by blocking AT1 receptors in a non competitive manner due to slow dissociation from AT1 receptors [194-196] which is more active than losartan and EXP3174 [197]. Esterification of 7-carboxyl group is involved in the discovery of orally active and long acting AT1 receptor blocker, candesartan and cilexitil 201 [198-202] which has research base activities to explore all the seven positions of the benzimidazole nucleus by various research groups to develop more potent compounds. It was found that the position-4 must remain unsubstituted for favorable interaction of N-3 of the benzimidazole nucleus with H-bond donor site in AT1receptor while a position-1 is reserved for biphenyl moiety. Compounds 202-205 are synthesized by the replacement of biphenyl moiety with other moieties which has produced higher potencies [203-207].
The position-5 of benzimidazole nucleus can be substituted using various substitutents like nitro, amino, alkylcarboxamido, alkyl/arylsulfonamido 206 and it was reported that a group of optimum size and hydrophilicity increases the antihypertensive activity significantly [208-210]. Sartans are synthesized by replacing various substituents at 2-, 5- and 6-positions in tetrazolylbiphenyl or carboxylbiphenyl substituted benzimidazole. These compounds were evaluated using invasive and non-invasive Ang II induced hypertension models and in vitro model for determination of vasodilator activity. Compounds 207-210are found to reduce the mean arterial blood pressure equivalent to losartan [211-218]. Estrada-Soto et al. [219] have synthesized a series of benzimidazole derivatives bearing substituted phenyl ring at 2-position and various substituents (–H, –CH3, NO2, –CF3) at 5- and 6- positions. They were tested in vitro for vasodilatation activity using rat aorta ring test. Compound 211 is identified as the most potent compound of the series, showing IC50 of 0.95 (with endothelium) and 2.01 �M (without endothelium). 2,5-Disubstituted benzimidazole derivatives represented by compound 212 have been reported as inhibitors of factor Xa and hence useful in thromboembolic disorders (Fig. 19). Many structural features of benzimidazole derived AT1receptor antagonists can be summarised as in Fig. 20 [220].
Naka et al. [221] have synthesized benzimidazole derivative 213 which have shown highly potent antihypertensive activity. Compound 214 was synthesized and evaluated for nonpeptide angiotensin II receptor antagonist for potent antihypertensive activity (Fig. 19) [222].
3.13. Antioxidant Activity
Cole et al. [223] have reported 5-hydroxybenzimidazole and 5-hydroxy-2-methylbenzimidazole as potent antioxidants. The drugs having antioxidant and free radical scavenging activity are used in the treatment of various diseases which are related to lack of antioxidant capacity of organism. Substitution of thiadiazoles, triazoles and thiosemicarbazides at position-1 of benzimidazole increases antioxidant activity. Various aryl and alkyl substituents on these hetero nuclei at position-1 also yielded potent antioxidants 215-217.Semicarbazide derivatives produced stronger inhibitory effects on lipid peroxidation levels as well as DPPH model [224, 225].
Cyclization of dialkylaminoethyl at position-1 to 4-substituted piperazines and piperidines 218 are synthesized for antioxidant activity [226]. Monodentate and bidentate ligands are derived from Cu2+ and Co2+ co-ordination compounds with 2-substituted benzimidazoles for NO scavenging and superoxide dismutase activity from which compounds 219 and 220 have shown significant NO scavenging (IC50 65 �g/ml) and potent dismutase (IC50 0.26 �M) activities respectively [227]. Schiff’s bases of benzimidazole 221 have been found to produce high lipid peroxidation inhibitory activity which increases with lipophilicity and compound 222 was found to be most potent antioxidant amongst the series [228]. 4-Carboxamidobenzimidazole analog 223 is identified to possess potent hydroxyl radical scavenging property through poly (ADP-Ribose) polymerase (PARP) inhibition (Fig. 21) [229].
1438 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
N
NR
COOH
NN
NHN
199 R = nC4H9200 R = OC2H5
N
NO
NN
NHN
CH3
OOO O
CH3O
201
N
N
CH3
R
202
N
N
SO3H
OCOOH
COOH
203
N
NR
NO
NH
O
OOO
O
O
204
N
N
CH3
COOCH3
N
NHN
NN
205
N
N
CH3
R
HOOC
206
(R = NO2, NH2, NHCOR, SO2NHR)
N
N
NH
NN N
NH
Cl
Cl
207
N
NN
NN N
NH
F
O2N
R
Cl
O
208
N
N
NN N
NH
Cl
H2N
N
R
209
N
N
CF3
BrCOOH
H3C
210
N
NH
NO2
OH
211
N
NH2N
HOOC
213
NN
NH2
HOOC
NH2
214
N
HN
S ClNH
ON
O
O
212
Fig. (19). Novel benzimidazole derivatives as antihypertensive agents.
N
N
ArAr Acidic function
UnsubstitutedBulky lipophilic groups with H-bonding capabilities
Short lipophilic or electronic group
COOR
C3-C4 linear or branched alkyl or alkoxy chain
Fig. (20). Features of Angiotensin I receptor antagonist for antihypertensive activity.
3.14. Antidiabetic Activity
The goal of treatment of non-insulin dependent diabetes mellitus (NIDDM) is controlling the levels of blood glucose. High blood pressure due to insulin resistance and relative
insulin deficiency is observed in diabetic mellitus. The sodium-glucose co-transporters (SGLTs) in the proximal tubules are required for the glucose re-absorption in the intestine (SLGT1) and kidney (SLGT2). Therefore, it
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1439
provides novel target for treatment of NIDDM through inhibition of renal glucose reabsorption and phlorizin was found as a natural SLGT2 inhibitor [230].
N
N
O
HN NH
NHAr/R
S
N
N
NN
S
HN
R/Ar
N
N
NHN N Ar/R
S
215 216 217
N
N NN
NCH3
NHN NHNCoCl
Cl
N
HN
N
XCuCl Cl
N
HN
N
H3CN
NN
O N
NH
CONH2
HN
218 219 220
221 222 223
Fig. (21). Novel benzimidazole derivatives as antioxidant agents.
Glucagon receptor (GCGR) was found as novel target for designing antidiabetics. Zhang et al. [230] have synthesized structural analogs of phlorizin and found a benzimidazole analog 224 to exhibit potent SGLT2 inhibitory activity. Kim et al. [231] have synthesized various derivatives of aminobenzimidazole as GCGR antagonists. Compound 225was found as orally efficacious inhibitor of glucagon-mediated glucose production in mice and rhesus monkeys at an oral dose of 3 mg/kg. Its chronic oral administration to mice with high-fat diet induced hyperglycemia caused significant reductions in blood glucose levels. Glucose Kinase (GK) activators catalyze reaction of glucose to glucose-6-phosphate and GK activation in liver increases hepatic glucose utilization. Modification of novel 2-(pyridin-2-yl)-1H-benzimidazole leds to discovery of highly potent and stable GK activator 226 which demonstrated glucose lowering efficacy in a dose-dependent manner at 3 mg/kg (Fig. 22) [232, 37].
N
N
O
OO
HO OHOH
HO
N
N
F3C
CH3
N
O
HNNH
NNN N
NH
N O
S OO
CH3
N
CH3
O224 225 226
Fig. (22). Novel benzimidazole derivatives as antidiabetic agents.
3.15. Anticoagulant Activity
Thrombin causes the proteolytic cleavage of fibrinogen and induces platelet activation which triggers a wide range of
effects secondary to thrombosis. For example, vascular smooth muscle cell and fibroblast proliferation, monocyte chemotaxis and neutrophil adhesion, etc. Benzimidazole nucleus is used as an appropriate template to place the various substitutents required for interaction with thrombin and inhibition of thrombin causes inhibition of coagulation [233].
Hauel et al. [233] have synthesized a series of benzimidazole derivatives. BIBR 953 227 has potent inhibitory potency and tolerability. Its double prodrug BIBR 1048 228 has exhibited good pharmacokinetic properties and is in clinical evaluations. 1, 2-Disubstituted benzimidazole derivatives 229 has basic amine moieties which have been reported as active site directed thrombin inhibitors [234]. Berlex Biosciences have reported tetrasubstituted benzimidazole with naphthylamidine group at position-1 230 as anticoagulant due to factor Xa (fXa) inhibition. Activity was found as independent of the substituent at C-2 where as substitution of a nitro group at 4-position on the benzimidazole template gives potent fXa inhibitors with thrombin selectivity [235]. However, simplification of the naphthylamidine group to yield a propenylbenzene group dramatically improved the potency and selectivity over the unsubstituted naphthalene analogues. Replacing the naphthylamidine with differently substituted biphenylamidines caused a disappointing change in in vitro profile. [236].
Ueno et al. [237] have reported the SAR studies of benzimidazole derivative 231 as potent and selective factor Xa inhibitors having potent anticoagulant activity with no fatal acute toxicity. The research group at Celera Genomics have designed and optimized compound 232 as safe anticoagulant but having less residence time due to excessive glucuronidation. Inhibitor of factor VIIa/Tissue Factor complex is used for the treatment of thromboembolic diseases. Further research into the compounds led to the development of selective dicarboxylic acid analog 233 with pharmacokinetic profile amenable to once daily subcutaneous dosing in humans (Fig. 23) [238].
3.16. Miscellaneous Activities
Bayer Yakuhin have synthesized different benzimidazole derivatives as luteinizing hormone-releasing hormone (LHRH) or gonadotropin releasing hormone antagonists. Initially, 1-benzyl-2-ethylsulfanyl-1H-benzimidazole-5-sulfonamide 234was reported as functional LHRH antagonist with micromolar range potency [239] and other related series of compound 235 was identified in nanomolar doses [240]. It was reported that the presence of phenyl group at 2-position, t-butylurea at position-5 and small alkyl groups at position-1 produced a potent LHRH antagonist 236 [241]. Pelletier et al. [242] have synthesized 2-phenyl-4-piperazinylbenzimidazoles as GnRH antagonists with nanomolar potency (237, IC50 1.7 nM) in in vitro binding and functional assays as well as highly potent bioavailability.
A series of compounds synthesized by substitution of small heterocycles to the 2-(4-tert-butylphenyl)-4-piperazinylbenzimidazole template, two imidazole analogs, 238 and 239, have shown to possess in vitro potency at the target receptor (hGnRH IC50 7 and 18 nM, respectively) as
1440 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 Barot et al.
well as aqueous solubility (55 and 100 �g/mL at pH 7.4, respectively). Both are reported and optimized to have good oral bioavalaibility [243]. Terefenko et al. [244] have synthesized a series of novel 6-phenyl benzimidazolones, compound 240 to exhibite potent progesterone receptor (PR) antagonist activity in T47D cell alkaline phosphatase assay. Zhang et al. [245] have reported the replacement of phenyl ring at the 5(6)-position of benzimidazole by pyrrole yielded potent progesterone antagonist 241 with less selectivity towards glucocorticoid and androgen receptors. A 2-(2,2,2) trifluoroethyl-benzimidazole nucleus has been reported as tissue-selective androgen receptor modulators (SARMs). They are agonist in muscles and antagonists in prostate to exhibit its therapeutic utility towards hypogonadism, cachexia etc. Compound 242 was found as the most potent compound in this category [246].
Sessions et al. [247] have synthesized benzimidazole derivative 243 as potent inhibitors of Rho kinase with IC50<1 nM. Rho kinase or a serine/threonine kinase expressed in vascular tissues is involved in the signal transduction pathways and has potent utilities in the many activities. Different positions of benzimidazole nucleus were reported by the same research group to determine the structure for selectivity towards other protein kinases. Compound 244was synthesized with the substitution in the chromane ring which showed Rho kinase inhibition in nanomolar doses
whereas affinity towards other protein kinases in micromolar concentrations. Sessions et al. [248] have synthesized compound 245 as inhibitor of neuropeptide calcitonin gene related peptide (CGRP) that plays an important role in the migraine pathology. A few other benzimidazole derived compounds acting on specific receptors include benzimidazole-(S)-isothiazolidinone ((S)-IZD) derivatives 246 as protein tyrosine phosphatase 1B (PTP1B) inhibitor and pyridyl-pyrimidine benzimidazole 247 as potent Tie-2 inhibitor (Fig. 24).
4. CONCLUSION
Benzimidazole nucleus is an important pharmacophore in the modern medicinal chemistry research. However, despite the exhaustive, active, and target based research on development of many compounds as anti-inflammatory, immunomodulatory, lipid modulators, etc. no molecule has made its way to the market and clinical practice which is mostly due to the lack of a comprehensive compilation of various research reports in each activity that is capable of giving an insight into the SAR of the compounds. Recently, attention has been increasingly given to the synthesis of benzimidazole derivatives as a source of novel therapeutics. Various recent new drug developments in benzimidazole derivatives show better effect and less toxicity which offers better pharmacodynamic characteristics. Now, researchers
N
NCH3
HNNH2
NHN
HOOCO
N
N
NCH3
HNNH2
NN
C2H5OOCO
N
O
O
H3C
N
N
N
OCH3
O
N
227
228
229
N
NCH3
NO2
NH
H2NO
N
NH
H3C
230
N
N
H2N
NH
HN
CH3
O
NO
COOHO
NNH
H3C
231
N
HN
H2N
NH
COOH
HOOH
F
N
NH
NH2
NHOH
NO2
COOHHOOC
232
233
Fig. (23). Novel benzimidazole derivatives as anticoagulant agents.
Novel Research Strategies of Benzimidazole Derivatives: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 10 1441
have been attracted toward designing more potent benzimidazole derivatives having wide diverse pharmacological activities. The present review is expected to provide rational of the benzimidazole derived compounds to a drug designers and medicinal chemists for a comprehensive and target based information for the development of clinically available drugs.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of interest.
ACKNOWLEDGEMENTS
Authors would like to thank Prof. Manjunath Ghate (Director, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India) for continuous support and
critical review of the manuscript. We are also thankful to Department of Science & Technology (DST), Govt. of India for providing INSPIRE Fellowship as financial support.
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N
NS
CH3SHN
O
O
OH3C
N
N
SHN
O
OF
N
NS
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H3CO
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NH
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