Benzimidazole: Structure Activity Relationship and Mechanism of Action as Antimicrobial Agent

 

Umesh Kumar, Rakesh Narang*, Surendra Kumar Nayak, Sachin Kumar Singh and Vivek Gupta

Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144401, India

 

ABSTRACT:

Benzimidazole is nitrogen containing heterocyclic organic compound. It is a bicyclic compound with fused benzene and imidazole nucleus. Various research groups revealed that benzimidazole is an important lead molecule for the development of anthelmintic, antibacterial, antifungal, antiprotozoal, antimycobacterial and antiviral agents. So, in present review, various biologically important derivatives of benzimidazole have been compiled. On the basis of their biological activity data and substitution pattern around the benzimidazole nucleus, structure activity relationship (SAR) has been analysed. An outline of mechanism of action of benzimidazole derivatives against various biological targets is also presented. Hence, present review can help the researchers in development of new benzimidazole derivative with significant biological activity.

 

 

 

 

 

INTRODUCTION:

Benzimidazole is a bicyclic compound having imidazole ring fused with benzene (Figure 1).¹ It is an important heterocyclic compound, shows attraction towards antibacterial,² antifungal,³ antimycobacterial,⁴ antiviral,⁵ and vermicidal⁶ activities.

 

Figure 1: Benzimidazole

 

Commercially available anthelmintic drugs having benzimidazole moieties are albendazole, thiabendazole, fenbendazole and mebendazole (Figure 2).⁷

 

Figure 2: Anthelmintic drugs having benzimidazole nucleus

 

STERIEOCHEMISTRY:

The benzimidazole shows annular type of tautomerism, presented below

 

The benzimidazole is less basic as compare to imidazole. The nucleophiles attack faster at 2^nd position of benzimidazole than imidazole nucleus.⁸ In present study we have compiled the antibacterial, antifungal, antimycobacterial and antiviral activity data of most potent bezimidazole derivatives, from various reported research work. Present work also enlightens the mechanism of action and structure activity relationship (SAR) of most active benzimidazole derivatives.

 

MECHANISM OF ACTION OF BENZIMIDAZOLE DERIVATIVES:

Reported data showed that benzimidazole derivatives can act on different targets for inhibition of various organisms (Figure 3)

 

Antiviral activity:

The benzimidazole derivatives showed antiviral activity by causing cytotoxicity and leads to viral cell inhibition.⁹

 

Anthelmintic activity:

Benzimidazole selectively bind with β-tubulin of nematode, inhibiting polymerization, prevent the formation of microtubules and hence stop cell division. They also causes impaired uptake of glucose, leading to depletion of glycogen, and reduced stores of ATP.

 

Benzimidazole derivatives are also reported to inhibit fumrate reductase enzyme involved in synthesis of ATP by oxidative phosporylation. ¹⁰

 

Antifungal activity:

The mode of action of benzimidazole as fungicide is binding with microtubule and stop cellular process viz. cytoskeleton formation and rearrangement, cell division and intracellular tracking. The selective toxicity of these fungicides to fungal microtubules suppress the growth of microorganism.¹¹

 

Antibacterial activity:

Antibacterial benzimidazole molecule act by forming a covalent adduct with membrane-bound bacterial transpeptidase enzymes [also known as penicillin binding proteins (PBPs)], which involved in the biosynthesis of cell walls. Consequently, they prevent the formation of cell wall, eventually lead to cell wall decomposition and death. Studies also revealed that benzimidazole-quinolone derivative could also inhibit topoisomerase IV in bacterial strains and stop the division of bacterial cells. ¹²

 

 

Figure 3: Various biological targets of benzimidazole derivatives

Anti-inflammatory activity:

Anti-inflammatory mechanism of action involves the inhibition of cyclooxygenases enzymes in the arachidonic acid cascade for synthesis of prostaglandins.¹³

 

Antimycobacterial activity:

Benzimidazole derivatives acts by inhibition of intracellular transport in mycobacteria.¹⁴

 

SAR OF BENZIMIDAZOLE AS ANTIMICROBIAL AGENT:

El-Gohary and Shaaban synthesized 2-substituted benzimidazole derivatives and screened for antimicrobial efficacy against Escherichia coli, Bacillus cereus, Staphylococcus aureus, Candida albicans and Aspergillus fumigatus. Antimicrobial results showed that compounds 1 and 2 have remarkable efficacy toward S. aureus (MIC =156.25 µg/ml), whereas 3 exhibited promising activity toward B. cereus (MIC =156.25 µg/ml). Moreover, compound 2 was proved to be the most active antifungal analogue against A. fumigatus. On the other hand, 1 (MIC = 76.125 µg/ml) displayed the highest activity against C. albicans.

 

Structure activity relationship (SAR) studies indicated that substitution of 6-fluorobenzo[d]thiazol-2-amine (1), N-methyl-6-nitroquinolin-5-amine (2) and 1-methyl-1H-pyrazol-5(4H)-one (3) at 2^nd position of benzimidazole enhanced antimicrobial efficacy of benzimidazole derivatives remarkably.¹⁵

 

 

 

 

 

Zhang et al. synthesized benzimidazole-incorporated sulfonamide analogues and accessed their activity against selected Gram-positive, Gram-negative bacteria and fungi to overcome the problem of increasing antibiotic resistance. Antimicrobial screening results showed that compound 4 have potent activity against tested fungi and Gram-positive bacteria among synthesized derivatives. On the other hand compound 5 showed potent activity against Gram-negative bacteria. Further, molecular docking results revealed that both active molecules might efficiently interact with DNA to form compound−DNA complex, which could block DNA replication to exert their powerful antimicrobial action. SAR results indicated that substitution of benzyl group having electron withdrawing halogen at 1^st position and N-(4-(methylsulfonyl)phenyl)acetamide at 2^nd position of benzimidazole enhanced antibacterial and antifungal potential of benzimidazole derivatives (4-5).¹⁶

 

Padalkar et al. synthesized 2-substituted benzimidazole, benzoxazole and benzothiazole derivatives and accessed their antibacterial activity against E. coli, and S. aureus and antifungal activity against C. albicans and A. niger strains using serial dilution method. Studies showed that benzimidazole derivatives have broad spectrum of activity as compared to benzoxazole and benzothiazole. Further, results of antimicrobial activity indicated that compound 6 was least active against both fungal strains C. albican and A. niger (MIC = 250 µg/ml and 400 µg/ml). Whereas, compounds 6-8 were highly potent against S. aureus and E. coli (MIC = 50 µg/ml).

 

 

SAR results of above studies indicated that presence of diethylaminophenol at 2^nd position of benzimidazole is important for antimicrobial activity (6-8). Further, unsubstituted benzimidazole at 5^th position showed very less efficay against studied fungal strains (6). Whereas, substitution of NO₂ group at 5^th position increased the antimicrobial profile against tested bacterial strains (7).¹⁷

 

Zhang et al. designed and synthesized a series of benzimidazole quinolone hybrids as antibacterial agent to overcome the problem of resistance in quinolone derivatives S. aureus and E. coli. Studies showed that most of synthesized derivatives exhibited good antimicrobial activity in comparison to standard drugs. Among the synthesized derivatives compound 9 was most potent, inhibited the topoisomerase IV in E. coli at concentration of 10 μM. Further, this compound showed very low toxicity against mammalian cells. Moreover, molecular docking results showed that hybrid molecule could efficiently bind with DNA and form a stable 9-DNA complex which might further block DNA replication and stop the division of microorganisms.

 

Aforementioned antimicrobial results revealed that hybrid molecule of benzimidazole and quinolone (9) with 2,4-dichlorobenzyl (at 1^st position of benzimidazole) could be an important lead molecule for further development of antimicrobial agent against resistant bacterial strains.¹⁸

 

Al-Mohammed et al. synthesized and evaluated antibacterial activity of benzimidazole sulfonamide hybrid molecules. The antibacterial activity of synthesized compounds investigated by micro broth dilution assay against Gram-positive and Gram-negative bacteria like S. aureus and E. coli, respectively. Among the synthesized derivatives compounds 10 and 11 was found to be most potent having 0.05 mg/ml MIC value against S.aureus and E. coli, respectively.

 

The presence of p-NO₂ (10) and OCH₃ (11) groups in phenyl ring increased the antibacterial activity of synthesized benzimidazole derivatives. Further, it is observed that compounds with electron withdrawing substitution (p-NO₂) showed greater activity (10) as compare to compound having electron donating groups (p-OCH₃, 11 ) against S. aureus and vice versa for E. coli.¹⁹

 

Mehta et al. synthesized and evaluated antibacterial activity of 2-azetidinone derivatives of benzimidazole by cup plate method against bacterial strains S. aureus, Bacillus megaterium and E. coli. Out of synthesized derivatives compound 12 was most potent, showed 18 mm and 16 mm zone of inhibition against S. aureus and B. megaterium, respectively. SAR studies showed that presence of 4-N,N-dimethyl amino phenyl moieties on azetidinone ring is important for antibacterial activity against S. aureus and B. megaterium (12).²⁰

 

Kumar et al. synthesized 2-substituted benzimidazole derivatives and evaluated their antifungal activity against. E. coli, B. subtilis, Pseudomonas aeruginosa, Bacillus pumilus, C. albican and A. niger using agar well diffusion method. All synthesized compounds showed good activity. Among synthesized derivatives, compound 13 was found to be most effective one, showed 22 mm, 20 mm, 20 mm, 19 mm, 22 mm and 20 mm zone of inhibition against E. coli, B. subtilis, P. aeruginosa, B. pumilus, C. albican  and A. niger, respectively. Substitution of pyridine ring at 2^nd position on benzimidazole ring increases the antibacterial and antifungal activity (13).²¹

 

Khan et al. synthesized substituted benzimidazole derivatives and screened their antibacterial activity by agar diffusion method against bacteria B. subtilis, E. coli, S. aureus and P. aeruginosa. All synthesized compounds showed good antibacterial activity, whereas compounds 14 and 15 were most active against all tested strains. SAR study of synthesized derivatives indicated that the presence of p-nitrophenyl ring at 2^nd position and chloro at 6^th position of quinoline ring, (attached to 2^nd position of benzimidazole) significant for antibacterial activity against screened bacterial strains (14-15).²²

 

Babu et al. synthesized 1,2 disubstituted benzimidazole derivatives and evaluated in vitro antibacterial activity against Gram-positive bacteria B. subtilis, S. aureus; Gram-negative E. coli and fungal strain A. niger by filter paper disc diffusion method. Out of all synthesized molecules compounds 16 and 17 were found to be effective against selected strains. Compound 16 showed lowest MIC value 12.8 µg/disc against all tested bacterial and fungal strains, which was equivalent to standard drug clotrimazole (for fungal strain) and ciprofloxacin (for bacterial strains). Halogens such as p-bromo (17) and p-F (16) on phenyl ring attached at 1^st position of benzimidazole via methylamine increased antimicrobial activity.²³

 

Rekha et al. have synthesized benzimidazole derivatives and evaluated their antibacterial activity. Antibacterial activities of synthesized compounds determined by modified cup plate method against S. aureus, B. subtilis, E.coli and Proteus vulgaris. Compound 18 was found to be most potent against all tested strains having zone of inhibition between 14-31 mm. SAR results showed that substitution of chlorine group at 6^th position and fluorine at 5^th position of benzimidazole nucleus required for antimicrobial activity. Further, presence of 4-(dimethylamino)benzylidene at 2^nd position of benzimidazole converted the molecule (9) most active among synthesized derivatives.²⁴

 

 

Shah et al. synthesized and evaluated antibacterial activity of pyrimido [1,2a] benzimidazole derivatives against bacterial strains such as S. aureus, S. epidermis, P. aeruginosa, E. coli and fungal strain A. niger using disc diffusion method. Among synthesized derivatives compounds 19 and 20 showed maximum inhibition against bacterial strains 45-85% and 38-90%, respectively. Further, compound 21 showed maximum inhibition against A. niger i.e. 83% among synthesized derivatives.  The result of antimicrobial activities demonstrated that presence of p-CH_3, o-Cl and p-OCH₃ groups on phenyl ring attached to benzimidazole via tetrahydropyrimidine ring significantly increased antibacterial and antifungal activities (19-21).²⁵

 

 

Selvam et al. synthesized and evaluated antimicrobial activity of 2-subsitituted benzimidazole derivatives against bacterial strains S. aureus, S. epidermidis, Klebsiella pneumonia, E. coli and fungal stains C. albicans and A. niger using streak dilution method. Among synthesized derivatives compound 1-[4-(1Hbenzo[d]imidazole-2-yl)phenyl]-3-chloro-4-(4-nitrophenyl)azetidin-2-one    (22) was most active against all tested bacterial and fungal strain with 14-28 mm zone of inhibition and 9-19 µg/ml MIC value. Analysis of results showed that presence of para substituted nitro phenyl attached to benzimidazole via 3-chloro-4-azitidin 2-one-1-phenyl ring is important for antimicrobial activity (22). Further, it is also observed that electronic nature of attached substituents showed significant variation in antibacterial activity.²⁶

 

Kumar et al. synthesized and evaluated antimicrobial activity of N-substituted 2(4-styrylphenyl)-1H- benzimidazole derivatives against Salmonella typhimurium and S. aureus by tube dilution method. Synthesized compounds showed poor activity against S. aureus and compounds 23 and 24 showed minimum MIC value i.e. 0.1µg/ml against S. typhimurium. The substituion of groups like methyl, ethyl at nitrogen of benzimidazole nucleus is significant for antimicrobial activity. Further, attachment of styryl phenyl group at 2^nd position of benzimidazole ring also increased antimicrobial activity of synthesized compounds (23-24).²⁷

 

Sugumaran et al. synthesized 2, 5- disubstituted benzimidazole derivatives and evaluated their antibacterial activity against Proteus vulgaris, Klesibella pneumonia, B. cereus and Enterococcus faecium;  antifungal  activity against A. niger and A. fumigatus using disc diffusion method. Out of synthesized derivatives compound 25 was most potent against K. pneumonia, B. cereus and E. faecium, showed 24-26.5 mm zone of inhibition at a dose of 100 mg. Further, compounds 26 and 27 were found to be most active against of inhibition against P. vulgaris (25 mm zone of inhibition at a dose of 100 mg) and tested fungal strains (21-22 mm zone of inhibition at a dose of 100 mg), respectively.

 

SAR studies revealed that substitution of amino group at 5^th position of benzimidazole ring increased antimicrobial activity of synthesized compounds. The substitution of p-nitro phenyl (25) and p-butyl phenyl (26) at 2^nd position of benzimidazole ring enhanced the antibacterial activity and p-isopropyl phenyl (27) enhanced antifungal activity.²⁸

Arora S. synthesized and evaluated antimicrobial activity of benzimidazole compounds against E. coli, B. pumilus, Micrococcus  luteus,  B. cereus,  K.   pneumonaie,  A.  niger,  A.  flavus,  Trichosporum flavurusclem and  Microsporum gypseum by disc diffusion method. Among synthesized derivatives, compound 28 found to be most potent antifungal agent having 15 mm, 35 mm, 22 mm, and 28 mm zone of inhibition against A.  niger,  A.  flavus,  Trichosporum flavurusclem and  M. gypseum, respectively and antibacterial agent against  K.  pneumonaie and B. cereus with zone of inhibition 32 mm and 28 mm, respectively. Presence of S-methylated group at 1^st position of benzimidazole increased the antimicrobial potential of synthesized compounds. Substitution CH₃ group on 2^nd position on benzimidazole ring also found to be important for antimicrobial activity of synthesized compound (28).²⁹

 

 

Chandhrasekar et al. synthesized and screened the antibacterial activity of 1-2-disubsitituted benzimidazole derivatives against P. aeruginosa by disc diffusion technique. The most active compound 29 showed 28 mm zone of inhibition. Antimicrobial results showed substitution of benzoyl group at 1^st position and phenyl acetic acid at 2^nd position on benzimidazole ring increased the antimicrobial activity of reported compounds (29).³⁰

 

Chavan et al. synthesized and evaluated antimicrobial activity of 2-subsituted benzimidazole derivatives combined with aspirin as potent antimicrobial agents against E. coli, S. aureus, P. aeruginosa and C. albicans. Antimicrobial activity of synthesized compounds was checked by tube dilution method. Compound 30 found to be most potent having 21 mm, 22 mm, 24 mm and 20 mm zone of inhibition against E. coli, S. aureus, P. aeruginosa and C. albicans, respectively.

 

The substitution of phenyl acetate at 2^nd position of benzimidazole ring increased the antimicrobial activity of synthesized benzimidazole derivatives (30).³¹

 

 

 

Dhua et al. synthesized and screened antimicrobial activity of 2- substituted benzimidazole analogues against S. aureus, B. subtilis and Salmonella typhi by cylinder plate method. Compounds 31-33 were found to be potent and showed zone of inhibition against all tested strains at a dose of 5 mg/ml, 2.5 mg/ml and 1.25 mg/ml. Whereas, compound 33 was active at dose of 5mg/ml and 2.5 mg/ml against all strains. The presence of cyclohexanamine (31) and p-aminobenzoic acid (32) increased antimicrobial activity and decreased by presence of p-OCH₃ phenylamine (33) ring attached at 2^nd position of benzimidazole ring via methylamine.³²

 

Ahmadi A. synthesized and evaluated antimicrobial activity of benzimidazole derivatives against E. coli, S. aureus and C. albicans by paper disc method. Compounds 34 (13.25 mm zone of inhibition) and 35 (11.26 mm zone of inhibition) showed most potent activity among synthesized derivatives, against S. aureus and E. coli, respectively. None of synthesized derivative was found to be active against C. albicans. Substitution of p-chlorophenyl (for S. aureus, 35) and o-chlorophenyl (for E. coli, 34) moieties at 2^nd position of benzimidazole nucleus increased the antimicrobial activity of synthesized compounds. Further, presence of 4-amino-2-chlorophenyl methanone at 1^st position of benzimidazole plays an important role in antibacterial activity of synthesized derivatives (34-35).³³

 

Devmurari et al. synthesized and evaluated antibacterial activity of benzimidazole-1- carbodithioate derivatives against Gram-positive bacteria S. aureus, E. faecalis, B. cereus, Gram-negative bacteria P. aeruginosa, K. pneumoniae and E. coli by agar well diffusion method. Compound 36, methyl 1H-benzo[d]imidazole-1-carbodithioate was found most effective against all tested bacterial strains. SAR studies showed that presence of carbodithioate at 1^st and unsustituted 2^nd position of benzimidazole ring significant for antimicrobial activity of synthesized compounds against all tested strains (36).³⁴

 

Utku et al. synthesized, characterized and screened antimicrobial activity of platinum (II) complexes of 2-phenylbenzimidazole ligand against Gram-positive bacteria, S. aureus, B. subtilis, and Enterococcus faecalis; Gram-negative bacteria P. aeruginosa, E.coli, and K. pneumonia and fungal strains C. glabrata, C. parapsilosis by macro dilution method. Compound 37 showed marked antibacterial potential against E.coli and K. pneumonia with MIC value of 0.02 µM and 0.02 µM. On the other hand, compound 38 showed marked inhibitory activity against rest of tested strains with MIC value of 0.14 µM. The Pt (II) complex bearing Cl₂ (37) and I₂ (38) ligand, attached with nitrogen of benzimidazole nucleus were found highly potent against tested bacterial and fungal strains.³⁵

 

Khan et al. synthesized and evaluated antimicrobial activity of synthesized benzimidazole complexes with different metals viz. Cu²⁺, CO²⁺, Mn²⁺ against Penicillium expansum, Botrydepladia thiobromine, Nigrospra sp., Trichothesium sp., Rhizopus  nigricans and  A. niger by cup plate method. Out of synthesized chelates compound 39 was found to be most potent, showed 74-80 mm zone of inhibition against tested strains. The analysis results of antimicrobial showed that synthesized benzimidazole and Cu²⁺ complexes contributes more antimicrobial activity as compare to other metal complexes .³⁶

 

Sarma et al. synthesized and screened antimicrobial activity of schiff base benzimidazole derivatives against  bacterial strains S. aureus, B. subtilis, E. coli and K. pneumoniae and fungal strains A. niger and C. albicans by agar diffusion method. Out of synthesized compounds, 40 have shown good antibacterial and antifungal capability with 11 mm, 12 mm, 14 mm, 11 mm, 14 mm and 3 mm zone of inhibition against S. aureus, B. subtilis,  E. coli,  K. pneumonia, A. niger and C. albicans, respectively. SAR of antimicrobial results indicated the presence of both electron donating and withdrawing group at para position of phenyl ring attached with Schiff base linkage influenced the activity. Compound having electron withdrawing Cl group (40) showed more antimicrobial activity than electron donating OH group.³⁷

 

Rao et al. synthesized and evaluated antimicrobial activity of 2-subsituted benzimidazole analogues against Gram-positive S. aureus, B. subtilis; Gram-negative E. coli, P. aeruginosa by cup plate method. Compound 41 was found to be most potent, showed 20 mm, 23 mm, 22 mm and 23 mm zone of inhibition against S. aureus, B. subtilis, E. coli, P. aeruginosa, respectively.

 

Antimicrobial activity result revealed that presence of o- hydroxyl phenyl ring  at 2^nd position of benzimidazole ring (41) have vital role in the antimicrobial activity of synthesized compounds, whereas electron withdrawing group (NO₂) at ortho position of phenyl ring decreased the antimicrobial activity  of synthesized compound.³⁸

 

Baviskar et al. synthesized and evaluated in vitro antibacterial activity of benzimidazole derivatives against bacterial strains S. aureus, E. coli, P. aeuroginosa and S. typhi and fungal strains A. niger and C. albicans by cup plate method. Out of synthesized derivatives, compound 42 has shown highest antibacterial potential against all tested bacterial strains and compound 43 showed maximum antifungal activities with 10-14 mm and 12-15 mm zone of inhibition, respectively. Compounds bearing p-methoxyphenyl (42) and p-bromoyphenyl (43) attached at 2^nd position of azetidinone ring showed good antibacterial and antifungal activity among synthesized compounds. Further, the presence of chloro group at azetidinone ring also important for antimicrobial activity.³⁹

    

Rathee et al. synthesized and evaluated antifungal activity of benzimidazole derivatives against C. albicans and A. fumigutus by tube dilution method. Among synthesized derivatives of benzimidazole, compound 44 and 45 showed good potency. Compound 45 found to be most potent having 105 mm and 63 mm zone of inhibition against C. albicans and A. fumigutus respectively. Results of antifungal activity signify that presence of –OH group at 6^th position and methyl group at 2^nd position of benzimidazole ring (44). Further, it is observed that presence of electron withdrawing group viz. –NO₂ at para position on benzoyl ring (attached at 1^st position of benzimidazole) increased antifungal activity of synthesized compounds (45).⁴⁰

 

Radhu et al. synthesized and evaluated antimicrobial activity of novel-N-substituted 2(4-bromophenoxy methyl)-1H benzimidazole derivatives against C. albicans, A. niger, A. clavatus, E. coli, S. pyogens, S. aureus and P. aeruginosa by tube dilution method. Out of synthesized compounds, most active compound 46 showed MIC value 12.5 µg/ml - 100 µg/ml against tested strains. Against fungal strains none of the compound was active, all compounds showed MIC value equal or above 250 µg/ml. Analysis of results demonstrated that substitution of ethyl carboxylate at 1^st position and 4-bromophenoxy at 2^nd position of benzimidazole are significant for antibacterial activity (46).⁴¹

 

Madhavi et al. synthesized and screened antimicrobial activity of substituted 1, 2-disubsituted benzimidazole derivatives against bacteria E. coli, Protease, S. aeruginosa, B. subtilis and fungal stain A. niger by cup and plate method. Out of synthesized derivatives compound 47 showed highest activity (Zone of inhibition = 23 mm) against A. niger and compounds 48 (Zone of inhibition = 15-19 mm) and 49 (Zone of inhibition = 14-19 mm) exhibited maximum activity against tested bacterial strains. The substitution of N-phenylmethylaniline and p-nitro/p-amino/o-chlorophenyl ring at 2^nd position of benzimidazole improved antifungal and antibacterial potential of synthesized compounds (47-49).⁴²

 

Lingala et al. synthesized and evaluated antimicrobial activity of benzimidazole derivatives. The antibacterial activity of synthesized compounds was analysed by modified cup and plate method against B. subtilis,  B. cereus,  S. epidermidis,  S. typhi,  P. aeruginosa, K. pneumoniae  and  antifungal activity against A. flavus, F. oxysporium and P. notatum. Among synthesized compounds, 50 showed maximum efficacy against all bacterial and fungal strains (Zone of inhibition range = 12-18.2 mm) at a dose of 2 mg/ml. Screening results showed that compounds bearing S-methyl 4-nitrobenzthioate moiety at 2^nd position and methylcarbamoylisonicotinoyl at 1^st position of benzimidazole nucleus increased antimicrobial activity (50).⁴³

 

Petker et al. synthesized and evaluated antifungal activity of 2-chlormethyl-1H-benzimidazole derivatives against C. albicans by well plate method. Compound 51 was most potent having 12.5 µg/ml MIC value among of all synthesized derivatives. SAR studies indicated that the substitution of 3-chloro-4-floroaniline at 2^nd position of benzimidazole ring linked via methylamine favoured antifungal activity of synthesized compounds (51).⁴⁴

   

 

Umaa et al. synthesized, characterized and evaluated antifungal activity of acetyl 2-methyl benzimidazole amino derivatives against A. niger and C. albicans by Kirby-bauer method. Compound 52 was found to be most active among synthesized compounds. It showed 32 mm zone of inhibition at a dose of 500 µg/disc against C. albicans which is equivalent to standard drug fluconazole at a dose of 10 µg/disc. It is observed that removal of methyl group from 2^nd position of benzimidazole ring, decreased antimicrobial activity, hence it is required for antifungal activity. Further, the presence 4-chlorophenyl and 4-chloroaniline moieties at 1^st position of benzimidazole attached via 2-hydroxypropanone increased antifungal activity of synthesized compounds (52).⁴⁵

 

Nandha et al. synthesized and screened antifungal activity of imidazolyl methyl substituted florobenzimidazole derivatives against C. albicans, C. krusei, C.  glabrata  and C.  tropicalis by agar diffusion and broth dilution method. Out of synthesized derivatives compound 53 was most potent, showed 17 mm, 18 mm, 18 mm and 17 zone of inhibition against C. albicans, C. glabrata, C. krusei and C.  tropicali, respectively. The presence of fluorine at 5^th position of benzimidazole ring is important for antifungal activity. Further, the substitution of imidazole ring at 2^nd and 6^th position on benzimidazole ring increased antifungal activity of synthesized compounds (53).⁴⁶

 

Jain et al. synthesized and screened antimicrobial potential of benzimidazole derivatives and evaluated their activity against Gram-positive (S. aureus, S. mutans and B. subtilis), Gram-negative (E. coli, S. typhi and P. aeruginosa) bacteria by disc diffusion method. Among synthesized compounds 54 and 55 found to be most active, showed 14-38 mm and 12-37 of zone of inhibition against selected strains. SAR results indicated that NO₂ group at 6^th position of benzimidazole ring is required for antimicrobial activity (54-55). Further para halogen substituted phenyl ring at 2^nd position of benzimidazole increased antimicrobial activity (54). It was also observed that antimicrobial activity reduced as the electron withdrawing ability of substituents decreased.⁴⁷

 

Kim et al. checked antifungal activity of methyl-2-benzimidazole carbamate against different species of Aspergillus, Fusarium, Penicillium, Rhizopus  stolonifer, Paecilomyces  farinosus and Trichoderma  viride by broth micro dilution test and agar disc diffusion method. Compound 56 have shown good antifungal capability with MIC value of 0.1 µg/ml, 0.1 µg/ml and 0.5 µg/ml against F. graminearum, P. italicum and A. niger, respectively. The presence of carbamate group at 2^nd position and methyl group at 7^th position of benzimidazole ring improved antimicrobial potential of synthesized derivatives (56).⁴⁸

 

Altintop et al. synthesized and evaluated antimicrobial activity of benzimidazole based acetamide derivatives and checked antifungal activities using microbroth dilution method against various pathogenic bacterial and fungal strains. Out of synthesized compounds, 57 and 58 showed maximum antifungal potential having 125 µg/ml MIC value against A.  niger, A.  flavus, A.  parasiticus, F.  solani, C.   glabrata,  C. tropicalis,  C. krusei and C. parapsilosis.

 

 

Compound	R
57
58

 

Antifungal screening results indicated that N-methyl substituted benzimidazole nucleus is required for antifungal activity. The presence of piperazine moiety increased the antimicrobial activity of benzimidazole derivatives. Further, the presence of p-methoxyphenyl and p-methylbenzyl moities on piperazine ring increased antimicrobial activity of synthesized compounds (57-58).⁴⁹

 

Al-ebaisat H. S. synthesized and evaluated biological activities of 2- substituted benzimidazole derivatives and screened antifungal activity against C. albicans, C. glabrata and C. krusei by tube dilution technique.  Among synthesized compounds, 59 found to be most active, showed 12.5 µg/ml MIC value against C. albicans and 6.25 µg/ml against C. glabrata and C. krusei. The presence of ethyl, p-bromophenyl and amino moities at 1^st, 3^rd and 6^th position of benzimidazole ring increased the antifungal activity of synthesized compounds (59).⁵⁰

 

Suken et al. synthesized and evaluated antimicrobial activity of benzopyrone substituted benzimidazole analogues and checked their activity against S. aureus, E coli, P.aeruginosa and B. subtilis by agar plate method. Out of synthesized compounds, 60 was found to be most active one, showed 18 and 23 zone of inhibition mm against S. aureus and P. aeruginosa, respectively.

 

The substitution of C₂H₅ group at 1^st position of benzimidazole increased antimicrobial activity of synthesized compounds. Further, the presence of substituted (NO₂ or OCH₃) benzopyrone at 2^nd position of benzimidazole nucleus increased antimicrobial activity of synthesized compounds (60).⁵¹

 

Eisa et al. synthesized benzimidazole oxadiazole hybrids and screened their activity against B. subtilis, S. aureus and E. coli, P. aeuroginosa by disc diffusion assay. Among synthesized compounds, 62 (B. subtilis), 63 (S. aureus), 64 (E. coli) and 65 (P. aeuroginosa) showed lowest MIC values i.e. 74 µg/ml, 67 µg/ml, 42 µg/ml and 115 µg/ml, respectively.

                               

SAR results indicated that presence of benzylthio at 2^nd position and triazole/oxadiazole attached via methyl group at 1^st position of benzimidazole is significant for antimicrobial activity.⁵²

 

Kale et al. synthesized and evaluated antimicrobial activity of benzimidazole acetic acid derivatives and evaluated their antimicrobial activity against S. aureus, E. coli, C. albicans and A. fumigutus at concentration of 75 µg/ml by cup plate method. Antimicrobial results indicated that compound 66 has maximum potency, 16 mm, 19 mm and 20 mm zone of inhibition against S. aureus, C. fumigutus and C. albicans, respectively. Whereas, compound 67 showed highest activity (19 mm zone of inhibition) against E. coli.

 

SAR results of synthesized derivatives showed that presence CH₂COOH moiety at 1^st position of benzimidazole is required to improve antifungal activity of synthesized compounds. The substitution of 4-methoxyystyryl group at 2^nd position of benzimidazole nucleus also improved antimicrobial potency. Contrary, substitution of p-chlorostyryl moiety at 2^nd position of benzimidazole nucleus slightly decreased the antimicrobial activity of synthesized compounds.⁵³

 

Noolvi et al. synthesized 2-substituted derivatives of benzimidazole and screened their antimicrobial activity against

Gram-positive bacteria (S. aureus, B. pumillus) and Gram-negative bacteria (P. aeruginosa, E. coli) by agar diffusion method. Compounds 68 and 69 were found most potent showed 13.6 mm, 12.4 mm,  14.4 mm, 11.7 mm and 13.2 mm, 11.2 mm and 13.6 mm, 10.9 mm zone of inhibition against S. aureus,  B. pumillus, E. coli and  P. aeruginosa, respectively.

 

From above results it was concluded that the substitution of p-chloro/nitrophenyl at 2^nd position on benzimidazole, attached via schiff base (68-69), increased the antimicrobial activity of synthesized compounds. On the other side substitution of electron donating groups (OCH₃) at ortho and meta position of phenyl ring, decreased antimicrobial activity.⁵⁴

 

Walia et al. synthesized and screened antimicrobial activity of substituted benzimidazole derivatives and evaluated their antibacterial activity against E. coli, S. aureus and antifungal activity against C. albicans by cup plate method. Among synthesized compounds, 70 showed maximum antimicrobial inhibition i.e. 25 mm, 28 mm and 19 mm zone of inhibition against E. coli, S. aureus and C. albicans, respectively. SAR results showed that presence of p-Cl on phenyl ring at 2^nd position of benzimidazole nucleus increased antimicrobial activity of synthesized compound (70). Further, it is observed that activity of synthesized compounds changes as electro-negativity changes.⁵⁵

 

Vasic et al. synthesized 5-subsitituted derivatives of benzimidazole and screened their antifungal activity against C. albicans and S. cerevisiae by microbroth dilution assay. Among synthesized derivatives, compound 71 showed minimum MIC activity among synthesized derivatives against C. albicans and S. cerevisiae i.e. 0.078 and 0.313 µg/ml^-1.

 

Analysis of antimicrobial results indicated that the presence of methyl group at 5^th position of benzimidazole nucleus is required for antimicrobial activity. Substitution of 2-chlorophenyl at 2^nd position of benzimidazole attached via propyl piperazine is required for interaction with target site (71).⁵⁶

 

Sarma et al. synthesized 2-subsituted of benzimidazole derivatives and screened their antimicrobial activity by agar diffusion method against A. niger and C. albicans. Compound 72 showed maximum zone of inhibition against A. niger (14 mm) and C. albicans (3 mm). Whereas, compound 73, showed minimum zone of inhibition against A. niger (3 mm) and inactive against C. albicans. Results showed that compounds containing electron withdrawing group like chlorine are more active (72) as compare to compounds containing electron donating groups like hydroxyl and methoxy (73).⁵⁷

 

Mehta et al. synthesized 2-azetidione derivatives of benzimidazole and evaluated their antibacterial activity against S. aureus, B. megaterium, E. coli, P. fluorescens; antifungal activity against A. flavus and C. albicans by cup plate method. Compound 74 showed highest potent zone of inhibition against A. flavus (18 mm), S. aureus (18 mm), B. megaterium (16 mm)  and C. albicans (14 mm).

 

Antimicrobial results observation showed that substitution of chlorine group at 3^rd position of azitidinone ring is significant for antimicrobial activity. Moreover, the substitution of 4-N,N dimethyl amino phenyl at 2^nd position of azetidinone ring, increased antimicrobial activity of synthesized compounds (74).⁵⁸

 

Alasmary et al. synthesized and evaluated antimicrobial activity of benzimidazole derivatives and screened their antibacterial activity against MRSA variant of S. aureus, E. coli, P. aeuroginosa, Serratia marcescens and Burkholderia cepacia; fungal strains of Candida, Aspergillus, Penicillium etc. by disc diffusion assay. Compounds 75-77 were found to be most active among the synthesized derivatives against tested strains. Further, antimicrobial results revealed that compounds 75 and 76 have consistent activity against various MRSA strains and MIC value was in the range of 32-64 µg/ml. Compound 77 was most active against tested fungal strains.

 

SAR results indicated that presence of CH₂SH and CH₂Cl at 2^nd position and electron withdrawing groups (Br and NO₂) at 5^th position of bezimidazole is significant for antimicrobial activity (75-77).⁵⁹

 

Maru and Shah synthesized mononuclear dichloro-bis[2-(2-chloro-6,7-substituted quinolin-3-yl)-1H benzo[d]imidazole] CO(II) complexes and evaluated their antimicrobial activity against Gram-positive S. aureus and Streptococcus pyogenes, Gram-negative E. coli and P. aeruginosa bacteria and fungal strains C. albicans, A. niger and A. clavatus by twofold serial dilution method. Among synthesized compounds, 78 found to be most active and showed 12.5 to 500 µg/ml^{- 1} MIC values against tested strains. Compounds were also evaluated against Mycobacterium tuberculosis H37Rv strain; none of the compound was active against reported derivatives. Above structure activity relationship concluded that formation of complex between benzimidazole nucleus and CO (II) led to increase in antimicrobial activity of synthesized compounds. Further, the presence of chlorine at 2^nd and methyl at 6^th position of quinolone ring, substituted at 2^nd position of benzimidazole ring, required for antimicrobial activity of studied compounds (78).⁶⁰

 

Yoon et al. synthesized and evaluated their antimycobacterial activity against Mycobacterium strains MTB-H37Rv and INHR-MTB by broth dilution method. Out of synthesized derivatives, compound 79 found to be most potent, showed 0.112 µm MIC against MTB-H37Rv and 6.12 µm against INHR-MTB.

 

SAR study of synthesized compounds showed that the presence of electron-withdrawing moieties 4-fluorophenyl pyridine and 4-(2-amino-4(ethoxy carbonyl)phenyl) piperazine at 2^nd and 1^st position of benzimidazole, enhanced antimycobacterial activity (79).⁶¹

 

Birajdar et al. synthesized and screened antitubercular activity of amino alcohol derivatives of 2-methylbenzimidazole by MABA assay method against M. tuberculosis. Antitubercular activity result showed that compounds 80 and 81 were most potent, showed 6.25 µg/ml MIC value. Reported compounds were also screened for antibacterial activity against S. aureus and E. coli. Same compounds 80 (14-23 mm zone of inhibition) and 81 (13-23 mm zone of inhibition), also showed most promising activity against selected bacterial strains at dose of 20, 40 and 60 μg/ml.

 

SAR of most active compounds indicated that the attachment of 3-(methoxymethyl)-3-methylazetidine (80) and (1R,5S,6S)-N, 3-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (81) moieties at 1^st position of benzimidazole nucleus attached via propan-2-ol increased antitubercular and antimicrobial activity of synthesized compounds. Methyl group at 2^nd position of benzimidazole was also important for both antibacterial and antimycobacterial activities (80-81).⁶²

 

Budow et al. synthesized and evaluated antiviral activity of substituted benzimidazole derivatives by cell based assays method against selected  RNA  and  DNA  viruses including  Pestivirus ( bovine  viral diarrhoea  virus, BVDV),  Flavi virus including yellow  fever  virus  (YFV),  dengue  virus type  2 (DENV-2)  and  West  Nile  virus  (WNV)  and Hepacivirus (hepatitis C virus;  HCV); representative   member   of   the Retroviridae (ssRNA⁺) the   human immunodeficiency  retrovirus  (HIV 1)  and  the  DNA  virus Hepatitis  B  (HBV); negative sense  single stranded RNA  virus  (ssRNA) Human Respiratory  Syncytial  Virus  (human  RSV). Studied showed that none of compound was found to be active against ssRNA⁺ viruses i.e. HIV-1, BVDV, YFV, DENV-2 or WNV. Compound 82 found to be most potent among synthesized derivatives against HIV-I. Compound 82 was also active against all selected ssRNA⁺ viruses having CC₅₀ value 13, 12, 19 and 9 against YFV, DENV and BVDV, respectively. SAR studies of synthesized compounds showed that substitution of NO₂ and 3,5-dinitrophenylthio at 5^th and 2^nd positions of benzimidazole ring required for antiviral activity (82).⁶³

 

Tonelli et al. synthesized and evaluated antiviral activity of benzimidazole derivatives and 2-phenylbenzimdazol derivatives against vaccinia virus, bovine viral diarrhoea virus (BVDV) by cell based assays method. Among synthesized derivatives, compounds 83 and 84 exhibited high potency against vaccinia virus (EC₅₀ = 0.1 µm) and BVDV (EC₅₀ = 0.8 µm), respectively.

 

Antiviral results showed that the presence of electron withdrawing Cl at 5^th and 6^th position (83) and NO₂ groups at 5^th position (84) required for antiviral activity. Further, substitution of NO₂ and acetamide (4^th position) and amino group (2^nd position) of phenyl ring attached at 2^nd position of bezimidazole (84) enhanced the antiviral activity.⁶⁴

 

CONCLUSION:

Benzimidazole derivatives can act on different targets like microtubules, DNA, transpeptidase and fumrate reductase enzymes for inhibition of various organisms. SAR data of anthelmintic drugs revealed the significance of methylcarbamate and thiazole at 2^nd position; phenylthio, propylthio and benzoyl moieties at 5^th position; unsubstituted 1^st and 3^rd position of benzimidazole nucleus for anthelmintic activity. In case of antibacterial activity, the presence of p-nitrophenyl, p-methoxyphenyl, 4-N,N-dimethylaminophenyl azetidinone,  chlorine substituted quinoline, p-isopropylphenyl and o-hydroxyphenyl at 2^nd position of benzimidazole enhanced their activity. In case of antifungal activity, the presence of propylpiperazine, methyl and 2-chloro-4-floroaniline at 2^nd position of benzimidazole enhanced their efficacy. Moreover, the presence of pyridine, electron withdrawing groups (Br, Cl, NO₂) and electron donating groups (OCH₃ and NH₂) at para position of phenyl ring, triazole, oxadiazole, methylthio and chloromethyl at 2^nd position of benzimidazole enhanced the activity against both bacteria and fungi. Formation of Co and Cu complex of benzimidazole derivatives also increased antimicrobial potential.  The presence of 4-fluorophenyl pyridine/1,3-dimethylazetidinone and 4-(2-amino-4(ethoxy carbonyl)phenyl) piperazine at 1^st and 4^th position of benzimidazole enhanced antimycobacterial activity. Antiviral results showed that presence of electron withdrawing Cl at 5^th and 6^th position; NO₂ group at 5^th position of benzimidazole, required for antiviral activity. Further, substitution of o-NH₂ and p-NHCOCH₃ substituted phenyl ring, at 2^nd position of benzimidazole also enhanced the antiviral activity.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Accepted on 01.07.2017          © RJPT All right reserved