Pharmacological significance of heterocyclic 1H-benzimidazole scaffolds: a review

Heterocyclic compounds are inevitable in a numerous part of life sciences. These molecules perform various noteworthy functions in nature, medication and innovation. Nitrogen-containing heterocycles exceptionally azoles family are the matter of interest in synthesis attributable to the way that they happen pervasively in pharmacologically dynamic natural products, multipurpose arranged useful materials also profoundly powerful pharmaceuticals and agrochemicals. Benzimidazole moiety is the key building block for several heterocyclic scaffolds that play central role in the biologically functioning of essential molecules. They are considered as promising class of bioactive scaffolds encompassing diverse varieties of activities like antiprotozoal, antihelminthic, antimalarial, antiviral, anti-inflammatory, antimicrobial, anti-mycobacterial and antiparasitic. Therefore in the present review we tried to compile the various pharmacological activities of different derivatives of heterocyclic benzimidazole moiety.


Introduction
Among heterocyclic pharmacophores, the benzimidazole ring system is quite common. These substructures are often called 'privileged' due to their wide recurrence in bioactive compounds [1]. Benzimidazole moiety is a fusion of benzene and imidazole ring system at the 4 and 5 positions of imidazole ring. They have properties of both acids and bases. The NH group here is highly acidic and also feebly basic. Another feature of it is that they comprise the ability to form salts. The benzimidazole moiety is useful for the development of novel medicinal compounds in pharmaceutical field. Benzimidazole is also a vital pharmacophore, a privileged sub-structure in medicinal chemistry which contributes as a key part for different natural activities [2].

Pharmacological significance of benzimidazole derivatives
Literature survey reveals that the various derivatives of benzimidazole have been synthesized for their pharmacological activities such as antimicrobial [3], anticancer [2], acetylcholinesterase [4], antiprotozoal [5], anti-inflammatory [6], analgesic [7], antihistaminic [8], antimalarial [9], antitubercular [10], anti-HIV [11] and antiviral [12]. Some of the already synthesized compounds from the above mentioned field have found very strong application in medicine praxis. The activity against bacteria, fungi and helminthes resulted their mode of action, which resulted in the blockage of microtubule in various nematode, trematode and cystode [13]. Benzimidazole-based drugs exhibit a wide range of different biological activities as a result of changing the groups on the core structure. Some marketed drugs containing benzimidazole nucleus are shown in Fig. 1.
Acetylcholinesterase (AChE) is a core chemical engaged with the ending of nerve signs via the hydrolysis of acetylcholine. It is an objective of medication advancement to battle the neuromuscular issue, for example, glaucoma, myasthenia gravis and Alzheimer's disease (AD). AChE has been focused in the cure of AD, a dynamic neurodegenerative disease portrayed by neurofibrillary tangles, β-amyloid plaques and loss of focal cholinergic ability. A lack in cholinergic neurotransmission is viewed as one of the real reasons for reminiscence weaknesses in the patients with AD. One of the compelling methodologies for improving the cholinergic transmission is to utilize the inhibitors of acetylcholinesterase [4]. Parasitic ailments are as yet overall issues that deeply affect general wellbeing. Contaminations brought about by protozoa, for example, Trypanosoma cruzi, Plasmodium falciparum, Entamoeba histolytica, Leishmania Mexicana, Trichomonas vaginalis, Giardia intestinalis and helminth, for example, Taenia solium or Trichinella spiralis are overall spread ailments that influence predominantly immature nations, where tropical or template temperatures exist, yet in addition poor uncontaminated and cleanliness conditions are normal [14].
Irritation is a confined reaction of body tissues to destructive incentives or injures bringing about the arrangement of protein-rich exudates. It is a defensive reaction of the nonspecific resistant framework that expels the essential driver of cell damage; eradicate necrotic cells and tissues harmed from the incendiary procedure and commence tissue repair. The essential indications of aggravation are redness, heat, torment, swelling and loss of capacity. Reason for aggravation is physical as well chemical means, immunological responses and contamination by pathogenic life form. Aggravation can be assigned as acute and chronic. Acute irritation is described by the exudation of liquid and plasma proteins (oedema) and the development of leukocytes, particularly neutrophils. Chronic irritation is otherwise called constant aggravation, in which tissue destruction and recovering are continuing all the while, for example, tuberculosis, rheumatoid joint inflammation, constant lung infections and atherosclerosis [6].
Mosquitoes are one of the deadliest creepy crawlies in earth which generate biting irritation and also transmit lethal infections, for example, intestinal sickness, yellow fever, filariasis, chikungunya, encephalitis and dengue. Mosquitoes in the class Aedes are liable for the transmission of chikungunya, dengue, yellow fever and other pathogenic arbo-infections. Likewise, the prime vector for lymphatic filariasis is Culex quinquefasciatus, as well called southern house mosquito. Cx. quinquefasciatus ordinarily stay around human lodging and on maturing like to nibble people than different warm blooded creatures. Intestinal sickness is a mosquito-borne infectious ailment which is mostly transmitted by a contaminated female Anopheles mosquito [15].
Tuberculosis (TB), which is caused prevalently by Mycobacterium tuberculosis (Mtb), is the main source of death from a reparable irresistible ailment, and has been recognized by the World Health Organization (WHO) as one of the three need illnesses for medication innovative work [16]. Viral hemorrhagic fever is a genuine sickness portrayed by broad vascular harm and draining diathesis, fever and various organ inclusions. Various infections can cause this disorder, each with its very own creature repository, method of transmission, mortality rate, and clinical result in people [17].
Worldwide infectious disease figures have attained an alarming level following the proliferation of Gram-positive and Gram-negative multi-drug-resistant species. Patient non-compliance and the occurrence of multidrugresistant pathogens often interfere innovative infection therapies that depend on a sustained multidrug course. Rational drug design has been shown to be very beneficial in this respect, since the biochemical basis of intrinsic and acquired resistance mechanisms is largely known [3].
One of the most commonly known gastrointestinal malignancies is colorectal tumor (CRC). Alterations in lifestyle, elevated-fat diet, physiological disillusionment and smoking are associated to pathogenesis of CRC. Approximately 25% of CRC cases were identified with early analysis metastases and at some stage of life nearly 50% of CRC patients would suffer from metastasis. The therapy results for these patients are largely unsatisfactory as normal regimens consider the possibility of homogeneous tumor mass distribution [2].
Rational designed based on literature survey of benzimidazole derivatives is shown in Fig. 2.

Antiprotozoal activity
Andrzejewska et al. synthesized two series of S-substituted 4,6-dihalogeno-2-mercapto-1H-benzimidazoles and assessed for their in vitro antiprotozoal potential towards G. intestinalis and T. vaginalis using albendazole and metronidazole as standard. Among them, compounds 3a, 3b and 3c were found to be most potent and comparable to standard drugs (  Fig. 3) [19].
Hernandez-Covarrubias et al. reported a class of benzimidazoles and evaluated for its antiprotozoal activity against G. duodenalis. All the tested compounds were found to be more active than standard metronidazole but the better activity observed with SH group compounds 5a-5c (   [20]. Hernandez-Luis et al. synthesized a series of 2-(trifluoromethyl)-1H-benzimidazole molecules and assessed in vitro for its antiparasitic activity towards various protozoan parasites: G. intestinalis (GI), T. vaginalis (TV) E. histolytica (EH) and L. mexicana (LM) using albendazole (ABZ), mebendazole (MBZ), pentamidine as standard drugs and in vivo towards Trichinella spiralis (TS) using albendazole (ABZ), triclabendazole (TBZ) and pentamidine as standard drugs. In this class, compounds 6a, 6b and 6c exhibited good antiparasitic activity and in addition, compound 6a and 6c showed good activity against T. spiralis at adult phase and 6d possessed the good antiprotozoal potential against the muscle larvae stage (Tables 4 and 5, Fig. 3) [14].
Kopanska et al. reported a series of 1H-benzimidazole analogues and assessed for its in vitro antiprotozoal activity against Acanthamoeba castellanii and compared with chlorhexidine as reference. The screening results indicated that compounds 7a and 7b were found most efficient in reducing the figure of trophozoites and cysts (  [2,3-d]pyrimidin-4(3H)-ones and screened for their in vitro antiparasitic activity against Trichinella spiralis using albendazole (as standard drug). Among them, compound 8a showed good antiparasitic activity. The significance results of the active compound shown in Table 7 and Fig. 3 [22].
Navarrete-Vazquez et al. synthesized a sequence of 2-(trifluoromethyl)-1H-benzimidazoles along with various bioisosteric substituents at 5-and 6-position (-Cl, -F, -CF 3 , -CN) and examined for its in vitro antiprotozoal activity towards the protozoa T. vaginalis and G. intestinalis using metronidazole and albendazole as reference. In this series, compound 9a showed most promising activity than metronidazole against G. intestinalis and compound 9b found more active against T. vaginalis than the reference drugs. The compound 9b as well displayed modest antimalarial activity against D6 and W2 strains of Plasmodium falciparum (Table 8, Fig. 4) [23].
Marquez-Navarro et al. developed new derivatives of benzimidazole moiety and examined for their in vivo antiprotozoal activity toward Hymenolepis nana adult and in vitro toward Toxocara canis larvae. In vitro screening results indicated that compound 10a showed significant activity toward T. canis whereas compounds 10b and 10c showed the good in vivo results against H. nana and compared to standard albendazole (Table 9,       and NINOA using reference drug (nifurtimox). Among the synthesized compounds, compound 16a showed potent activity towards the T. cruzi epimastigote INC-5 strain while compound 16b found active against the NINOA strain and comparable to nifurtimox (Table 15, Fig. 4) [30].

Anti-inflammatory activity
Achar et al. prepared a class of 2-methylaminobenzimidazole compounds and screened in vivo for its analgesic (acetic acid induced writhing in mice) and anti-inflammatory activities (carrageenan induced paw oedema in rats). Among them, compounds 17a and 17b were displayed considerable analgesic and antiinflammatory activities in comparison to reference nimesulide (Tables 16, 17 and 18, Fig. 4) [6]. El-Feky et al. designed novel fluorinated quinoline incorporated benzimidazoles and evaluated for their in vivo anti-inflammatory activity by carrageenin induced edema bioassay method in rats using celecoxib. Among them, compound 18a demonstrated the highest anti-inflammatory activity and exhibited best binding profiles into the COX-2 binding site as compared to celecoxib. The significance result of the active compound is shown in Table 19, Fig. 4 [31].
Gaba et al. reported phenylsulfonyl substituted benzimidazoles and evaluated in vivo for their anti-inflammatory activity (carrageenan-induced paw edema in rats) and analgesic activity (acetic acid-induced writhing test in mice), respectively. Among them, compounds 19a, 19b, 19c and 19d showed significant reduction in edema and compared to standard drug indomethacin and protection in the number of writhes produced by acetic acid, and comparable to the reference drug acetyl salicylic acid (Tables 20 and 21      20b showed more potent than diclofenac (Tables 22 and  23, Fig. 5) [32].
Mariappan et al. developed some 2-substituted benzimidazole molecules and screened for their in vivo antiinflammatory and analgesic activities using pentazocine as standard. Among the synthesized derivatives, compounds 21a, 21b, 21c showed significant analgesic and anti-inflammatory activity (Tables 24 and 25, Fig. 5) [33].
Paramashivappa et al. synthesized a class of substituted benzimidazoles and assessed for its human cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzyme inhibition activity in human whole blood assay using rofecoxib as reference. In this series, compound 22a and 22b were found as most active agents ( imidazolyl tetrahydropyridine carboxylates and evaluated for their anti-inflammatory activity by the Carrageenan-induced paw edema test in rats using diclofenac sodium as a reference drug for comparison. All synthesized compounds (23a-23d) displayed appreciable activity. The significance results of the active compounds are shown in Table 27, Fig. 5 [35].
Sondhi et al. developed a class of benzimidazole acridine derivatives and tested for its anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activities using ibuprofen as standard. Among the series, compound 25a displayed considerable activity against kinase while compounds 25b and 25c displayed significant anti-inflammatory and analgesic activities (Table 28, Fig. 6) [36].
Vicini et al. synthesized benzimidazole tetrazolyl-and carboxyl-derivatives and screened for their anti-inflammatory and antipyretic activities in rat paw oedema and rat Escherichia coli derived LPS-induced pyrexia along       19a-19d, 20a-20b, 21a-21c, 22a-22b, 23a-23d) with antinociceptive property examined in writhing and hot plate tests in mice. Among them, compound 26a (1H-benzimidazol-2-yl) acetic acid showed central analgesic activity. The significance results of the active compounds are shown in Table 29, Fig. 6 [37]. Wang et al. prepared a class of benzimidazole compounds and assessed for its in vitro H 1 antihistamine activity. Among them, compound 27a found to display excellent activity to reduce mast cell degranulation, moderate anti-PAF activity and decreased potency on hERG as compared to standard astermizole and desloratadine (Table 30, Fig. 6) [8].
Yang et al. designed new benzimidazoles and then assessed for their in vitro phosphodiesterase 10A (PDE10A) inhibitor activity. From the newly developed compounds, compound 28a (Fig. 6) showed good IC 50 = 3.73 ± 0.60 nM along with selectivity (> 1000-fold) for PDE10A [38].     hemoglobin hydrolysis and then in vivo in rodent Plasmodium berghei for its antimalarial efficacy. Compounds 30a and 30b showed good antimalarial activity via inhibition of β-hematin formation and as proficient as chloroquine (Table 31, Fig. 6) [9]. Divatia et al. synthesized novel thiosemicarbazones containing benzimidazole nucleus and evaluated for their in vitro antimalarial activity towards P. falciparum by minimum inhibitory concentration using chloroquine and quinine as standards. Among them, compounds 31a, 31b, 31c, 31d, 31e, 31f and 31g showed excellent antimalarial activity. From structure activity relationship study it was observed that compounds having electron withdrawing groups (EWG) (chloro, fluoro and iodo) showed promising activity (Table 32, Fig. 6) [39].

Antiviral activity
Cheng et al. synthesized some novel benzimidazoles and demonstrated for their antiviral activity against Coxsackie virus B 3 in VERO cells. Among the synthesized derivatives, compounds 42a and 42b (Fig. 8) showed potent selective activity with IC 50 values (1.43 and 0.54 µg/mL) as compared to ribavirin (RVB) with IC 50 value and eminent selective index (411.7 µg/mL and > 2.42) [47].
Fonseca et al. synthesized benzimidazole compounds incorporated into a hydrophenanthrene and naphthalene skeleton and screened for their in vitro antiviral activity against several RNA and DNA viruses. Among them, compounds 43a, 43b and 43c (Fig. 8) displayed good activity against VZV and CMV replication and comparable to that of acyclovir and ganciclovir (Table 36) [48].
Hwu et al. developed some new benzimidazole derivatives bearing coumarin ring and evaluated for their antiviral activity against the hepatitis C virus. Among the synthesized derivatives, compounds 44a and 44b (Fig. 8) were found to be most active and showed EC 50 values (3.4 µM and 4.1 µM) [49].     (Fig. 9) exhibited promising antiviral activity having IC 50 of 2 nM, a 1000-fold cytotoxicity window and a twofold protein shift. A modification in side chain and stereochemical optimization led to significantly enhancement in potency and protein shift to afford compounds with low nanomolar anti-HIV activity [52].
Starcevic et al. synthesized 2-substituted-5-amidinobenzimidazoles and assessed for their in vitro inhibitory activity against GMK cell line and HeLa cell line by MTT assay. From this series, compound 49a showed prominent activity against all four types of viruses with no cytotoxicity (Table 40, Fig. 9) [12].
Zhang et al. reported some new benzimidazole derivatives and screened for their anti-Coxsackie virus B3 (CVB3) activity in VERO cells. In this series, compounds 50a and 50b (Fig. 9) exhibited better inhibitory activity with IC 50 values (5.30 and 1.06 µg/mL) together with good selective indexes (12.1 and 7.5) than those of ribavirin (RBV) with IC 50 value 353.33 [53].

Anticancer activity
In this study, Tahlan et al. developed a new class of benzimidazole benzamide compounds and demonstrated for its anticancer activity against cancer cell line (HCT116) by SRB method and compared to standard drugs (5-fluorouracil). From the synthesized derivatives, compound 51a and 51b (Fig. 9) showed the significant anticancer activity (Table 41) [3].
Designed and synthesized a novel series of benzimidazole derivatives by Tahlan et al. and evaluated for its anticancer potency towards cancer cell line (HCT116)      by SRB assay. In this series, compound 52a ( Fig. 9) was found to be most promising anticancer compound. The significant result of the most active compound is shown in Table 42 [2].

Antimicrobial activity
Novel class of benzimidazole Schiff base derivatives has been synthesized by Tahlan et al. and evaluated for their antimicrobial activity against Gram positive and Gram negative bacterial and fungal species by tube dilution method. In this series, compounds 53a and 53b (Fig. 9) displayed potent antifungal activity against A. niger and C. albicans. The significant result of the active compounds is shown in Table 43 [54]. Tahlan et al. synthesized a class of benzimidazole Schiff base derivatives and screened for its antimicrobial activity toward selected microbial species. From the series compounds 54a and 54b (Fig. 9) exhibited promising antimicrobial activity towards bacterial and fungal species. The significant result of the active compounds is shown in Table 44 [55].

Conclusion
The present review based on reported heterocyclic benzimidazole derivatives which displayed the significant biological potentials in medicinal chemistry. Benzimidazole moiety is the key building block for several heterocyclic     scaffolds that play central role in the biologically functioning of essential molecules and are surprisingly effective with their restraint movement and favorable selectiveness. The present review article is based on various reported pharmacological activities of heterocyclic 1H-benzimidazole derivatives. The review article shows the pharmacological activities of the reported synthesized benzimidazole derivatives in medicinal field. We hope this paper may be helpful in the development of new derivatives of benzimidazole based on medicinal chemistry and as well as designing of new drug molecule in future.