Benzimidazole: An emerging scaffold for analgesic and anti-inflammatory agents

European Journal of Medicinal Chemistry 76 (2014) 494e505

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Benzimidazole: An emerging scaffold for analgesic and anti-inflammatory agents Monika Gaba a, *, Sarbjot Singh b, Chander Mohan c a

Department of Pharmaceutical Sciences, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab, India Drug Discovery Research, Panacea Biotec Pvt. Ltd., Mohali, Punjab, India c Rayat-Bahra Institute of Pharmacy, Hoshiarpur, Punjab, India b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 October 2013 Received in revised form 19 January 2014 Accepted 20 January 2014 Available online 18 February 2014

Within the vast range of heterocycles, benzimidazole and its derivatives are found to be trendy structures employed for discovery of drugs in the field of pharmaceutical and medicinal chemistry. The unique structural features of benzimidazole and a wide range of biological activities of its derivatives made it privileged structure in drug discovery. Recently, benzimidazole scaffold has emerged as a pharmacophore of choice for designing analgesic and anti-inflammatory agents active on different clinically approved targets. To pave the way for future research, there is a need to collect the latest information in this promising area. In the present review we have collated published reports on this versatile core to provide an insight so that its full therapeutic potential can be utilized for the treatment of pain and inflammation. Ó 2014 Elsevier Masson SAS. All rights reserved.

Keywords: Analgesic Benzimidazole Cyclooxygenase-2 (COX-2) inhibitors Non-steroidal anti-inflammatory drugs (NSAIDs)

1. Introduction The heterocyclic benzimidazole scaffold is a useful structural motif for the development of molecules of pharmaceutical or biological interest. In 1872, Hobrecker reported the first benzimidazole synthesis of 2,5- and 2,6-dimethylbenzimidazole and he never suspected that benzimidazole scaffold would become such a preeminent structure [1]. The interest in benzimidazole chemistry has been spawned by the discovery that N-ribosyl-dimethylbenzimidazole is the most prominent benzimidazole compound in nature which serves as an axial ligand for cobalt in vitamin B12 [2]. Over the years of active research, benzimidazole and its derivatives have evolved as important privileged structures in medicinal chemistry encompassing a diverse range of biological activities including antiparasitic (specifically anthelmintics, e.g., albendazole, mebendazole), antiulcer (proton pump inhibitors (PPIs), e.g., omeprazole), antihypertensive (angiotensin II receptor blockers, e.g., candesartan, telmisartan), antihistaminic (H1-receptor antagonists, e.g., bilastine), anti-cancer (nitrogen mustard alkylating agents, e.g., bendamustine), antiemetic/antipsychotics (e.g., droperidol) [3e5].

* Corresponding author. Tel.: þ91 9872390321. E-mail addresses: [email protected], (M. Gaba).

[email protected]

http://dx.doi.org/10.1016/j.ejmech.2014.01.030 0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

In the recent years, pain and inflammation are recognized as an overwhelming burden to the healthcare status of our population and the underlying basis of a significant number of diseases [6]. From Medical Expenditure Panel Survey it is found that the total cost of pain in the US market was $560e$635 billion in 2010 [7]. According to forecasts from Global Business Intelligence Research from 2002, the anti-inflammatory drug market grew at a rate of 7.6% to $57.8 billion in 2010 and is forecast to grow at the rate of 5.8% to produce revenues of $85.9 billion in 2017 [8]. Relieving pain and reduction of inflammation are urgent goals to reduce severity and symptoms of inflammation. Management of pain and inflammatory disorders involves a stepwise approach which includes classical NSAIDs, selective COX-2 inhibitors, corticosteroids and immunosuppressive agents [9]. Classical NSAIDs are widely used as a first choice of drug for the treatment of various inflammatory diseases as well as to relieve aches and pain but long term use of NSAIDs is associated with side effects like cardiovascular toxicity, gastrointestinal (GI) ulcerations, renal and hepatic toxicity, platelet dysfunction and bleeding, aplastic anemia and decreased bone healing [10e13]. Some selective COX-2 inhibitors were developed with the hope of significantly reducing GI toxicity associated with acute and chronic use of NSAIDs. However, increased knowledge of the physiological roles of COX-2 enzyme in a variety of tissues including stomach and kidney have challenged the benefits of selective COX-2 inhibition and initial enthusiasm in

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

495

Fig. 1. Structural requirements around benzimidazole nucleus for analgesic and anti-inflammatory activity.

this new class of anti-inflammatory drugs [14]. Synthetic forms of natural cortisol termed as glucocorticoids are also widely used to treat many inflammatory diseases, and despite their potentially debilitating side effects, glucocorticoids still remain a mainstay for reducing inflammation [15]. It is still a challenge for the pharmaceutical chemist to develop more effective and less toxic agents to treat signs and symptoms of pain and inflammatory disorders. A large amount of effort has been invested in the past decade to develop benzimidazole based compounds as modulator of pain and inflammation which are active on different clinically approved therapeutic targets showing excellent therapeutic potency. By looking into the importance of this therapeutic area we decided to collect the published analgesic and anti-inflammatory data on benzimidazole, the indispensable anchor in medicinal chemistry. In this review, we have attempted to shed light and compile published reports on benzimidazole derivatives along with some opinion on different approaches to help the medicinal chemists in designing future generation potent yet safer analgesic and anti-inflammatory agents. 2. Benzimidazole: chemistry and structural requirements for analgesic and anti-inflammatory activity Benzimidazole is a class of heterocyclic aromatic organic compound which share a fundamental structural characteristic of sixmembered benzene fused to the 4 and 5-position of five membered imidazole ring system. The hydrogen atom attached to nitrogen in the 1-position of benzimidazole nucleus readily

tautomerizes which is responsible for isomerization in the derived compounds [1,16]. The NH group present in benzimidazole is relatively strongly acidic and also weakly basic in nature [16]. Benzimidazole is an amphoteric compound with ionization constant (pKa) value for benzimidazole and its conjugate acid is 12.8 and 5.6, respectively [17]. From collected published data, it is found that the benzimidazole nucleus substituted at 1, 2, 5 and 6-position with varied substituents has produced potent analgesic as well as antiinflammatory agents. However, the 4 and 7-position of the nucleus is unsubstituted (Fig. 1). The 1-position of benzimidazole may be unsubstituted (TRPV-1 antagonists) or substituents may vary from polyhydroxy sugars, methyl or phenylsulfonyl groups, and cycloalkanes to aryl/heteroaryl moieties appropriately substituted with alkyl, electronic or heterocyclic groups. Similarly the 2position may be substituted with alkyl or bulky lipophilic aryl/ heteroaryl moieties substituted with alkyl, electronic or heterocyclic groups. The 5 or 6-position of the nucleus may be unsubstituted or substituents may range from functional groups like halogens, nitro, amino, methyl, trifluoromethyl, hydroxyl, alkoxy, sulfonyl or N-sulfonamide to substituted aryl/heteroaryl groups. 3. Benzimidazole derivatives for treatment of pain and inflammation A spectrum of pharmacological activities exhibited by benzimidazole and its derivatives has been reviewed by several authors. Here we will discuss about benzimidazole derivatives as analgesic

Fig. 2. Benzimidazoles acting on clinically approved targets for analgesic and anti-inflammatory activity.

496

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

Scheme 1. Benzimidazole derivative (1) and celecoxib as COX-2 inhibitors.

and anti-inflammatory agents which act on various therapeutic targets such as cyclooxygenase (COX) enzyme, transient receptor potential vanilloid-1 (TRPV-1) ion channels, cannabinoid receptors, bradykinin receptors, specific cytokines and 5-lipoxygenase activating protein (FLAP) (Fig. 2). 3.1. Selective COX-2 inhibitors COX is the key enzyme which catalyses the conversion of arachidonic acid into prostaglandins and thromboxanes [18,19]. The two isoforms of COX enzyme, i.e. COX-1 is a constitutive enzyme produced in many tissues such as kidney and GI tract while COX-2 is inducible and is expressed during inflammation at the site of injury [20e22]. Prostaglandins made by COX-1 enzyme exert cytoprotective effects on the gastric mucosa and maintenance of renal homeostasis, whereas, prostaglandins made by COX-2 cause inflammation [23]. Therefore, complete inhibition of COX-1 is not preferred and the drugs that inhibit COX-2 enzyme are better antiinflammatory agents in terms of GI tolerability. In search of potent and safer anti-inflammatory agents Paramashivappa et al. reported

semisynthetic derivatives of anacardic acid bearing benzimidazole scaffold and investigated their ability to inhibit human COX-1 as well as COX-2 enzymes. Compound 1 (Scheme 1) was observed to exhibit 384-fold selectivity towards COX-2 inhibition over COX-1 which is comparable to 375-fold selectivity of clinically approved celecoxib as COX-2 inhibitor (IC50 ¼ 0.04 mM on COX-2 and IC50 ¼ 15 mM for COX-1) (Scheme 1) [24,25]. 3.2. TRPV-1 antagonists TRPV-1 is a member of ion channels which allow the transient influx of Ca2þ ions when activated and predominantly expressed in peripheral sensory neurons that are involved in nociception and neurogenic inflammation [26]. TRPV-1 is activated by endogenous ligands such as lipoxygenase metabolites, a variety of stimuli such as heat or acid and exogenous chemical stimuli such as capsaicin. TRPV-1 activation by agonists is known to have analgesic effect because it leads to desensitization of sensory neurons and making them less sensitive to painful stimuli. However, prolonged use of such agonists is associated with side

Scheme 2. Benzimidazole derivatives as TRPV-1 antagonists (2e6).

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

effects such as burning sensation, irritation and neurotoxicity due to the continuous influx of Ca2þ ions into the cells [27e29]. TRPV1 receptor antagonists on the other hand inhibit the activation of primary sensory neurons and therefore may have fewer side effects than TRPV-1 agonists [30e33]. A series of 2-(4-pyridin-2ylpiperazin-1-yl)-1H-benzo-[d]imidazoles as potent TRPV-1 antagonists have been reported by Ognyanov et al. Compound 2 (Scheme 2) with benzimidazole nucleus was the most potent orally bioavailable and efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. Compound 2 has also reversed the thermal hyperalgesia in a model of inflammatory pain induced by Complete Freund’s Adjuvant [34]. Furthermore, a patent application from Amgen has also defined the utility of piperazine-linked benzimidazole derivative WO 04035549 (Scheme 2) as TRPV-1 antagonist [32]. Further, Fletcher et al. reported benzimidazole containing compound 3 (Scheme 2) with potent affinity at the hTRPV-1 receptors measured in a FLIPR-based assay. However minor modifications to compound 3 such as replacement of the 4-CF3 group with tert-butyl (compound 4), CH3 (compound 5), or F (compound 6) (Scheme 2) led to decrease in activity [35]. 3.3. Cannabinoid receptor agonists Recent studies have demonstrated that cannabinoid receptor agonists are effective for the treatment of pain in different neuropathic and inflammatory pain models. These effects are mediated via two subtypes of cannabinoid receptors located centrally and peripherally (CB1) or on immune cells or in the peripheral tissues (CB2). A large preclinical data support the hypothesis that either CB2-selective agonists or CB1 agonists acting at peripheral sites or with limited central nervous system (CNS) exposure will inhibit pain and neuroinflammation without side effects within the CNS.

497

So, there has been a growing interest in developing cannabinoid agonists. AstraZeneca has disclosed a series of benzimidazole derivatives as selective CB2 agonists as well as CB1/CB2 dual agonists for the management of pain and inflammation. Compound 7 (Scheme 3) was found to be a highly selective CB2 agonist having 970-fold selectivity over CB1 receptors with Ki value 3170 nM and 3.3 nM for human CB1 and CB2 receptors, respectively. Replacement of carboxamido group at C5 of compound 7 (Scheme 3) with sulfamoyl group claimed another cannabinoid receptor agonist as shown by compound 8 (Scheme 3). In addition, scientists from AstraZeneca have also reported potent benzimidazole-based compound 9 (Scheme 3) with large polar 5-N-sulfonamide substituent as CB1/CB2 dual agonist for the management of pain [36]. Recently, Watson et al. from Pfizer have reported a novel series of sulfonylbenzimidazole derivatives 10 and 11 (Scheme 3) as CNS penetrant selective CB2 agonists as potential analgesic agents devoid of the side effects associated with CB1 agonists [37]. In 2012, Verbist and coworkers described potent highly selective and peripherally restricted 5-sulfonylbenzimidazole derivatives as CB2-receptor agonists. One of the key compounds arising from this series was compound 12 (Scheme 3) which combined the selectivity with an acceptable drug-like profile. Although this translated in a decent pharmacokinetic profile, no analgesic effect was demonstrated in pain models. Further to improve the metabolic stability and solubility, the same group optimized the 5-sulfonylbenzimidazole derivatives and led to the discovery of relatively polar and peripherally acting CB2 agonists as compounds 13 and 14 (Scheme 3) [38]. 3.4. Bradykinin receptor antagonists The kinins, bradykinin and kallidin provoke a number of acute and chronic inflammatory pathways resulting in pain, edema and vasodilation [39e41]. These effects are mediated by the G-protein

Scheme 3. Benzimidazole derivatives as cannabinoid receptor agonists (7e14).

498

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

coupled receptors of bradykinin B1 and B2 [42]. The bradykinin B2 receptor is constitutively expressed under normal conditions in most cell types, whereas the bradykinin B1 receptor is induced under pathophysiological conditions such as infections, inflammatory diseases and traumatic tissue injury [41]. Recent studies in mice showed that the bradykinin B1 receptor is constitutively expressed in the CNS suggesting a potential central role for this receptor as well. The bradykinin B1 receptor null mice exhibited less inflammatory response and hyperalgesia supporting the hypothesis that bradykinin B1 receptor antagonists will be effective

analgesic anti-inflammatory drugs. Efforts have been made by Guo et al. to find new bradykinin B1 receptor antagonists. In 2008, the authors reported selective, non-peptide, potent bradykinin B1 receptor antagonists bearing benzodiazepine template with excellent in vivo efficacy in rodent models of pain. But because of high molecular weight and poor oral bioavailability in rodents the phenethylbenzodiazepine moiety of 15 (Scheme 4) was replaced by benzimidazole core a low molecular weight surrogate, led to potent compound at both human and rat bradykinin B1 receptors with improved oral bioavailability. The 2-carboxamide group was

Scheme 4. Benzimidazole derivatives as bradykinin receptor antagonists (15e19).

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

important for the activity and a number of different linkers and amine groups like pyridine and piperidine moieties were studied but the combination of b-alanine linker and 2-imidazoline-5aminopyridine group, however, led to the identification of compound 16 (Scheme 4) showing excellent potency with IC50 ¼ 2 nM [43]. Similarly, Zischinsky et al. reported benzimidazole derivatives as small molecule bradykinin B1 receptor antagonist 17 (Scheme 4) with IC50 value 3500 nM. Moreover, to improve the activity an acetamide moiety was added to compound 17 (Scheme 4) which lead to identification of compound 18 (Scheme 4) with IC50 value 15 nM. Optimization of the biaryl and amide moieties resulted in compound 19 (Scheme 4) having excellent potency at the B1 receptor with IC50 ¼ 0.7 nM [44]. 3.5. Anticytokines 3.5.1. MAP (mitogen-activated protein) kinase inhibitors The anticytokine therapies have revealed to be highly effective in reducing local and systemic inflammation [45]. Over the past decade, the pursuit of p38a MAP kinase inhibitors has received an extraordinary level of attention in the medicinal chemistry and drug candidates for the treatment of both pain and inflammatory diseases [46]. Inhibition of the p38a MAP kinase through their downstream blockage of the production of tumor necrosis factor-a, interleukin (IL)-1b, IL-6, COX-2 and arachidonic acid mobilization have tremendous therapeutic potential [47,48]. Recently, Dios et al. reported potent and selective 2-aminobenzimidazole based MAP kinase inhibitor 20 (Scheme 5) but the pyridinoyl-5methoxybenzimidazole derivative 21 (Scheme 5) showed the highest efficacy and selectivity [49].

499

3.5.2. Lck (lymphocyte specific kinase) inhibitors Lck is a 56-kD Src family protein tyrosine kinase that plays critical role in the development and activation of T-cells including T-cell antigen receptor phosphorylation (an event necessary for signal transduction in the T-cell signaling cascade of T-cell receptors). Activation of this cascade results in the production of cytokines such as IL-2 and interferon gamma which cause activation and proliferation of T-lymphocytes to generate an immune response. The inhibition of Lck has been proposed as a potential treatment for a number of inflammatory and autoimmune diseases. Sabat et al. synthesized a series of 1-(substituted pyrimidin-2-yl) benzimidazoles of which compound 22 (Scheme 5) has elicited anti-inflammatory effect with low nM activity for inhibition of Lck kinase and inhibitor of IL-2 cytokine production with potency at 0.054 mM [50]. Further, exploration of pyrimidobenzimidazoles has led to a series of pyrimido[1,2-a]benzimidazol-5-ones as potent orally active specific inhibitors of Lck. The SAR studies have revealed compound 23 (Scheme 5) as the most potent Lck inhibitor [51]. In 2009, Hunt et al. developed a family of 4-benzimidazolyl-Npiperazinethyl-pyrimidin-2-amines as potent Lck kinase as well as cellular IL-2 release inhibitors. Compound 24 (Scheme 5) combines the optimized piperazine-ethyl moiety at the pyrimidine C2 with the optimized benzimidazolyl substituent at pyrimidine C4, as inhibitor of both Lck kinase with IC50 value 0.1 nM and cellular IL-2 release with IC50 value 8 nM [52]. Due to the metabolic instability of f152A1, Shen et al. reported synthetic analog of f152A1 i.e. compound 25 (Scheme 5) by the fusion of an imidazole nucleus with the phenyl ring of an active metabolite isolated from fermentation broth of fungus Curvularia verruculosa as a promising and stable candidate that retained the in vitro inhibitory effect on

Scheme 5. Benzimidazole derivatives as anticytokines (20e25).

500

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

tumor necrosis factor-a transcription of f152A1 and wider therapeutic windows in in vivo model of arthritis [53].

for further investigations in the field of medicinal chemistry in search of potent and safer analgesic anti-inflammatory agents.

3.6. FLAP inhibitors

4. Future directions

Leukotrienes are lipid mediators responsible for initiation and amplification of the inflammatory response by regulating the recruitment and activation of leukocytes in inflamed tissues. Besides targeting 5-lipoxygenase, inhibition of leukotrienes biosynthesis may also be achieved by targeting FLAP. Drug candidates like MK-886, BAY X1005 and MK-591 all target FLAP and underwent phase I and II studies demonstrated the clinical benefits in allergic asthma trials but these were not further developed for unpublished reasons. However, recently developed FLAP inhibitors such as AM803, AM643 and AM103 efficacious in preclinical studies of inflammatory diseases as well as in trials with patients suffering from asthma are currently under clinical investigations [54e58]. Banoglu et al. reported benzimidazole derivatives as FLAP inhibitors as a promising strategy to intervene inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model lead to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl) ethyl)-1H-benzimidazole derivative 26 (Scheme 6) as developable candidate potently suppressed the leukotriene formation in intact neutrophils with IC50 ¼ 0.31 mM. By optimizing the structure of compound 26 (Scheme 6), potent benzimidazole-based derivatives 27e31 (Scheme 6) have been synthesized with IC50 ¼ 0.12e0.19 mM in intact neutrophils [59].

NSAIDs have been used successfully for centuries for the alleviation of pain and inflammation and continue to be used every day by millions of patients worldwide. Despite the tremendous advances in the last 2e3 decades, the design and development of safe and effective therapy for treating pain and inflammatory conditions still presents a major challenge. The discovery of two COX isoforms i.e. COX-1 and COX-2, was a breakthrough that led to obtaining selective COX-2 inhibitors which are less gastrotoxic than classical NSAIDs. However, withdrawal of some coxibs from the market because of cardiovascular toxicity has challenged the benefits of this class of drugs. As a consequence, the interest in alternative approaches to reduce GI side effects associated with NSAIDs has re-emerged. Fixed dose combination of NSAID/PPIs or NSAID/H2-receptor antagonists will likely help the above discussed problem. However, this approach is associated with the disadvantages that it limits the choice of analgesic anti-inflammatory component, which could be an issue for some patients who are intolerant or refractory to a particular NSAID. Furthermore, there are also concerns about the interactions of PPIs with other commonly prescribed drugs most notably clopidogrel. Though H2-receptor antagonists are safe but tolerance to these drugs has been reported to develop after a few days of therapy. This therapeutic noncompliance and limitations of existing therapies result in a substantial unmet clinical need, which we believe can be appropriately addressed with a drug having analgesic anti-inflammatory activity along with GI protective actions. Benzimidazole being a common scaffold in various analgesic/ anti-inflammatory molecules and PPIs, it is possible to design a molecule having both properties in a single entity. Recently, ElNezhawy et al. reported a series of benzimidazole derivatives with anti-inflammatory and PPIs activity which supports our opinion [72].

3.7. Miscellaneous Various benzimidazole derivatives have been reported by a number of authors as analgesic and anti-inflammatory agents but without their exact mechanism of action. In Table 1, we have compiled different benzimidazole derivatives with functional groups promoting their activity to help chemists and biochemists

Scheme 6. Benzimidazole derivatives as FLAP inhibitors (26e31).

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

501

Table 1 Miscellaneous benzimidazole derivatives as analgesic and anti-inflammatory agents. Compounds

Salient features

-

-

-

-

-

-

-

-

-

40, R= -CH2=CHCH3 41, R= n-C3H7 42, R= -CH(CH3)2

-

-

-

References

Compounds 32 and 33 are neutral molecules bearing eNH2 functional group at para and ortho positions, respectively. Devoid of acidic character. Exhibited moderate to good analgesic anti-inflammatory activity. Low ulcerogenic potential.

[60]

Compound 34 bearing eOCH3 group and disubstituted pyrrolidino at the nitrogen exhibited potent anti-inflammatory activity. Compound 35 bearing eNO2 group and disubstituted morpholino at the nitrogen exhibited potent analgesic activity.

[61]

The benzo[d]imidazolyltetrahydropyridine carboxylates 36 and 37 were synthesized by one-pot multi-component reaction using ceric ammonium nitrate as catalyst. Exhibited moderate anti-inflammatory activity in the rat paw edema model.

[62]

SAR studies of the 2-(2,4-dinitrophenylthio)-1-((3-isoxazol)methyl) benzimidazole hybrids were carried out. Compounds 38 and 39 possessing electron withdrawing groups eF and eCN showed superior analgesic and anti-inflammatory activity.

[63]

The 1-acyl-2-alkylthio-1,2,4-triazolobenzimidazole derivatives were synthesized in good yields. The p-chlorobenzoyl substituted compounds 40e42 were potent analgesic and anti-inflammatory agents. Compound 42 elicited superior GI safety profile as compared to indomethacin.

[64]

(continued on next page)

502

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

Table 1 (continued ) Compounds

Salient features

References

The mannich bases of 1-(N-substituted amino)methyl-2-ethylbenzimidazoles were synthesized. Compounds 43e45 exhibited significant analgesic and anti-inflammatory response.

[65]

-

The fused pyrimido[1,2-a]benzimidazole ring system with phenylsulfonyl moiety 46 exhibited comparable analgesic and anti-inflammatory activity to indomethacin.

[9]

-

The 2-methylaminobenzimidazoles 47 and 48 bearing eCl group at para position in aniline ring exhibited potent analgesic anti-inflammatory activity compared to nimesulide.

[66]

-

The pyridyl substituted oxadiazole ring attached to benzimidazole moiety through thioacetamide linkage. Compound 49 demonstrated good antioxidant and anti-inflammatory activity.

[67]

-

The tricyclic benzimidazole compounds 50 and 51 were synthesized under microwave irradiation resulted in potent anti-inflammatory activity comparable to standard drug ibuprofen.

[68]

-

The 3-methyl-8-nitro-3,4,4a,5-tetrahydropyrimido[1,6-a] benzimidazol-1(2H)-thione, compound 52 showed potent analgesic and anti-inflammatory activity comparable to ibuprofen.

[69]

-

-

-

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

503

Table 1 (continued ) Compounds

Salient features

-

-

-

-

-

-

-

-

-

-

-

References

The 2-aminobenzimidazole derivative 53 exhibited potent analgesic and anti-inflammatory activity. Replacement of amino with methylene group at 2-position cause complete loss of activity which supports the importance of guanidine moiety for anti-inflammatory activity.

[70]

Structure based 2-methyl-N-substituted benzimidazole with sugar moieties 54 and 55 were obtained with good yield in the presence of trimethylsilyl trifluoromethanesulfonate as catalyst. Compounds 54 and 55 exhibited significant analgesic and anti-inflammatory activity.

[71]

Benzimidazole derivatives 56 and 57 substituted with pyrid-2-yl moiety and polyhydroxy sugar conjugated to the N-benzimidazole moiety displayed dose-dependent anti-inflammatory activity diclofenac. Compound 56 and 57 were GI tolerable.

[72]

BenzimidazoleeNSAID conjugates retained the anti-inflammatory activity of the corresponding parent NSAIDs. BenzimidazoleeNSAID conjugates significantly reduced the gastric ulcers and exhibited potent immunostimulatory as well as antioxidant activity. Compound 58 was the maximally potent NSAID-conjugate.

[73]

The 1,2,4-triazolobenzimidazol-3-yl acetohydrazide derivatives exhibited significant analgesic and anti-inflammatory activity. Compounds 59 and 60 were the most active analgesic, anti-inflammatory and GI safer comparable to indomethacin.

[74]

504

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

Another major adverse effect of chronic usage of NSAIDs is cardiovascular complications and benzimidazole is the common scaffold which possesses analgesic/anti-inflammatory along with angiotensin II receptor blocking activity (i.e. candesartan, telmisartan). So, a similar approach can be utilized to design drugs having dual action as analgesic/anti-inflammatory with better cardiovascular tolerability. Simple inhibition of prostaglandin synthesis cannot completely stop the inflammatory process. Therefore, new agents are tested for their influence on many other pathways of pain and inflammation like formation of inflammatory cytokines, free radicals and biogenic amines from stimulated inflammatory cells. Benzimidazole derivatives are found to act through different mechanisms such as anticytokines, TRPV-1 antagonists, cannabinoid receptor agonists and FLAP inhibitors. So, there is a possibility that a single benzimidazole derivative can be optimized to act through multiple pathways involved in the pain and inflammation. This approach may possess benefits as effective pain relief can be achieved with fewer or no side effects as compared to combination of analgesic anti-inflammatory drugs acting through different mechanisms. In this way, benzimidazole scaffold offers a unique set of properties to be pursued as a pharmacophore for designing of orally active small molecules that may holds considerable promise for treatment of pain and inflammatory disorders. 5. Concluding remarks Despite improvements in our understanding the pathophysiological mechanisms of pain and inflammatory states, the discovery of an ultimate magic bullet to treat pain and inflammation is still a dream. A good number of reports demonstrated the use of benzimidazole derivatives active on different clinically approved therapeutic targets for treatment of pain and inflammation. Further research in this field will bring innovative pharmaceutical developments with a considerable spectrum of use. References [1] J.B. Wright, The chemistry of the benzimidazoles, Chem. Rev. 48 (3) (1951) 397e541. [2] H.A. Barker, R.D. Smyth, H. Weissbach, J.I. Toohey, J.N. Ladd, B.E. Volcani, Isolation and properties of crystalline cobamide coenzymes containing benzimidazole or 5,6 dimethylbenzimidazole, J. Biol. Chem. 235 (2) (1960) 480e488. [3] A.A. Spasov, I.N. Yozhitsa, L.I. Bugaeva, V.A. Anisimova, Benzimidazole derivatives: spectrum of pharmacological activity and toxicological properties, Pharm. Chem. J. 33 (5) (1999) 232e243. [4] S.L. Khokra, D. Choudhary, Benzimidazole an important scaffold in drug discovery, Asian J. Biochem. Pharm. Res. 3 (1) (2011) 476e486. [5] V.K. Vyas, M. Ghate, Substituted benzimidazole derivatives as angiotensin IIAT1 receptor antagonist: a review, Mini-Rev. Med. Chem. 10 (14) (2010) 1366e1384. [6] T. Edwards, Inflammation, pain, and chronic disease: an integrative approach to treatment and prevention, Altern. Ther. Health Med. 11 (6) (2005) 20e27. [7] D.J. Gaskin, P. Richard, The economic costs of pain in the United States, J. Pain 13 (8) (2012) 715e724. [8] http://www.thepharmaletter.com/file/108598/anti-inflammatorytherapeutics-market-to-grow-to859-billion-in-2017.htm. [9] M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A. Mansour, A.M. Farag, Synthesis and analgesic/anti-inflammatory evaluation of fused heterocyclic ring systems incorporating phenylsulfonyl moiety, Bioorg. Med. Chem. 16 (12) (2008) 6344e6352. [10] M.S. Bergh, S.C. Budsberg, The coxib NSAIDs: potential clinical and pharmacologic importance in veterinary medicine, J. Vet. Intern. Med. 19 (5) (2005) 633e643. [11] B. Feldman, J. Zinkl, N. Jain (Eds.), Veterinary Hematology, fifth ed., Lippincott Williams and Wilkins, Philadelphia, PA, 2000, p. 213. [12] L.A. Trepanier, Mechanisms of drug-associated hepatotoxicity in the dog and cat, in: Proceedings of the 20th annual forum of the ACVIM, Dallas, 2002, pp. 669e671. [13] I.L. Meek, M.A.F.J. Van de Laar, H.E. Vonkeman, Non-steroidal antiinflammatory drugs: an overview of cardiovascular risks, Pharmaceuticals 3 (2010) 2146e2162.

[14] S.X. Sun, K.Y. Lee, C.T. Bertram, J.L. Goldstein, Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization, Curr. Med. Res. Opin. 23 (8) (2007) 1859e 1866. [15] C.A. Dinarello, Anti-inflammatory agents: present and future, Cell 140 (6) (2010) 935e950. [16] R.G. Ingle, D.D. Magar, Heterocyclic chemistry of benzimidazoles and potential activities of derivatives, Int. J. Drug. Res. Technol. 1 (1) (2011) 26e32. [17] H. Walba, R.W. Isensee, Acidity constants of some arylimidazoles and their cations, J. Org. Chem. 26 (1961) 2789e2791. [18] J.R. Vane, Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs, Nat. New Biol. 231 (1971) 232e235. [19] J.B. Smith, A.L. Willis, Aspirin selectively inhibits prostaglandin production in human platelets, Nat. New Biol. 231 (1971) 235e237. [20] W.L. Xie, J.G. Chipman, D.L. Robertson, R.L. Erikson, D.L. Simmons, Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing, Proc. Natl. Acad. Sci. U.S.A. 88 (1991) 2692e2696. [21] D.A. Kubuju, B.S. Fletcher, B.C. Varnum, R.A. Lim, H.R. Herschman, TIS10, a phorbol ester tumor promoter/inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue, J. Biol. Chem. 266 (1991) 12866e12872. [22] T. Hla, K. Neilson, Human cyclooxygenase-2 cDNA, Proc. Natl. Acad. Sci. U.S.A. 89 (1992) 7384e7388. [23] H.R. Herschman, Prostaglandin synthase 2, Biochim. Biophys. Acta 1299 (1) (1996) 125e140. [24] R. Paramashivappa, P.P. Kumar, P.V.S. Rao, A.S. Rao, Design, synthesis and biological evaluation of benzimidazole/benzothiazole and benzoxazole derivatives as cyclooxygenase inhibitors, Bioorg. Med. Chem. Lett. 13 (4) (2003) 657e660. [25] C.J. Smith, Y. Zhang, C.M. Koboldt, J. Muhammad, B.S. Zweifel, A. Shaffer, J.J. Talley, J.L. Masferrer, K. Seibert, P.C. Isakson, Pharmacological analysis of cyclooxygenase-1 in inflammation, Proc. Natl. Acad. Sci. U.S.A. 95 (1998) 13313e13318. [26] I. Nagy, P. Santha, G. Jancso, L. Urban, The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology, Eur. J. Pharmacol. 500 (1e3) (2004) 351e369. [27] D. Smart, M.J. Gunthrope, J.C. Jerman, S. Nasir, J. Gray, A.I. Muir, J.K. Chambers, A.D. Randal, J.B. Davis, The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1), Br. J. Pharm. 129 (2) (2000) 227e230. [28] S.W. Hwang, H. Cho, J. Kwak, S.Y. Lee, C.J. Kang, J. Jung, S. Cho, K.H. Min, Y.G. Suh, D. Kim, U. Oh, Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances, Proc. Natl. Acad. Sci. U.S.A. 97 (2000) 6155e6160. [29] M.J. Caterina, D. Julius, The vanilloid receptor: a molecular gateway to the pain pathway, Annu. Rev. Neurosci. 24 (2001) 487e517. [30] A. Szallasi, G. Appendino, Vanilloid receptor TRPV1 antagonists as the next generation of painkillers. Are we putting the cart before the horse, J. Med. Chem. 47 (11) (2004) 2717e2723. [31] K.J. Valenzano, Q. Sun, Current perspectives on the therapeutic utility of VR1 antagonists, Curr. Med. Chem. 11 (2004) 3185e3202. [32] H.K. Rami, M.J. Gunthorpe, The therapeutic potential of TRPV1 (VR1) antagonists: clinical answers await, Drug Discov. Today: Ther. Strateg. 1 (2004) 97e 104. [33] M.L. Lopez-Rodriguez, A. Viso, S. Ortega-Gutierrez, VR1 receptor modulators as potential drugs for neuropathic pain, Mini-Rev. Med. Chem. 3 (7) (2003) 729e748. [34] V.I. Ognyanov, C. Balan, A.W. Bannon, Y. Bo, C. Dominguez, C. Fotsch, V.K. Gore, L. Klionsky, V.V. Ma, Y.X. Qian, R. Tamir, X. Wang, N. Xi, S. Xu, D. Zhu, N.R. Gavva, J.J. Treanor, M.H. Norman, Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structureeactivity relationships of 2-piperazin-1-yl-1H benzimidazoles, J. Med. Chem. 49 (12) (2006) 3719e3742. [35] S.R. Fletcher, E. McIver, S. Lewis, F. Burkamp, C. Leech, G. Mason, S. Boyce, D. Morrison, G. Richards, K. Sutton, A.B. Jones, The search for novel TRPV1antagonists: from carboxamides to benzimidazoles and indazolones, Bioorg. Med. Chem. Lett. 16 (2006) 2872e2876. [36] Y. Cheng, S.A. Hitchcock, Targeting cannabinoid agonists for inflammatory and neuropathic pain, Expert Opin. Invest. Drugs 16 (7) (2007) 951e965. [37] C. Watson, D.R. Owen, D. Harding, K. Kon-I, M.L. Lewis, H.J. Mason, M. Matsumizu, T. Mukaiyama, M. Rodriguez-Lens, A. Shima, M. Takeuchi, I. Tran, T. Young, Optimisation of a novel series of selective CNS penetrant CB2 agonists, Bioorg. Med. Chem. Lett. 21 (2011) 4284e4287. [38] H.J.M. Gijsen, M.A.J. De Cleyn, M. Surkyn, G.R.E. Van Lommen, B.M.P. Verbist, M.J.M.A. Nijsen, T. Meert, J.V. Wauwe, J. Aerssens, 5-Sulfonyl-benzimidazoles as selective CB2 agonists-Part 2, Bioorg. Med. Chem. Lett. 22 (2012) 547e552. [39] D.J. Campbell, The kallikrein-kinin system in humans, Clin. Exp. Pharmacol. Physiol. 28 (12) (2001) 1060e1065. [40] E.G. Erdos, Kinins, the long march-a personal view, Cardiovasc. Res. 54 (3) (2002) 485e491. [41] F. Marceau, J.F. Hess, D.R. Bachvarov, The B1 receptors for kinins, Pharmacol. Rev. 50 (3) (1998) 357e386. [42] D. Regoli, J. Barabe, Pharmacology of bradykinin and related kinins, Pharmacol. Rev. 32 (1) (1980) 1e46. [43] Q. Guo, J. Chandrasekhar, D. Ihle, D.J. Wustrow, B.L. Chenard, J.E. Krause, A. Hutchison, D. Alderman, C. Cheng, D. Cortright, D. Broom, M.T. Kershaw,

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

J. Simmermacher-Mayer, Y. Peng, K.J. Hodgetts, 1-Benzylbenzimidazoles: the discovery of a novel series of bradykinin B1 receptor antagonists, Bioorg. Med. Chem. Lett. 18 (2008) 5027e5031. G. Zischinsky, R. Stragies, M. Schaudt, J.R. Pfeifer, C. Gibson, E. Locardi, D. Scharn, U. Richter, H. Kalkhof, K. Dinkel, K. Schnatbaum, Novel small molecule bradykinin B1 receptor antagonists. Part 2: 5-membered diaminoheterocycles, Bioorg. Med. Chem. Lett. 20 (2010) 1229e1232. A. Tincani, L. Andreoli, C. Bazzani, D. Bosiso, S. Sozzani, Inflammatory molecules: a target for treatment of systemic autoimmune diseases, Autoimmun. Rev. 7 (1) (2007) 1e7. Y. Hu, N. Gren, L.K. Gavrin, K. Janz, N. Kaila, H.Q. Li, Inhibition of Tpl2 kinase and TNFa production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis, Bioorg. Med. Chem. Lett. 16 (2006) 6067e6072. J.C. Lee, J.T. Laydon, P.C. McDonnell, T.F. Gallagher, S. Kumar, D.A. Green, Protein kinase involved in the regulation of inflammatory cytokine biosynthesis, Nature 372 (2002) 739e746. A.G. Borsch-Haubold, R.M. Kramer, S.P. Watson, Phosphorylation and activation of cytosolic phospholipase A2 by 38-kDa mitogen-activated protein kinase in collagen-stimulated human platelets, Eur. J. Biochem. 245 (1997) 751e759. A.D. Dios, C.B. Shih, L.D. Uralde, C. Sanchez, M.D. Prado, M.M. Cabrejas, Design of potent and selective 2-aminobenzimidazole-based p38a MAP kinase inhibitors with excellent in vivo efficacy, J. Med. Chem. 48 (2005) 2270e2273. M. Sabat, J.C. VanRens, M.J. Laufersweiler, T.A. Brugel, J. Maier, A. Golebiowski, B. De, V. Easwaran, L.C. Hsieh, R.L. Walter, M.J. Mekel, A. Evdokimov, M.J. Janusz, The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck), Bioorg. Med. Chem. Lett. 16 (2006) 5973e5977. M.W. Martin, J. Newcomb, J.J. Nunes, C. Boucher, L. Chai, L.F. Epstein, T. Faust, S. Flores, P. Gallant, A. Gore, Y. Gu, F. Hsieh, X. Huang, J.L. Kim, S. Middleton, K. Morgenstern, A. Oliveira-dos-Santos, V.F. Patel, D. Powers, P. Rose, Y. Tudor, S.M. Turci, A.A. Welcher, D. Zack, H. Zhao, L. Zhu, X. Zhu, C. Ghiron, M. Ermann, D. Johnston, C.G. Saluste, Structure-based design of novel 2-amino-6-phenylpyrimido[50 ,40 :5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): synthesis, SAR and in vivo anti-inflammatory activity, J. Med. Chem. 51 (6) (2008) 1637e1648. J.A. Hunt, R.T. Beresis, J.L. Goulet, M.A. Holmes, X.J. Hong, E. Kovacs, S.G. Mills, R.D. Ruzek, F. Wong, J.D. Hermes, Y. Park, S.P. Salowe, L.M. Sonatore, L. Wu, A. Woods, D.M. Zaller, P.J. Sinclair, Disubstituted pyrimidines as Lck inhibitors, Bioorg. Med. Chem. Lett. 19 (2009) 5440e5443. Y. Shen, R. Boivin, N. Yoneda, H. Du, S. Schiller, T. Matsushima, M. Goto, H. Shirota, F. Gusovsky, C. Lemelin, Y. Jiang, Z. Zhang, R. Pelletier, M. IkemoriKawada, Y. Kawakami, A. Inoue, M. Schnaderbeck, Y. Wang, Discovery of antiinflammatory clinical candidate E6201, inspired from resorcylic lactone LLZ1640-2, III, Bioorg. Med. Chem. Lett. 20 (10) (2010) 3155e3157. J.F. Evans, A.D. Ferguson, R.T. Mosley, J.H. Hutchinson, What’s all the FLAP about? 5-lipoxygenase-activating protein inhibitors for inflammatory diseases, Trends Pharmacol. Sci. 29 (2) (2008) 72e78. J.H. Hutchinson, Y. Li, J.M. Arruda, C. Baccei, G. Bain, C. Chapman, L. Correa, J. Darlington, C.D. King, C. Lee, D. Lorrain, P. Prodanovich, H. Rong, A. Santini, N. Stock, P. Prasit, J.F. Evans, 5-Lipoxygenase-activating protein inhibitors: development of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), J. Med. Chem. 52 (19) (2009) 5803e5815. N. Stock, C. Baccei, G. Bain, A. Broadhead, C. Chapman, J. Darlington, C. King, C. Lee, Y. Li, D.S. Lorrain, P. Prodanovich, H. Rong, A. Santini, J. Zunic, J.F. Evans, J.H. Hutchinson, P. Prasit, 5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (AM679)-a potent FLAP inhibitor, Bioorg. Med. Chem. Lett. 20 (1) (2010) 213e217. N. Stock, C. Baccei, G. Bain, C. Chapman, L. Correa, J. Darlington, C. King, C. Lee, D.S. Lorrain, P. Prodanovich, A. Santini, K. Schaab, J.F. Evans, J.H. Hutchinson, P. Prasit, 5-Lipoxygenase-activating protein inhibitors. Part 3: 3-{3-tertbutylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM643)-a potent FLAP inhibitor suitable for topical administration, Bioorg. Med. Chem. Lett. 20 (15) (2010) 4598e4601.

505

[58] N.S. Stock, G. Bain, J. Zunic, Y. Li, J. Ziff, J. Roppe, A. Santini, J. Darlington, P. Prodanovich, C.D. King, C. Baccei, C. Lee, H. Rong, C. Chapman, A. Broadhead, D. Lorrain, L. Correa, J.H. Hutchinson, J.F. Evans, P. Prasit, 5-Lipoxygenaseactivating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor, J. Med. Chem. 54 (23) (2011) 8013e8029. [59] E. Banoglu, B. Caliskan, S. Luderer, G. Eren, Y. Ozkan, W. Altenhofen, C. Weinigel, D. Barz, J. Gerstmeier, C. Pergola, O. Werz, Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP), Bioorg. Med. Chem. 20 (2012) 3728e3741. [60] M. Gaba, D. Singh, S. Singh, V. Sharma, P. Gaba, Synthesis and pharmacological evaluation of novel 5-substituted-1-(phenylsulfonyl)-2-methylbenzimidazole derivatives as anti-inflammatory and analgesic agents, Eur. J. Med. Chem. 45 (6) (2010) 2245e2249. [61] G.M. Rao, Y.N. Reddy, B.V. Kumar, Evaluation of analgesic and antiinflammatory activities of N-mannich bases of substituted 2-mercapto-1Hbenzimidazoles, Int. J. Appl. Biol. Pharm. Technol. 4 (1) (2013) 38e46. [62] A. Ravindernath, M.S. Reddy, Synthesis and evaluation of anti-inflammatory, antioxidant and antimicrobial activities of densely functionalized novel benzo-[d]-imidazolyl tetrahydropyridine carboxylates, Arab. J. Chem. (2013) in press. [63] S. Kankala, R.K. Kankala, P. Gundepaka, N. Thota, S. Nerella, M.R. Gangula, H. Guguloth, M. Kagga, R. Vadde, C.S. Vasam, Regioselective synthesis of isoxazole-mercapto benzimidazole hybrids and their in vivo analgesic and anti-inflammatory activity studies, Bioorg. Med. Chem. Lett. 23 (5) (2013) 1306e1309. [64] B.G. Mohamed, A.M. Abdel-Alim, M.A. Hussein, Synthesis of 1-acyl-2alkylthio-1,2,4-triazolobenzimidazoles with antifungal, anti-inflammatory and analgesic effects, Acta Pharm. Res. 56 (2006) 31e48. [65] G. Mariappan, N.R. Bhuyan, P. Kumar, D. Kumar, K. Murali, Synthesis and biological evaluation of Mannich bases of benzimidazole derivatives, Ind. J. Chem. 50B (2011) 1216e1219. [66] K.C.S. Achar, K.M. Hosamani, H.R. Seetharamareddy, In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives, Eur. J. Med. Chem. 45 (5) (2010) 2048e2054. [67] S. Rajasekaran, G. Rao, A. Chatterjee, Synthesis, anti-inflammatory and antioxidant activity of some substituted benzimidazole derivatives, Int. J. Drug Dev. Res. 4 (3) (2012) 303e309. [68] S.M. Sondhi, R. Rani, J. Singh, P. Roy, S.K. Agrawal, A.K. Saxena, Solvent free synthesis, anti-inflammatory and anticancer activity evaluation of tricyclic and tetracyclic benzimidazole derivatives, Bioorg. Med. Chem. Lett. 20 (7) (2010) 2306e2310. [69] S.M. Sondhi, S. Rajvanshi, M. Johar, N. Bharti, A. Azam, A.K. Singh, Anti-inflammatory, analgesic and antiamoebic activity evaluation of pyrimido[1,6-a] benzimidazole derivatives synthesized by the reaction of ketoisothiocyanates with mono and diamines, Eur. J. Med. Chem. 37 (10) (2002) 835e843. [70] K. Taniguchi, S. Shigenaga, T. Ogahara, T. Fujitsu, M. Matsuo, Synthesis and anti- inflammatory and analgesic properties of 2-amino-1H-benzimidazole and 1,2-dihydro-2- iminocycloheptimidazole derivatives, Chem. Pharm. Bull. 41 (2) (1993) 301e309. [71] A.O.H. El-Nezhawy, S.T. Gaballah, M.A.A. Radwan, A.R. Baiuomy, O.M.E. AbdelSalam, Structure-based design of benzimidazole sugar conjugates: synthesis, SAR and in vivo anti-inflammatory and analgesic activities, Med. Chem. 5 (2009) 558e569. [72] A.O.H. El-Nezhawy, A.R. Biuomy, F.S. Hassan, A.K. Ismaiel, H.A. Omar, Design, synthesis and pharmacological evaluation of omeprazole-like agents with anti-inflammatory activity, Bioorg. Med. Chem. 21 (7) (2013) 1661e1670. [73] Y. Bansal, O. Silakari, Synthesis and pharmacological evaluation of polyfunctional benzimidazole-NSAID chimeric molecules combining antiinflammatory, immunomodulatory and antioxidant activities, Arch. Pharm. Res. (2013) in press. [74] A.F. Mohammed, S.G. Abdel-Moty, M.A. Hussein, A.M. Abdel-Alim, Design, synthesis and molecular docking of some new 1,2,4-triazolobenzimidazol-3yl acetohydrazide derivatives with anti-inflammatory analgesic activities, Arch. Pharm. Res. 36 (12) (2013) 1465e1479.