lable at ScienceDirect

European Journal of Medicinal Chemistry 76 (2014) 494e505

Contents lists avai

European Journal of Medicinal Chemistry

journal homepage: http: / /www.elsevier .com/locate/ejmech

Mini-review

Benzimidazole: An emerging scaffold for analgesicand anti-inflammatory agents

Monika Gaba a,*, Sarbjot Singh b, Chander Mohan c

aDepartment of Pharmaceutical Sciences, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab, IndiabDrug Discovery Research, Panacea Biotec Pvt. Ltd., Mohali, Punjab, IndiacRayat-Bahra Institute of Pharmacy, Hoshiarpur, Punjab, India

a r t i c l e i n f o

Article history:Received 11 October 2013Received in revised form19 January 2014Accepted 20 January 2014Available online 18 February 2014

Keywords:AnalgesicBenzimidazoleCyclooxygenase-2 (COX-2) inhibitorsNon-steroidal anti-inflammatory drugs(NSAIDs)

* Corresponding author. Tel.: þ91 9872390321.E-mail addresses: monikagaba12@gmail.com,

(M. Gaba).

http://dx.doi.org/10.1016/j.ejmech.2014.01.0300223-5234/� 2014 Elsevier Masson SAS. All rights re

a b s t r a c t

Within the vast range of heterocycles, benzimidazole and its derivatives are found to be trendy structuresemployed for discovery of drugs in the field of pharmaceutical and medicinal chemistry. The uniquestructural features of benzimidazole and a wide range of biological activities of its derivatives made itprivileged structure in drug discovery. Recently, benzimidazole scaffold has emerged as a pharmaco-phore of choice for designing analgesic and anti-inflammatory agents active on different clinicallyapproved targets. To pave the way for future research, there is a need to collect the latest information inthis promising area. In the present review we have collated published reports on this versatile core toprovide an insight so that its full therapeutic potential can be utilized for the treatment of pain andinflammation.

� 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction

The heterocyclic benzimidazole scaffold is a useful structuralmotif for the development of molecules of pharmaceutical or bio-logical interest. In 1872, Hobrecker reported the first benzimidazolesynthesis of 2,5- and 2,6-dimethylbenzimidazole and he neversuspected that benzimidazole scaffold would become such a pre-eminent structure [1]. The interest in benzimidazole chemistry hasbeen spawned by the discovery that N-ribosyl-dimethylbenzimi-dazole is the most prominent benzimidazole compound in naturewhich serves as an axial ligand for cobalt in vitamin B12 [2]. Overthe years of active research, benzimidazole and its derivatives haveevolved as important privileged structures in medicinal chemistryencompassing a diverse range of biological activities includingantiparasitic (specifically anthelmintics, e.g., albendazole, meben-dazole), antiulcer (proton pump inhibitors (PPIs), e.g., omeprazole),antihypertensive (angiotensin II receptor blockers, e.g., cande-sartan, telmisartan), antihistaminic (H1-receptor antagonists, e.g.,bilastine), anti-cancer (nitrogen mustard alkylating agents, e.g.,bendamustine), antiemetic/antipsychotics (e.g., droperidol) [3e5].

gaba_monika12@yahoo.co.in

served.

In the recent years, pain and inflammation are recognized as anoverwhelming burden to the healthcare status of our populationand the underlying basis of a significant number of diseases [6].From Medical Expenditure Panel Survey it is found that the totalcost of pain in the US market was $560e$635 billion in 2010 [7].According to forecasts from Global Business Intelligence Researchfrom 2002, the anti-inflammatory drug market grew at a rate of7.6% to $57.8 billion in 2010 and is forecast to grow at the rate of5.8% to produce revenues of $85.9 billion in 2017 [8].

Relieving pain and reduction of inflammation are urgent goals toreduce severity and symptoms of inflammation. Management ofpain and inflammatory disorders involves a stepwise approachwhich includes classical NSAIDs, selective COX-2 inhibitors, corti-costeroids and immunosuppressive agents [9]. Classical NSAIDs arewidely used as a first choice of drug for the treatment of variousinflammatory diseases as well as to relieve aches and pain but longterm use of NSAIDs is associated with side effects like cardiovas-cular toxicity, gastrointestinal (GI) ulcerations, renal and hepatictoxicity, platelet dysfunction and bleeding, aplastic anemia anddecreased bone healing [10e13]. Some selective COX-2 inhibitorswere developed with the hope of significantly reducing GI toxicityassociated with acute and chronic use of NSAIDs. However,increased knowledge of the physiological roles of COX-2 enzyme ina variety of tissues including stomach and kidney have challengedthe benefits of selective COX-2 inhibition and initial enthusiasm in

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

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505 495

this new class of anti-inflammatory drugs [14]. Synthetic forms ofnatural cortisol termed as glucocorticoids are also widely used totreat many inflammatory diseases, and despite their potentiallydebilitating side effects, glucocorticoids still remain a mainstay forreducing inflammation [15]. It is still a challenge for the pharma-ceutical chemist to develop more effective and less toxic agents totreat signs and symptoms of pain and inflammatory disorders. Alarge amount of effort has been invested in the past decade todevelop benzimidazole based compounds as modulator of pain andinflammation which are active on different clinically approvedtherapeutic targets showing excellent therapeutic potency. Bylooking into the importance of this therapeutic area we decided tocollect the published analgesic and anti-inflammatory data onbenzimidazole, the indispensable anchor in medicinal chemistry. Inthis review, we have attempted to shed light and compile publishedreports on benzimidazole derivatives along with some opinion ondifferent approaches to help the medicinal chemists in designingfuture generation potent yet safer analgesic and anti-inflammatoryagents.

2. Benzimidazole: chemistry and structural requirements foranalgesic and anti-inflammatory activity

Benzimidazole is a class of heterocyclic aromatic organic com-pound which share a fundamental structural characteristic of six-membered benzene fused to the 4 and 5-position of fivemembered imidazole ring system. The hydrogen atom attached tonitrogen in the 1-position of benzimidazole nucleus readily

Fig. 2. Benzimidazoles acting on clinically approved ta

tautomerizes which is responsible for isomerization in the derivedcompounds [1,16]. The NH group present in benzimidazole isrelatively strongly acidic and also weakly basic in nature [16].Benzimidazole is an amphoteric compound with ionization con-stant (pKa) value for benzimidazole and its conjugate acid is 12.8and 5.6, respectively [17].

From collected published data, it is found that the benzimid-azole nucleus substituted at 1, 2, 5 and 6-position with variedsubstituents has produced potent analgesic as well as anti-inflammatory agents. However, the 4 and 7-position of the nu-cleus is unsubstituted (Fig. 1). The 1-position of benzimidazole maybe unsubstituted (TRPV-1 antagonists) or substituents may varyfrom polyhydroxy sugars, methyl or phenylsulfonyl groups, andcycloalkanes to aryl/heteroaryl moieties appropriately substitutedwith alkyl, electronic or heterocyclic groups. Similarly the 2-position may be substituted with alkyl or bulky lipophilic aryl/heteroaryl moieties substituted with alkyl, electronic or heterocy-clic groups. The 5 or 6-position of the nucleusmay be unsubstitutedor substituents may range from functional groups like halogens,nitro, amino, methyl, trifluoromethyl, hydroxyl, alkoxy, sulfonyl orN-sulfonamide to substituted aryl/heteroaryl groups.

3. Benzimidazole derivatives for treatment of pain andinflammation

A spectrum of pharmacological activities exhibited by benz-imidazole and its derivatives has been reviewed by several authors.Here we will discuss about benzimidazole derivatives as analgesic

rgets for analgesic and anti-inflammatory activity.

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

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505496

and anti-inflammatory agents which act on various therapeutictargets such as cyclooxygenase (COX) enzyme, transient receptorpotential vanilloid-1 (TRPV-1) ion channels, cannabinoid receptors,bradykinin receptors, specific cytokines and 5-lipoxygenase acti-vating protein (FLAP) (Fig. 2).

3.1. Selective COX-2 inhibitors

COX is the key enzyme which catalyses the conversion ofarachidonic acid into prostaglandins and thromboxanes [18,19].The two isoforms of COX enzyme, i.e. COX-1 is a constitutiveenzyme produced in many tissues such as kidney and GI tract whileCOX-2 is inducible and is expressed during inflammation at the siteof injury [20e22]. Prostaglandins made by COX-1 enzyme exertcytoprotective effects on the gastric mucosa and maintenance ofrenal homeostasis, whereas, prostaglandins made by COX-2 causeinflammation [23]. Therefore, complete inhibition of COX-1 is notpreferred and the drugs that inhibit COX-2 enzyme are better anti-inflammatory agents in terms of GI tolerability. In search of potentand safer anti-inflammatory agents Paramashivappa et al. reported

Scheme 2. Benzimidazole derivative

semisynthetic derivatives of anacardic acid bearing benzimidazolescaffold and investigated their ability to inhibit human COX-1 aswell as COX-2 enzymes. Compound 1 (Scheme 1) was observed toexhibit 384-fold selectivity towards COX-2 inhibition over COX-1which is comparable to 375-fold selectivity of clinically approvedcelecoxib as COX-2 inhibitor (IC50 ¼ 0.04 mM on COX-2 andIC50 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 transientinflux of Ca2þ ions when activated and predominantly expressedin peripheral sensory neurons that are involved in nociceptionand neurogenic inflammation [26]. TRPV-1 is activated byendogenous ligands such as lipoxygenase metabolites, a variety ofstimuli such as heat or acid and exogenous chemical stimuli suchas capsaicin. TRPV-1 activation by agonists is known to haveanalgesic effect because it leads to desensitization of sensoryneurons and making them less sensitive to painful stimuli.However, prolonged use of such agonists is associated with side

s as TRPV-1 antagonists (2e6).

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505 497

effects such as burning sensation, irritation and neurotoxicity dueto the continuous influx of Ca2þ ions into the cells [27e29]. TRPV-1 receptor antagonists on the other hand inhibit the activation ofprimary sensory neurons and therefore may have fewer side ef-fects than TRPV-1 agonists [30e33]. A series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo-[d]imidazoles as potent TRPV-1 an-tagonists have been reported by Ognyanov et al. Compound 2(Scheme 2) with benzimidazole nucleus was the most potentorally bioavailable and efficacious in blocking capsaicin-inducedflinch in rats in a dose-dependent manner. Compound 2 hasalso reversed the thermal hyperalgesia in a model of inflamma-tory pain induced by Complete Freund’s Adjuvant [34]. Further-more, a patent application from Amgen has also defined theutility of piperazine-linked benzimidazole derivative WO04035549 (Scheme 2) as TRPV-1 antagonist [32].

Further, Fletcher et al. reported benzimidazole containingcompound 3 (Scheme 2) with potent affinity at the hTRPV-1 re-ceptors measured in a FLIPR-based assay. However minor modifi-cations to compound 3 such as replacement of the 4-CF3 groupwithtert-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 receptoragonists are effective for the treatment of pain in different neuro-pathic and inflammatory pain models. These effects are mediatedvia two subtypes of cannabinoid receptors located centrally andperipherally (CB1) or on immune cells or in the peripheral tissues(CB2). A large preclinical data support the hypothesis that eitherCB2-selective agonists or CB1 agonists acting at peripheral sites orwith limited central nervous system (CNS) exposure will inhibitpain and neuroinflammation without side effects within the CNS.

Scheme 3. Benzimidazole derivatives as c

So, there has been a growing interest in developing cannabinoidagonists. AstraZeneca has disclosed a series of benzimidazole de-rivatives as selective CB2 agonists as well as CB1/CB2 dual agonistsfor the management of pain and inflammation. Compound 7(Scheme 3) was found to be a highly selective CB2 agonist having970-fold selectivity over CB1 receptors with Ki value 3170 nM and3.3 nM for human CB1 and CB2 receptors, respectively. Replacementof carboxamido group at C5 of compound 7 (Scheme 3) with sul-famoyl group claimed another cannabinoid receptor agonist asshown by compound 8 (Scheme 3). In addition, scientists fromAstraZeneca have also reported potent benzimidazole-based com-pound 9 (Scheme 3) with large polar 5-N-sulfonamide substituentas CB1/CB2 dual agonist for the management of pain [36]. Recently,Watson et al. from Pfizer have reported a novel series of sulfo-nylbenzimidazole derivatives 10 and 11 (Scheme 3) as CNS pene-trant selective CB2 agonists as potential analgesic agents devoid ofthe side effects associated with CB1 agonists [37]. In 2012, Verbistand coworkers described potent highly selective and peripherallyrestricted 5-sulfonylbenzimidazole derivatives as CB2-receptor ag-onists. One of the key compounds arising from this series wascompound 12 (Scheme 3) which combined the selectivity with anacceptable drug-like profile. Although this translated in a decentpharmacokinetic profile, no analgesic effect was demonstrated inpain models. Further to improve the metabolic stability and solu-bility, the same group optimized the 5-sulfonylbenzimidazole de-rivatives and led to the discovery of relatively polar and peripherallyacting CB2 agonists as compounds 13 and 14 (Scheme 3) [38].

3.4. Bradykinin receptor antagonists

The kinins, bradykinin and kallidin provoke a number of acuteand chronic inflammatory pathways resulting in pain, edema andvasodilation [39e41]. These effects are mediated by the G-protein

annabinoid receptor agonists (7e14).

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505498

coupled receptors of bradykinin B1 and B2 [42]. The bradykinin B2receptor is constitutively expressed under normal conditions inmost cell types, whereas the bradykinin B1 receptor is inducedunder pathophysiological conditions such as infections, inflam-matory diseases and traumatic tissue injury [41]. Recent studies inmice showed that the bradykinin B1 receptor is constitutivelyexpressed in the CNS suggesting a potential central role for thisreceptor as well. The bradykinin B1 receptor null mice exhibitedless inflammatory response and hyperalgesia supporting the hy-pothesis that bradykinin B1 receptor antagonists will be effective

Scheme 4. Benzimidazole derivatives as br

analgesic anti-inflammatory drugs. Efforts have been made by Guoet al. to find new bradykinin B1 receptor antagonists. In 2008, theauthors reported selective, non-peptide, potent bradykinin B1 re-ceptor antagonists bearing benzodiazepine template with excellentin vivo efficacy in rodent models of pain. But because of high mo-lecular weight and poor oral bioavailability in rodents the phene-thylbenzodiazepine moiety of 15 (Scheme 4) was replaced bybenzimidazole core a lowmolecular weight surrogate, led to potentcompound at both human and rat bradykinin B1 receptors withimproved oral bioavailability. The 2-carboxamide group was

adykinin receptor antagonists (15e19).

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505 499

important for the activity and a number of different linkers andamine groups like pyridine and piperidine moieties were studiedbut the combination of b-alanine linker and 2-imidazoline-5-aminopyridine group, however, led to the identification of com-pound 16 (Scheme 4) showing excellent potency with IC50 ¼ 2 nM[43]. Similarly, Zischinsky et al. reported benzimidazole derivativesas small molecule bradykinin B1 receptor antagonist 17 (Scheme 4)with IC50 value 3500 nM. Moreover, to improve the activity anacetamide moiety was added to compound 17 (Scheme 4) whichlead to identification of compound 18 (Scheme 4) with IC50 value15 nM. Optimization of the biaryl and amide moieties resulted incompound 19 (Scheme 4) having excellent potency at the B1 re-ceptor with IC50 ¼ 0.7 nM [44].

3.5. Anticytokines

3.5.1. MAP (mitogen-activated protein) kinase inhibitorsThe anticytokine therapies have revealed to be highly effective

in reducing local and systemic inflammation [45]. Over the pastdecade, the pursuit of p38a MAP kinase inhibitors has received anextraordinary level of attention in the medicinal chemistry anddrug candidates for the treatment of both pain and inflammatorydiseases [46]. Inhibition of the p38a MAP kinase through theirdownstream blockage of the production of tumor necrosis factor-a,interleukin (IL)-1b, IL-6, COX-2 and arachidonic acid mobilizationhave tremendous therapeutic potential [47,48]. Recently, Dios et al.reported potent and selective 2-aminobenzimidazole based MAPkinase inhibitor 20 (Scheme 5) but the pyridinoyl-5-methoxybenzimidazole derivative 21 (Scheme 5) showed thehighest efficacy and selectivity [49].

Scheme 5. Benzimidazole derivati

3.5.2. Lck (lymphocyte specific kinase) inhibitorsLck is a 56-kD Src family protein tyrosine kinase that plays

critical role in the development and activation of T-cells includingT-cell antigen receptor phosphorylation (an event necessary forsignal transduction in the T-cell signaling cascade of T-cell re-ceptors). Activation of this cascade results in the production ofcytokines such as IL-2 and interferon gamma which cause activa-tion and proliferation of T-lymphocytes to generate an immuneresponse. The inhibition of Lck has been proposed as a potentialtreatment 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 elicitedanti-inflammatory effect with low nM activity for inhibition of Lckkinase and inhibitor of IL-2 cytokine production with potency at0.054 mM [50]. Further, exploration of pyrimidobenzimidazoles hasled to a series of pyrimido[1,2-a]benzimidazol-5-ones as potentorally active specific inhibitors of Lck. The SAR studies haverevealed compound 23 (Scheme 5) as the most potent Lck inhibitor[51]. In 2009, Hunt et al. developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines as potent Lck kinase as well ascellular IL-2 release inhibitors. Compound 24 (Scheme 5) combinesthe optimized piperazine-ethyl moiety at the pyrimidine C2 withthe optimized benzimidazolyl substituent at pyrimidine C4, as in-hibitor of both Lck kinase with IC50 value 0.1 nM and cellular IL-2release with IC50 value 8 nM [52]. Due to the metabolic instabilityof f152A1, Shen et al. reported synthetic analog of f152A1 i.e.compound 25 (Scheme 5) by the fusion of an imidazole nucleuswith the phenyl ring of an active metabolite isolated fromfermentation broth of fungus Curvularia verruculosa as a promisingand stable candidate that retained the in vitro inhibitory effect on

ves as anticytokines (20e25).

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505500

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

3.6. FLAP inhibitors

Leukotrienes are lipid mediators responsible for initiation andamplification of the inflammatory response by regulating therecruitment and activation of leukocytes in inflamed tissues. Be-sides targeting 5-lipoxygenase, inhibition of leukotrienes biosyn-thesis may also be achieved by targeting FLAP. Drug candidates likeMK-886, BAY X1005 and MK-591 all target FLAP and underwentphase I and II studies demonstrated the clinical benefits in allergicasthma trials but these were not further developed for unpublishedreasons. However, recently developed FLAP inhibitors such asAM803, AM643 and AM103 efficacious in preclinical studies of in-flammatory diseases as well as in trials with patients suffering fromasthma are currently under clinical investigations [54e58]. Banogluet al. reported benzimidazole derivatives as FLAP inhibitors as apromising strategy to intervene inflammatory, allergic and car-diovascular diseases. Virtual screening targeting FLAP based on acombined ligand- and structure-based pharmacophore model leadto the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole derivative 26 (Scheme 6) as developablecandidate potently suppressed the leukotriene formation in intactneutrophils with IC50 ¼ 0.31 mM. By optimizing the structure ofcompound 26 (Scheme 6), potent benzimidazole-based derivatives27e31 (Scheme 6) have been synthesized with IC50 ¼ 0.12e0.19 mMin intact neutrophils [59].

3.7. Miscellaneous

Various benzimidazole derivatives have been reported by anumber of authors as analgesic and anti-inflammatory agents butwithout their exact mechanism of action. In Table 1, we havecompiled different benzimidazole derivatives with functionalgroups promoting their activity to help chemists and biochemists

Scheme 6. Benzimidazole derivativ

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

4. Future directions

NSAIDs have been used successfully for centuries for the allevi-ation of pain and inflammation and continue to be used every day bymillions of patientsworldwide. Despite the tremendous advances inthe last 2e3 decades, the design and development of safe andeffective therapy for treating pain and inflammatory conditions stillpresents a major challenge. The discovery of two COX isoforms i.e.COX-1 andCOX-2,was a breakthrough that led to obtaining selectiveCOX-2 inhibitors which are less gastrotoxic than classical NSAIDs.However, withdrawal of some coxibs from the market because ofcardiovascular toxicity has challenged the benefits of this class ofdrugs. As a consequence, the interest in alternative approaches toreduce GI side effects associated with NSAIDs has re-emerged.

Fixed dose combination of NSAID/PPIs or NSAID/H2-receptorantagonists will likely help the above discussed problem. However,this approach is associated with the disadvantages that it limits thechoice of analgesic anti-inflammatory component, which could bean issue for some patients who are intolerant or refractory to aparticular NSAID. Furthermore, there are also concerns about theinteractions of PPIs with other commonly prescribed drugs mostnotably clopidogrel. Though H2-receptor antagonists are safe buttolerance to these drugs has been reported to develop after a fewdays of therapy. This therapeutic noncompliance and limitations ofexisting therapies result in a substantial unmet clinical need, whichwe believe can be appropriately addressed with a drug havinganalgesic anti-inflammatory activity along with GI protective ac-tions. Benzimidazole being a common scaffold in various analgesic/anti-inflammatory molecules and PPIs, it is possible to design amolecule having both properties in a single entity. Recently, El-Nezhawy et al. reported a series of benzimidazole derivativeswith anti-inflammatory and PPIs activity which supports ouropinion [72].

es as FLAP inhibitors (26e31).

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

Compounds Salient features References

- Compounds 32 and 33 are neutral moleculesbearing eNH2 functional group at para andortho positions, respectively.

- Devoid of acidic character.- Exhibited moderate to good analgesic

anti-inflammatory activity.- Low ulcerogenic potential.

[60]

- Compound 34 bearing eOCH3 group and disubstitutedpyrrolidino at the nitrogen exhibited potentanti-inflammatory activity.

- Compound 35 bearing eNO2 group and disubstitutedmorpholino at the nitrogen exhibited potentanalgesic activity.

[61]

- The benzo[d]imidazolyltetrahydropyridine carboxylates36 and 37 were synthesized by one-pot multi-componentreaction using ceric ammonium nitrate as catalyst.

- Exhibited moderate anti-inflammatory activity in the ratpaw 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 withdrawinggroups eF and eCN showed superior analgesic andanti-inflammatory activity.

[63]

40, R= -CH2=CHCH341, R= n-C3H742, R= -CH(CH3)2

- The 1-acyl-2-alkylthio-1,2,4-triazolobenzimidazole derivativeswere synthesized in good yields.

- The p-chlorobenzoyl substituted compounds 40e42 werepotent analgesic and anti-inflammatory agents.

- Compound 42 elicited superior GI safety profile as comparedto indomethacin.

[64]

(continued on next page)

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505 501

Table 1 (continued )

Compounds Salient features References

- The mannich bases of 1-(N-substitutedamino)methyl-2-ethylbenzimidazoles were synthesized.

- Compounds 43e45 exhibited significant analgesicand anti-inflammatory response.

[65]

- The fused pyrimido[1,2-a]benzimidazole ring systemwith phenylsulfonyl moiety 46 exhibited comparableanalgesic and anti-inflammatory activity to indomethacin.

[9]

- The 2-methylaminobenzimidazoles 47 and 48bearing eCl group at para position in aniline ringexhibited potent analgesic anti-inflammatory activitycompared to nimesulide.

[66]

- The pyridyl substituted oxadiazole ring attached tobenzimidazole moiety through thioacetamide linkage.

- Compound 49 demonstrated good antioxidant andanti-inflammatory activity.

[67]

- The tricyclic benzimidazole compounds 50 and 51were synthesized under microwave irradiationresulted in potent anti-inflammatory activity comparableto standard drug ibuprofen.

[68]

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

[69]

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505502

Table 1 (continued )

Compounds Salient features References

- The 2-aminobenzimidazole derivative 53 exhibitedpotent analgesic and anti-inflammatory activity.

- Replacement of amino with methylene group at2-position cause complete loss of activity which supports theimportance of guanidine moiety for anti-inflammatory activity.

[70]

- Structure based 2-methyl-N-substituted benzimidazole withsugar moieties 54 and 55 were obtained with good yield in thepresence of trimethylsilyl trifluoromethanesulfonate as catalyst.

- Compounds 54 and 55 exhibited significant analgesicand anti-inflammatory activity.

[71]

- Benzimidazole derivatives 56 and 57 substituted with pyrid-2-ylmoiety and polyhydroxy sugar conjugated to the N-benzimidazolemoiety displayed dose-dependent anti-inflammatory activitydiclofenac.

- Compound 56 and 57 were GI tolerable.

[72]

- BenzimidazoleeNSAID conjugates retained theanti-inflammatory activity of the corresponding parent NSAIDs.

- BenzimidazoleeNSAID conjugates significantly reduced thegastric ulcers and exhibited potent immunostimulatory aswell as antioxidant activity.

- Compound 58 was the maximally potent NSAID-conjugate.

[73]

- The 1,2,4-triazolobenzimidazol-3-yl acetohydrazidederivatives exhibited significant analgesic andanti-inflammatory activity.

- Compounds 59 and 60 were the most active analgesic,anti-inflammatory and GI safer comparable to indomethacin.

[74]

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505 503

M. Gaba et al. / European Journal of Medicinal Chemistry 76 (2014) 494e505504

Another major adverse effect of chronic usage of NSAIDs iscardiovascular complications and benzimidazole is the commonscaffold which possesses analgesic/anti-inflammatory along withangiotensin II receptor blocking activity (i.e. candesartan, telmi-sartan). So, a similar approach can be utilized to design drugshaving dual action as analgesic/anti-inflammatory with bettercardiovascular tolerability.

Simple inhibition of prostaglandin synthesis cannot completelystop the inflammatory process. Therefore, new agents are tested fortheir influence on many other pathways of pain and inflammationlike formation of inflammatory cytokines, free radicals and biogenicamines from stimulated inflammatory cells. Benzimidazole de-rivatives are found to act through different mechanisms such asanticytokines, TRPV-1 antagonists, cannabinoid receptor agonistsand FLAP inhibitors. So, there is a possibility that a single benz-imidazole derivative can be optimized to act through multiplepathways involved in the pain and inflammation. This approachmay possess benefits as effective pain relief can be achieved withfewer or no side effects as compared to combination of analgesicanti-inflammatory drugs acting through different mechanisms. Inthis way, benzimidazole scaffold offers a unique set of properties tobe pursued as a pharmacophore for designing of orally active smallmolecules that may holds considerable promise for treatment ofpain and inflammatory disorders.

5. Concluding remarks

Despite improvements in our understanding the pathophysio-logical mechanisms of pain and inflammatory states, the discoveryof an ultimate magic bullet to treat pain and inflammation is still adream. A good number of reports demonstrated the use of benz-imidazole derivatives active on different clinically approved ther-apeutic targets for treatment of pain and inflammation. Furtherresearch in this field will bring innovative pharmaceutical de-velopments 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 containingbenzimidazole 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 de-rivatives: 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 dis-covery, Asian J. Biochem. Pharm. Res. 3 (1) (2011) 476e486.

[5] V.K. Vyas, M. Ghate, Substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonist: a review, Mini-Rev. Med. Chem. 10 (14) (2010)1366e1384.

[6] T. Edwards, Inflammation, pain, and chronic disease: an integrative approachto 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. Pain13 (8) (2012) 715e724.

[8] http://www.thepharmaletter.com/file/108598/anti-inflammatory-therapeutics-market-to-grow-to859-billion-in-2017.htm.

[9] M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A. Mansour, A.M. Farag, Synthesis andanalgesic/anti-inflammatory evaluation of fused heterocyclic ring systemsincorporating phenylsulfonyl moiety, Bioorg. Med. Chem. 16 (12) (2008)6344e6352.

[10] M.S. Bergh, S.C. Budsberg, The coxib NSAIDs: potential clinical and pharma-cologic importance in veterinary medicine, J. Vet. Intern. Med. 19 (5) (2005)633e643.

[11] B. Feldman, J. Zinkl, N. Jain (Eds.), Veterinary Hematology, fifth ed., LippincottWilliams and Wilkins, Philadelphia, PA, 2000, p. 213.

[12] L.A. Trepanier, Mechanisms of drug-associated hepatotoxicity in the dog andcat, 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 anti-inflammatory 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 selectiveinhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotectivedrug prescribing and utilization, Curr. Med. Res. Opin. 23 (8) (2007) 1859e1866.

[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 potentialactivities of derivatives, Int. J. Drug. Res. Technol. 1 (1) (2011) 26e32.

[17] H. Walba, R.W. Isensee, Acidity constants of some arylimidazoles and theircations, J. Org. Chem. 26 (1961) 2789e2791.

[18] J.R. Vane, Inhibition of prostaglandin synthesis as a mechanism of action foraspirin-like drugs, Nat. New Biol. 231 (1971) 232e235.

[19] J.B. Smith, A.L. Willis, Aspirin selectively inhibits prostaglandin production inhuman platelets, Nat. New Biol. 231 (1971) 235e237.

[20] W.L. Xie, J.G. Chipman, D.L. Robertson, R.L. Erikson, D.L. Simmons, Expressionof a mitogen-responsive gene encoding prostaglandin synthase is regulatedby 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, aphorbol ester tumor promoter/inducible mRNA from Swiss 3T3 cells, encodesa 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 andbiological evaluation of benzimidazole/benzothiazole and benzoxazole de-rivatives 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 ofcyclooxygenase-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 atthe 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 oflipoxygenases: 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 painpathway, Annu. Rev. Neurosci. 24 (2001) 487e517.

[30] A. Szallasi, G. Appendino, Vanilloid receptor TRPV1 antagonists as the nextgeneration 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 VR1antagonists, Curr. Med. Chem. 11 (2004) 3185e3202.

[32] H.K. Rami, M.J. Gunthorpe, The therapeutic potential of TRPV1 (VR1) antag-onists: clinical answers await, Drug Discov. Today: Ther. Strateg. 1 (2004) 97e104.

[33] M.L. Lopez-Rodriguez, A. Viso, S. Ortega-Gutierrez, VR1 receptor modulatorsas 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 an-tagonists of the transient receptor potential vanilloid 1. Structureeactivityrelationships 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 TRPV1-antagonists: from carboxamides to benzimidazoles and indazolones, Bioorg.Med. Chem. Lett. 16 (2006) 2872e2876.

[36] Y. Cheng, S.A. Hitchcock, Targeting cannabinoid agonists for inflammatory andneuropathic 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 CB2agonists, 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-benzimidazolesas 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, Pharma-col. 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 505

J. Simmermacher-Mayer, Y. Peng, K.J. Hodgetts, 1-Benzylbenzimidazoles: thediscovery of a novel series of bradykinin B1 receptor antagonists, Bioorg. Med.Chem. Lett. 18 (2008) 5027e5031.

[44] G. Zischinsky, R. Stragies, M. Schaudt, J.R. Pfeifer, C. Gibson, E. Locardi,D. Scharn, U. Richter, H. Kalkhof, K. Dinkel, K. Schnatbaum, Novel smallmolecule bradykinin B1 receptor antagonists. Part 2: 5-membered dia-minoheterocycles, Bioorg. Med. Chem. Lett. 20 (2010) 1229e1232.

[45] A. Tincani, L. Andreoli, C. Bazzani, D. Bosiso, S. Sozzani, Inflammatory mole-cules: a target for treatment of systemic autoimmune diseases, Autoimmun.Rev. 7 (1) (2007) 1e7.

[46] Y. Hu, N. Gren, L.K. Gavrin, K. Janz, N. Kaila, H.Q. Li, Inhibition of Tpl2 kinaseand TNFa production with quinoline-3-carbonitriles for the treatment ofrheumatoid arthritis, Bioorg. Med. Chem. Lett. 16 (2006) 6067e6072.

[47] 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 biosyn-thesis, Nature 372 (2002) 739e746.

[48] A.G. Borsch-Haubold, R.M. Kramer, S.P. Watson, Phosphorylation and activa-tion of cytosolic phospholipase A2 by 38-kDa mitogen-activated protein ki-nase in collagen-stimulated human platelets, Eur. J. Biochem. 245 (1997)751e759.

[49] A.D. Dios, C.B. Shih, L.D. Uralde, C. Sanchez, M.D. Prado, M.M. Cabrejas, Designof potent and selective 2-aminobenzimidazole-based p38a MAP kinase in-hibitors with excellent in vivo efficacy, J. Med. Chem. 48 (2005) 2270e2273.

[50] 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 pyrimidinebased inhibitors of lymphocyte specific kinase (Lck), Bioorg. Med. Chem. Lett.16 (2006) 5973e5977.

[51] 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-phenyl-pyrimido[50 ,40:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent andorally active inhibitors of lymphocyte specific kinase (Lck): synthesis, SAR andin vivo anti-inflammatory activity, J. Med. Chem. 51 (6) (2008) 1637e1648.

[52] 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.

[53] 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. Ikemori-Kawada, Y. Kawakami, A. Inoue, M. Schnaderbeck, Y. Wang, Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III, Bioorg. Med. Chem. Lett. 20 (10) (2010) 3155e3157.

[54] J.F. Evans, A.D. Ferguson, R.T. Mosley, J.H. Hutchinson, What’s all the FLAPabout? 5-lipoxygenase-activating protein inhibitors for inflammatory dis-eases, Trends Pharmacol. Sci. 29 (2) (2008) 72e78.

[55] 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.

[56] 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-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-pro-pionic acid (AM679)-a potent FLAP inhibitor, Bioorg. Med. Chem. Lett. 20 (1)(2010) 213e217.

[57] 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-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyr-idin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM643)-apotent FLAP inhibitor suitable for topical administration, Bioorg. Med. Chem.Lett. 20 (15) (2010) 4598e4601.

[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-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butyl-sulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-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 novelbenzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtualscreening 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 pharmacologicalevaluation of novel 5-substituted-1-(phenylsulfonyl)-2-methylbenzimidazolederivatives 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 anti-inflammatory activities of N-mannich bases of substituted 2-mercapto-1H-benzimidazoles, 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 novelbenzo-[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 ofisoxazole-mercapto benzimidazole hybrids and their in vivo analgesic andanti-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-2-alkylthio-1,2,4-triazolobenzimidazoles with antifungal, anti-inflammatoryand analgesic effects, Acta Pharm. Res. 56 (2006) 31e48.

[65] G. Mariappan, N.R. Bhuyan, P. Kumar, D. Kumar, K. Murali, Synthesis andbiological 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 andanti-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 anti-oxidant activity of some substituted benzimidazole derivatives, Int. J. DrugDev. Res. 4 (3) (2012) 303e309.

[68] S.M. Sondhi, R. Rani, J. Singh, P. Roy, S.K. Agrawal, A.K. Saxena, Solvent freesynthesis, anti-inflammatory and anticancer activity evaluation of tricyclicand 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-in-flammatory, analgesic and antiamoebic activity evaluation of pyrimido[1,6-a]benzimidazole derivatives synthesized by the reaction of ketoisothiocyanateswith mono and diamines, Eur. J. Med. Chem. 37 (10) (2002) 835e843.

[70] K. Taniguchi, S. Shigenaga, T. Ogahara, T. Fujitsu, M. Matsuo, Synthesis andanti- inflammatory and analgesic properties of 2-amino-1H-benzimidazoleand 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. Abdel-Salam, 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 withanti-inflammatory activity, Bioorg. Med. Chem. 21 (7) (2013) 1661e1670.

[73] Y. Bansal, O. Silakari, Synthesis and pharmacological evaluation of polyfunc-tional benzimidazole-NSAID chimeric molecules combining antiin-flammatory, 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-3-yl acetohydrazide derivatives with anti-inflammatory analgesic activities,Arch. Pharm. Res. 36 (12) (2013) 1465e1479.