Structure–Activity Relationship Analysis of Benzimidazoles As Emerging Anti-Inﬂammatory Agents: an Overview

pharmaceuticals Review Structure–Activity Relationship Analysis of Benzimidazoles as Emerging Anti-Inflammatory Agents: An Overview Ravichandran Veerasamy 1,2,*, Anitha Roy 3 , Rohini Karunakaran 4 and Harish Rajak 5 1 Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling 08100, Kedah, Malaysia 2 Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai 600077, Tamil Nadu, India 3 Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai 600077, Tamil Nadu, India; [email protected] 4 Faculty of Medicine, AIMST University, Semeling 08100, Kedah, Malaysia; [email protected] 5 SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495009, India; [email protected] * Correspondence: [email protected] Abstract: A significant number of the anti-inflammatory drugs currently in use are becoming obso- lete. These are exceptionally hazardous for long-term use because of their possible unfavourable impacts. Subsequently, in the ebb-and-flow decade, analysts and researchers are engaged in developing new anti-inflammatory drugs, and many such agents are in the later phases of clinical trials. Molecules with heterocyclic nuclei are similar to various natural antecedents, thus acquiring immense consideration from scientific experts and researchers. The arguably most adaptable heterocyclic cores are benzimidazoles containing nitrogen in a bicyclic scaffold. Numerous benzimidazole drugs are broadly used in the treatment of numerous diseases, showing promising therapeutic poten- Citation: Veerasamy, R.; Roy, A.; tial. Benzimidazole derivatives exert anti-inflammatory effects mainly by interacting with transient Karunakaran, R.; Rajak, H. receptor potential vanilloid-1, cannabinoid receptors, bradykinin receptors, specific cytokines, 5- Structure–Activity Relationship lipoxygenase activating protein and cyclooxygenase. Literature on structure–activity relationship Analysis of Benzimidazoles as (SAR) and investigations of benzimidazoles highlight that the substituent’s tendency and position Emerging Anti-Inflammatory Agents: on the benzimidazole ring significantly contribute to the anti-inflammatory activity. Reported SAR An Overview. Pharmaceuticals 2021, 14, 663. https://doi.org/10.3390/ analyses indicate that substitution at the N1, C2, C5 and C6 positions of the benzimidazole scaf- ph14070663 fold greatly influence the anti-inflammatory activity. For example, benzimidazole substituted with anacardic acid on C2 inhibits COX-2, and 5-carboxamide or sulfamoyl or sulfonyl benzimidazole Academic Editor: Mary J. Meegan antagonises the cannabinoid receptor, whereas the C2 diarylamine and C3 carboxamide substitution of the benzimidazole scaffold result in antagonism of the bradykinin receptor. In this review, we Received: 23 May 2021 examine the insights regarding the SARs of anti-inflammatory benzimidazole compounds, which Accepted: 9 July 2021 will be helpful for researchers in designing and developing potential anti-inflammatory drugs to Published: 11 July 2021 target inflammation-promoting enzymes. Publisher’s Note: MDPI stays neutral Keywords: benzimidazole; cyclooxygenase; bradykinin; cannabinoid; effect of structural modification with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Inflammation is derived from the Latin word “inflammare”. The body’s immune system initiates an immediate response to harmful stimuli, such as infections or any type Copyright: © 2021 by the authors. of irritation [1]. The inflammatory responses entail several biochemical events (Figure1 ). Licensee MDPI, Basel, Switzerland. They are a defensive attempt by the body to heal infections; however, if inflammation This article is an open access article is not controlled, it can prompt a cluster of acute, chronic and systemic inflammatory distributed under the terms and disorders [2,3]. The major symptoms of inflammation are redness, pain and swelling [4]. conditions of the Creative Commons Some diseases, such as cardiovascular disease, autoimmune diseases, periodontal disease, Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Alzheimer’s disease, asthma, diabetes and COPD, are related to chronic inflammation [1,2]. 4.0/). Steroid drugs have traditionally been used to treat inflammation, but their use has gradually Pharmaceuticals 2021, 14, 663. https://doi.org/10.3390/ph14070663 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 663 2 of 32 ease, Alzheimer’s disease, asthma, diabetes and COPD, are related to chronic inflamma- Pharmaceuticals 2021, 14, 663 tion [1,2]. Steroid drugs have traditionally been used to treat inflammation,2 of 32 but their use has gradually decreased due to their adverse effects [5]. Non-steroidal anti-inflammatory drugs have been introduced to overcome the adverse effects of steroidal drugs. The role ofease, cyclooxygenase Alzheimer’s disease, and asthma, its coenzyme diabetes and in COPD,the inflammatory are related to chronicprocess inflamma- was an uncreditable discoverytion [1,2]. Steroid [6,7]. drugs In recent have traditionallyyears, elucidatin been usedg the to treatvarious inflammation, complex but mechanisms their use behind the has gradually decreased due to their adverse effects [5]. Non-steroidal anti-inflammatory Pharmaceuticals 2021, 14, 663 2 of 31 inflammatorydrugs have been processintroduced has to indicatedovercome the new adverse methods effects for of steroidalits treatment drugs. [8,9].The role of cyclooxygenaseOver 75% of and the its medications coenzyme in currentlythe inflammatory used haveprocess heterocyclics was an uncreditable containing nitrogen, oxygendiscovery or [6,7]. sulphur, In recent and years, nitrogen elucidatin heterocyclicsg the various complexare present mechanisms in various behind therapeutically the ac- decreasedtiveinflammatory compounds due toprocess their [10,11]. adverse has indicated Pyrazole/pyrazoline, effects [new5]. Non-steroidal methods for its anti-inflammatory benzimidazole, treatment [8,9]. drugs indole have and been pyrimidine are introduced to overcome the adverse effects of steroidal drugs. The role of cyclooxygenase importantOver 75% nitrogen-containing of the medications currently heterocyclic used haves in heterocyclics anti-inflammatory containing research nitrogen, [12]. andoxygen its coenzyme or sulphur, in theand inflammatory nitrogen heterocyclics process was are an present uncreditable in various discovery therapeutically [6,7]. In recent ac- years,tive compounds elucidating [10,11]. the various Pyrazole/pyrazoline, complex mechanisms benzimidazole, behind the indole inflammatory and pyrimidine process has are indicatedimportant new nitrogen-containing methods for its treatment heterocyclic [8,9s]. in anti-inflammatory research [12]. FigureFigure 1.1. TheThe biochemicalbiochemical processprocess ofof inflammation. inflammation. COX—cyclooxygenase;COX—cyclooxygenase; LOX—lipoxygenase;LOX—lipoxygenase; γ PG—prostaglandin;PG—prostaglandin; LT—leukotriene; LT—leukotriene; Tx—thromboxane; Tx—thromboxane; NO—nitric NO—nitric oxide; oxide; IFN-γ—interferon; IFN- —interferon; TNF— Figure 1. The biochemical process of inflammati on. COX—cyclooxygenase; LOX—lipoxygenase; tumourTNF—tumour necrosis necrosis factor; NF- factor;κB—nuclear NF- B—nuclear factor-κB; factor- MAPK—mitogenB; MAPK—mitogen activated proteinactivated kinase; protein JAK— ki- PG—prostaglandin;nase; JAK—Janus kinase; LT—leukotriene;IL—interleukin. Tx—thromboxane; NO—nitric oxide; IFN-γ—interferon; Janus kinase; IL—interleukin. TNF—tumour necrosis factor; NF-B—nuclear factor-B; MAPK—mitogen activated protein kinase;OverBenzimidazole JAK—Janus 75% of the kinase; is medications bicyclic, IL—interleukin. comprising currently useda benzene have heterocyclics fused with an containing imidazole nitrogen, ring, a oxygenheteroaromatic or sulphur, compound and nitrogen with heterocyclicsan amphoteric are property present in(Figure various 2). therapeutically This privileged active scaffold exhibits anti-convulsant, antioxidant, anti-microbial, anticancer, anthelmintic, an- compoundsBenzimidazole [10,11]. Pyrazole/pyrazoline, is bicyclic, comprising benzimidazole, a benzene indole fused and pyrimidine with an imidazole are ring, a importantti-inflammatory, nitrogen-containing anti-fungal, antiviral, heterocyclics antipsychotic in anti-inflammatory and antihistaminic research [effects,12]. among heteroaromaticothersBenzimidazole [13]. Research compound is on bicyclic, the benzimidazole comprisingwith an amphoteric a nucleus benzene has fused property resulted with an in(Figure imidazoledrugs such2). ring,This as al- aprivileged scaf- heteroaromaticfoldbendazole, exhibits mebendazole, compoundanti-convulsant, thia withbendazole, an amphoteric antioxidant, omeprazole, property anti-microbial, lansop (Figurerazole,2). This pantoprazole, anticancer, privileged scaf- aste-anthelmintic, an- foldti-inflammatory,mizole, exhibits enviroxime, anti-convulsant, anti-fungal,candesartan, antioxidant, cilexitil, antiviral, anti-microbial,telmisartan antipsychotic and anticancer, numerous and anthelmintic,antihistaminicother compounds anti- effects, among inflammatory,othersfor treating [13]. other anti-fungal,Research diseases (Figure antiviral,on the 3) benzimidazole antipsychotic[14]. and nucleus antihistaminic has effects,resulted among in oth-drugs such as al- ersbendazole, [13]. Research

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