RESEARCH ARTICLE Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile Muhammad T. Khan 1 | Humaira Nadeem 1 | Arif-ullah Khan 3 | Muzaffar Abbas 2 | Muazzam Arif 1 | Nadia Shamshad Malik 2 | Zulkifal Malik 2 | Ibrahim Javed 4 1 Department of Pharmaceutical Chemistry, Riphah International University, Islamabad, Pakistan 2 Deparment of Pharmacy, Capital University of Science and Technology, Islamabad, Pakistan 3 Department of Pharmacology, Riphah International University, Islamabad, Pakistan 4 ARC Centre of Excellence in Convergent Bio- Nano Science and Technology, Monash University, Parkville, Australia Correspondence Prof. Dr. Humaira Nadeem, Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan. Email: humaira.nadeem@riphah.edu.pk Dr. Ibrahim Javed, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville Victoria 3052, Australia. Email: ibrahim.javed@monash.edu Abstract Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant anal- gesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1 H NMR and 13 C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to pos- sess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H + /K + -ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation. KEYWORDS analgesic, anti-inflammatory, benzimidazoles, gastroprotective, in-silico studies 1 | INTRODUCTION Benzimidazole is an essential pharmacophore in the field of medicinal chemistry. Structural modification of the benzimidazole scaffold is useful in the development of pharmacologically active molecules (Sahoo, Banik, Rao, & Raju, 2019). This heterocycle is a part of several therapeutically used drugs and patent molecules developed in the last few years (Akhtar et al., 2017). The presence of benzimidazole nucleus in a wide variety of bioactive and potential compounds, such as anticonvulsant, antiparasitic, antimicrobial, antifungal, antidiabetic, antihypertensive, anticoagulants, analgesic, anti-inflammatory, antihis- taminic and proton pump inhibitors have made it an important and functional heterocyclic system (Narasimhan, Sharma, & Kumar, 2012; Shingalapur, Hosamani, Keri, & Hugar, 2010; Walia, Hedaitullah, Naaz, Iqbal, & Lamba, 2011). The associated side effects of drug molecules, along with their bioavailability and efficacy has been addressed via different nano-formulations or conjugation-based approaches.(Giorgi, Agusti, & de Lederkremer, 2014; Javed et al., 2015, 2016; Larson & Received: 31 March 2020 Revised: 8 June 2020 Accepted: 10 July 2020 DOI: 10.1002/ddr.21728 Drug Dev Res. 2020;1–16. wileyonlinelibrary.com/journal/ddr © 2020 Wiley Periodicals LLC 1