Design, Synthesis and Evaluation of Antiinflammatory Activity of Substituted Dihydrothiophenes

Abstract

Inflammation is the host’s invasive form of defense mechanism. It usually results in protection from spread of infection and resolution i.e. restoration of the affected tissues, failure of which can result in number of pathological conditions and disorders including cancer, asthma, rheumatoid arthritis and many more. Metabolism of arachidonic acid into prostanoids and leukotriene via the action of cyclooxygenases (COXs) and Lipoxygenases (LOXs) enzymes respectively forms the basis for inflammatory disorders. Dual inhibition of COXs and LOX-5 is the latest approach to provide more efficacious and safer alternatives of the current therapy of non-steroidal anti-inflammatory drugs (NSAIDs). Thiophene ring remained a key component as a part of different drug structures belonging to different classes since many years. Drugs with pharmacological action varying from antimicrobial, local anesthesia, anti-depressant, anti-diabetic, anti-cholinergic and antiinflammatory activity have been found possessing thiophene ring. Molecular docking studies were performed on series of compounds to obtain, understand and study the essential structural requirement of a dual COX-2/LOX-5 inhibitor. Synthesis of several benzamido substituted dihydrothiophene compounds have been carried out on the basis of their molecular docking scores. The target molecules have been synthesized using three step reaction protocol of reflux, one pot synthesis and coupling reaction. Structure elucidation of the synthesized target compounds was performed by complete spectral data with interpretation. Compounds with best docking scores were screened for anti-inflammatory activity. Compounds with smaller ortho-substitution on the benzamido group of the dihydrothiophene ring system showed better pharmacological activity while comparing with Diclofenac sodium as standard. Key words: benzamido substituted dihydrothiophenes, molecular docking, anti-inflammatory activity, arachidonic acid, Diclofenac sodium.