Synthesis and Evaluation of Anti-inflammatory and Analgesic Activities and Ulcerogenic Potential of Substituted Dihydrothiophenes

Abstract

Inflammation is a multifactorial process. It reflects the response of organism to various stimuli and is related to many disorders such as arthritis, asthma, and psoriasis, which require prolonged or chronic treatment. Cyclooxygenase (COX) and Lipoxygenase (LOX) produce two groups of arachidonic acid metabolites, prostaglandins and leukotrienes respectively, which play a key role in inflammation. It is recently proposed that compounds with equal capabilities of inhibiting COX and 5-LOX are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). Thiophene is the backbone of several pharmaceutical drugs including anti-inflammatory, antihypertensive, antibiotic, antiasthmatic, antifungal, antiglaucoma and antispasmodic agents. Molecular docking studies were performed on a library of compounds which revealed the essential structural profile of a dual COX/LOX inhibitor. Based on these studies two series of acetamido and benzamido derivatives of piperidinyl and morpholino substituted dihydrothiophenes were synthesized. The synthesis of the target molecules involved reactions like Domino reaction, Michael addition and Schotten-Baumann reaction; with the use of microwave-assisted synthesis in addition to conventional methods, which gave better yield in shorter periods of time. Structure elucidation of the synthesized compounds was done by complete spectral analysis. Selected compounds (with best docking scores) were screened for anti-inflammatory, analgesic activities as well as for the ulcerogenic potential. Compounds having the disubstituted aryl group at the fourth position and piperidinyl group at the amide side chain of the thiophene ring system exhibited better pharmacological activity in addition to comparatively very low ulcerogenic potential in comparison to the standard Indomethacin.