Rationale Design, Synthesis, Pharmacological and <i>In‐silico</i> Investigation of Indole‐Functionalized Isoxazoles as Anti‐inflammatory Agents

Abstract

Abstract The current anti‐inflammatory drugs are associated with various severe adverse or side effects which mark the question on long term clinical use of such medications. These factors necessitate the development of new heterocyclic molecules having anti‐inflammatory potential with minimal to no adverse effect or toxicity. In continuation to our work, in herein report design and synthesis of a series of 15 indole‐3‐subtituted isoxazoles having potential anti‐inflammatory as well as analgesic properties. Most of the compounds exhibited comparable in‐vivo anti‐inflammatory and analgesic activity in rats to the reference drugs. Compound 9 d, 9 f and 9 i were found to show most significant anti‐inflammatory activity and reduced the paw edema by 67.74 %, 61.29 %, and 77.42 % respectively which were comparable to reference drug indomethacin. The COX inhibition studies reveled that these compounds have 2–3 folds selectivity for COX‐2 with moderate inhibition activity. In final, molecular docking studies were performed to understand the mechanistic and binding modes at catalytic active sites of COX‐2. The results revealed good selectivity of compounds for COX‐2 preferably over other inflammatory targets. The compound 9 i is obtained as lead molecule from the current series as promising structural feature for further development of novel anti‐inflammatory agent.