Design, synthesis, preliminary pharmacological evaluation, molecular docking and ADME studies of some new pyrazoline, isoxazoline and pyrimidine derivatives bearing nabumetone moiety targeting cyclooxygenase enzyme

Abstract

Nabumetone is a prodrug, its active metabolite 6-methoxy-2-naphthylacetic (6MNA) acid has low selectivity toward COX-2 enzyme; PLP fitness was 67.36 Kcal/Mol. A series of pyrazolines, oxazolines and pyrimidines bearing nabumetone moiety have been designed, synthesized, and evaluated as a potential cyclooxygenase-2 (COX-2) inhibitors. These new compounds were evaluated for their in vivo anti-inflammatory activity and in vitro COX-2 selectivity through molecular docking via GOLD suite v. 5.6.2. All tested compounds in molecular docking exhibited significant activities compared with diclofenac, naproxen, and 6MNA as reference drugs due to their hydrogen bonding interaction with key amino acids in COX isozymes Arg120, Tyr355, and Ser530, and these results are compatible with their in vivo acute anti-inflammatory study for tested compounds. Also, ADME studies were performed to predict which of them are candidate to be given orally, site of absorption, bioavailability, topological polar surface area and drug-likeness. The ADME results showed that all synthesized compounds absorbed from GIT while, only compounds 3, 2a, 2c, and 3a -3c fulfilled the Lipinski rule.