Design and synthesis of anti–inflammatory 1,2,3–triazolylpyrrolobenzodiazepinone derivatives and impact of molecular structure on COX–2 selective targeting

Abstract

COX–2, a key enzyme that catalyzes the rate–limiting steps in the conversion of arachidonic acid to prostaglandins, plays a pivotal role in the inflammatory process. Therapeutic utilization of selective COX–2 inhibitors has been considered an effective approach for treating inflammation with emasculated side effects. This study describes the design and enantioselective synthesis of a library of twenty–six novel 1,2,3–triazolylpyrrolobenzodiazepinone derivatives. The molecules were found to exhibit good drug–like properties as implied by the ADMET studies. Nine compounds of the library showing promising results in silico studies were evaluated for cell toxicity on HeLa cells and in vitro COX–1/COX–2 enzyme inhibition. Compounds (2b) and (4l) were found to significantly inhibit COX–2 in vitro in comparison to the standard and compound (4l) with S–geometry showed extraordinary COX–2 inhibition (IC50 = 18.9 nM) and the best selectivity (COX–1/COX–2 = 1060). (4l) also exhibited the most potent anti–inflammatory activity in vivo in comparison to the standard drugs (Indomethacin and Celecoxib) without inducing any gastric ulceration. Molecular modeling studies aided in the understanding of the interaction modes between this compound and the COX–2 enzyme. Findings in this study may thus serve as a pivotal avenue for developing next–generation selective COX–2 anti–inflammatory drugs using pyrrolobenzodiazepinone (PBD), scaffold.