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

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 inhibi-tion. 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 be-tween 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.(c) 2022 Published by Elsevier B.V.

Automated summary

This study focuses on the synthesis of 26 novel compounds and their potential for treating inflammation. Two compounds were found to significantly inhibit the COX-2 enzyme, with one compound showing the best selectivity and strongest anti-inflammatory activity without causing gastric ulcers in vivo. Molecular modeling studies provided insights into the interaction between the compound and COX-2.