Computer-assisted rational design, synthesis, and bioassay of non-steroidal anti-inflammatory agents

A focused dataset of previously synthesized and tested [1,2,4]-triazolo[1,5-a]pyridines and pyridine-3-carboxylates was studied by Molecular Field Topology Analysis (MFTA) to identify steric and electronic determinants of anti-inflammatory activity useful for the design and synthesis of new anti-inflammatory agents. Rational design based on the MFTA model identified eleven novel pyridine-3-carboxylates (2a–e and 3a–f) as promising. After synthesis and screening, three of (2a, 2c, 3a) revealed potent anti-inflammatory activity exceeding that of indomethacin, the reference inhibitor for artificially induced edema in rats.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► MFTA can effectively identify molecular determinants of anti-inflammatory activity. ► Rational design suggested eleven novel compounds for synthesis and bioassay. ► Three of the eleven compounds were found to be potent anti-inflammatory agents.