A Divergent SAR Study Allows Optimization of a Potent 5-HT2c Inhibitor to a Promising Antimalarial Scaffold

09 Feb 2012

Félix Calderón, Jaume Vidal-Mas, Jeremy Burrows, Juan Carlos de la Rosa, María Belén Jiménez-Díaz, Teresa Mulet, Sara Prats, Jorge Solana, Michael Witty, Francisco Javier Gamo, and Esther Fernández

ACS Medicinal Chemistry Letters
DOI: 10.1021/ml300008j

Photo: Prapann/Shuttershock.com


From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of the most promising hits was the TCMDC-139046, a molecule presenting an indoline core, which is well-known for its anxiolytic properties by interacting with serotonin antagonist receptors 5-HT2. The inhibition of this target will complicate the clinical development of these compounds as antimalarials. Herein, we present the antimalarial profile of this series and our efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency. By using a double-divergent structure–activity relationship analysis, we have obtained a novel lead compound harboring an indoline core.

View the full article on the ACS Publications website.