Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

• DOI: 10.1016/j.ejmech.2018.06.033
• Publication Date: 2018-06-18T23:33:28Z
• Authors: Laurent R. Chiarelli; Matteo Mori; Daniela Barlocco; Giangiacomo Beretta; Arianna Gelain; Elena Pini; Marianna Porcino; Giorgia Mori; Giovanni Stelitano; Luca Costantino; Margherita Lapillo; Davide Bonanni; Giulio Poli; Tiziano Tuccinardi; Stefania Villa; Fiorella Meneghetti
• Keywords: Antimycobacterial; Lead compound; Furan

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (Ki = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.