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.

Discovery and development of novel salicylate synthase (MbtI) Furanic inhibitors as antitubercular agents / L.R. Chiarelli, M. Mori, D. Barlocco, G. Beretta, A. Gelain, E. Pini, M. Porcino, G. Mori, G. Stelitano, L. Costantino, M. Lapillo, D. Bonanni, G. Poli, T. Tuccinardi, S. Villa, F. Meneghetti. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 155(2018 Jul 15), pp. 754-763.

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

M. Mori
Secondo
;
D. Barlocco;G. Beretta;A. Gelain;E. Pini;S. Villa
Penultimo
;
F. Meneghetti
Ultimo
2018

Abstract

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.
tuberculosis, iron, siderophores, antimycobacterial drugs, virtual screening, drug design
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/10 - Biochimica
Settore CHIM/06 - Chimica Organica
15-lug-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/579371
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