One of the strategies adopted to control bacterial pathogens is to target the biosynthesis of mycobactins, high affinity iron chelating molecules called siderophores. Iron is an essential redox cofactor for several bacterial cellular processes for mycobacterial growth in the host. Bacterial strains unable to produce siderophores, loose their ability to grow within macrophages and their virulence. MbtI, the salicylate synthase from Mycobacterial tuberculosis (Mtb), which catalyzes the conversion of chorismic acid to salicylate in the first step in mycobactin biosynthesis via an isochorismate intermediate, is a validated target for fighting tuberculosis [1]. Here, we report on the design, synthesis, and biological evaluation of new 4-furan derivatives targeting MbtI. Docking studies allowed the development of a new pharmacophoric model, that was applied to screen the Enamine commercial database. A hit compound bearing the furan ring was identified, which has proven to possess moderate inhibitory activity on the target enzyme. SAR performed among this compound allowed the obtainment of compound MM40, to date the most potent competitive MbtI inhibitor identified. The antibacterial activity of the MM40 prodrug was assessed in vitro against Mtb and exhibited a promising antibiotic activity.

Design and synthesis of novel antituberculars targeting the salicylate synthase (MbtI) / S. Villa, L.R. Chiarelli, M. Mori, A. Gelain, L. Costantino, D. Bonanni, T. Tuccinardi, F. Meneghetti. ((Intervento presentato al 2. convegno Symposium on Medicinal Chjemistry for Global Health tenutosi a Madrid nel 2017.

Design and synthesis of novel antituberculars targeting the salicylate synthase (MbtI)

S. Villa;M. Mori;A. Gelain;F. Meneghetti
2017-06-19

Abstract

One of the strategies adopted to control bacterial pathogens is to target the biosynthesis of mycobactins, high affinity iron chelating molecules called siderophores. Iron is an essential redox cofactor for several bacterial cellular processes for mycobacterial growth in the host. Bacterial strains unable to produce siderophores, loose their ability to grow within macrophages and their virulence. MbtI, the salicylate synthase from Mycobacterial tuberculosis (Mtb), which catalyzes the conversion of chorismic acid to salicylate in the first step in mycobactin biosynthesis via an isochorismate intermediate, is a validated target for fighting tuberculosis [1]. Here, we report on the design, synthesis, and biological evaluation of new 4-furan derivatives targeting MbtI. Docking studies allowed the development of a new pharmacophoric model, that was applied to screen the Enamine commercial database. A hit compound bearing the furan ring was identified, which has proven to possess moderate inhibitory activity on the target enzyme. SAR performed among this compound allowed the obtainment of compound MM40, to date the most potent competitive MbtI inhibitor identified. The antibacterial activity of the MM40 prodrug was assessed in vitro against Mtb and exhibited a promising antibiotic activity.
Settore CHIM/08 - Chimica Farmaceutica
Design and synthesis of novel antituberculars targeting the salicylate synthase (MbtI) / S. Villa, L.R. Chiarelli, M. Mori, A. Gelain, L. Costantino, D. Bonanni, T. Tuccinardi, F. Meneghetti. ((Intervento presentato al 2. convegno Symposium on Medicinal Chjemistry for Global Health tenutosi a Madrid nel 2017.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/526582
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