Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. (15th September 2021)

• Record Type: Journal Article
• Authors: Biteau, Nicolas G.; Roy, Vincent; Lambry, Jean-Christophe; Becker, Hubert F.; Myllykallio, Hannu; Agrofoglio, Luigi A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 46(2021)
• Publication Date: 2021-09-15
• Subjects: Flavin-dependent thymidylate synthase -- Acyclic nucleoside phosphonate -- Ruthenium-catalyzed cross-metathesis -- Sonogashira cross-coupling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116351
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Flavin-Dependent Thymidylate Synthase ( FDTS ) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 % of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural's cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX . Several synthetic efforts were performed to optimize regioselective N1-alkylation, cross-coupling metathesis and Sonogashira cross-coupling. Compound 19c showed a poor 31.8% inhibitory effect on ThyX at 200 μM.