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A hit expansion of 3-benzamidopyrazine-2-carboxamide: Toward inhibitors of prolyl-tRNA synthetase with antimycobacterial activity

VSK. Pallabothula, NT. Abdalrahman, M. Mori, AH. Fekri, O. Janďourek, K. Konečná, P. Paterová, M. Novák, P. Dudášová-Hatoková, P. Štěrbová-Kovaříková, C. Castellano, F. Meneghetti, S. Villa, J. Kuneš, M. Juhás, J. Zitko

. 2024 ; 357 (8) : e2400171. [pub] 20240506

Jazyk angličtina Země Německo

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019583

Grantová podpora
NU21-05-00482 (grant to J. Z.) Supported by Ministry of Health of the Czech Republic
The publication was supported by the research project 2200/04/2024-2026 as part of the "Competition for 2024-2026 Postdoctoral Job Positions at the University of Hradec Králové", at the Faculty of Science, University of Hradec Králové (grant to M. J.)
Grant Agency of Charles University with Project GA UK No. 349 721 and Charles University with project SVV 260 666

This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring. This series brought two new compounds (21: R = 2-F, 4-Cl and 22: R = 2-F, 4-Br) with in vitro activity against Mycobacterium tuberculosis H37Rv as well as multidrug-resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25 μg/mL. The lactone-type derivatives 4H-pyrazino[2,3-d][1,3]oxazin-4-ones (Series-3) were inactive, but solvent stability studies of compound 29 indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).

Citace poskytuje Crossref.org

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