Discovery of a Pyrimidinedione Derivative with Potent Inhibitory Activity against Mycobacterium tuberculosis Ketol-Acid Reductoisomerase.

Autor:	Lin X; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., Kurz JL; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., Patel KM; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., Wun SJ; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., Hussein WM; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia.; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Ein Helwan, Helwan University, Helwan, Egypt., Lonhienne T; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., West NP; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., McGeary RP; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., Schenk G; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia., Guddat LW; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia.
Jazyk:	angličtina
Zdroj:	Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2021 Feb 10; Vol. 27 (9), pp. 3130-3141. Date of Electronic Publication: 2021 Jan 12.
DOI:	10.1002/chem.202004665
Abstrakt:	New drugs aimed at novel targets are urgently needed to combat the increasing rate of drug-resistant tuberculosis (TB). Herein, the National Cancer Institute Developmental Therapeutic Program (NCI-DTP) chemical library was screened against a promising new target, ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway. From this library, 6-hydroxy-2-methylthiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (NSC116565) was identified as a potent time-dependent inhibitor of Mycobacterium tuberculosis (Mt) KARI with a K i of 95.4 nm. Isothermal titration calorimetry studies showed that this inhibitor bound to MtKARI in the presence and absence of the cofactor, nicotinamide adenine dinucleotide phosphate (NADPH), which was confirmed by crystal structures of the compound in complex with closely related Staphylococcus aureus KARI. It is also shown that NSC116565 inhibits the growth of H37Ra and H37Rv strains of Mt with MIC 50 values of 2.93 and 6.06 μm, respectively. These results further validate KARI as a TB drug target and show that NSC116565 is a promising lead for anti-TB drug development. (© 2020 Wiley-VCH GmbH.)
Databáze:	MEDLINE
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