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Discovery of a Pyrimidinedione Derivative with Potent Inhibitory Activity against Mycobacterium tuberculosis Ketol–Acid Reductoisomerase
Author(s) -
Lin Xin,
Kurz Julia L.,
Patel Khushboo M.,
Wun Shun Jie,
Hussein Waleed M.,
Lonhienne Thierry,
West Nicholas P.,
McGeary Ross P.,
Schenk Gerhard,
Guddat Luke W.
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202004665
Subject(s) - isothermal titration calorimetry , mycobacterium tuberculosis , chemistry , cofactor , biochemistry , stereochemistry , tuberculosis , nicotinamide , nicotinamide adenine dinucleotide phosphate , enzyme , medicine , pathology , oxidase test
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(4 H ,6 H )‐dione (NSC116565) was identified as a potent time‐dependent inhibitor of Mycobacterium tuberculosis ( Mt ) KARI with a K i of 95.4 n m . Isothermal titration calorimetry studies showed that this inhibitor bound to Mt KARI 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 μ m , respectively. These results further validate KARI as a TB drug target and show that NSC116565 is a promising lead for anti‐TB drug development.