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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 33, Number 12
BKCSDE 33(12)
December 20, 2012 

Mechanism Studies of Substituted Triazol-1-yl-pyrimidine Derivatives Inhibition on Mycobacterium tuberculosis Acetohydroxyacid Synthase
Pham Ngoc Chien, In-Pil Jung, Katta Venugopal Reddy, Moon-Young Yoon*
Acetohydroxyacid synthase, Docking, Mycobacterium tuberculosis, Tuberculosis, Triazol-1-ylpyrimidines
The first step in the common pathway for the biosynthesis of branched chain amino acids is catalyzed by acetohydroxyacid synthase (AHAS). The AHAS is found in plants, fungi and bacteria. With an aim to identify new anti-tuberculosis drugs that inhibit branched chain amino acid biosynthesis, we screened a chemical library against Mycobacterium tuberculosis AHAS. The screening identified four compounds, AVS 2087, AVS 2093, AVS 2236, and AVS 2387 with IC50 values of 0.28, 0.21, 3.88, and 0.25 μM, respectively. Moreover, these four compounds also showed strong inhibition against reconstituted AHAS with IC50 values of 0.37, 0.26, 1.0, and 1.18 μM, respectively. The basic scaffold of the AVS group consists of 1-pyrimidin-2-yl-1H-[1,2,4]- triazole-3-sulfonamide. The most active compound, AVS 2387, showed the lowest total interaction energy –8.75 Kcal/mol and illustrates its binding mode by hydrogen bonding with Hε of Gln517 with the distance of 2.24 Å.
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