Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Mechanism Studies of Substituted Triazol-1-yl-pyrimidine Derivatives Inhibition on Mycobacterium tuberculosis Acetohydroxyacid Synthase

  • Chien, Pham Ngoc (Department of Chemistry and Institute of Natural Sciences, Hanyang University) ;
  • Jung, In-Pil (Department of Chemistry and Institute of Natural Sciences, Hanyang University) ;
  • Reddy, Katta Venugopal (Department of Chemistry, Vikrama Simhapuri University) ;
  • Yoon, Moon-Young (Department of Chemistry and Institute of Natural Sciences, Hanyang University)
  • Received : 2012.07.03
  • Accepted : 2012.09.19
  • Published : 2012.12.20
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Abstract

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 $IC_{50}$ values of 0.28, 0.21, 3.88, and $0.25{\mu}M$, respectively. Moreover, these four compounds also showed strong inhibition against reconstituted AHAS with $IC_{50}$ values of 0.37, 0.26, 1.0, and $1.18{\mu}M$, 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 $H_{\varepsilon}$ of Gln517 with the distance of $2.24{\AA}$.

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