Mechanism Studies of Substituted Triazol-1-yl-pyrimidine Derivatives Inhibition on Mycobacterium tuberculosis Acetohydroxyacid Synthase

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 IC50 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 IC50 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 HE of Gln517 with the distance of 2.24 angstrom.This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2008516) and Rural Development Administration, Republic of Korea and Bio-industry Technology Development Program, Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea (111079-3)