Benzo[ d]thiazole-2-carboxamides as new antituberculosis chemotypes inhibiting mycobacterial ATP phosphoribosyl transferase

Abstract

Aims: The screening of antimycobacterial benzo[d]thiazole-2-carboxamides against ATP-phosphoribosyl transferase (ATP-PRTase) was conducted. Materials & methods: The antitubercular potential of compounds 1 and 2 against ATP-PRTase was assessed through the determination of half maximal effective concentration (EC₅₀) and binding constant (K_d), as well as competitive inhibitory studies and studies of perturbation of secondary structure, molecular modeling and L-histidine complementation assay. Results & conclusion: Compounds 1n and 2a significantly inhibited ATP-PRTase as evidenced by their EC₅₀ and K_d values and the perturbation of the secondary structure study. Compound 1n exhibited stronger competitive inhibition toward ATP compared with 2a. The inhibition of the growth of Mycobacterium tuberculosis by targeting the L-histidine biosynthesis pathway and molecular modeling studies further supported the inhibition of ATP-PRTase.

Keywords: ATP-PRTase (HisG) inhibition; L-histidine complementation assay; anti-TB drug target; benzo[d]thiazole-2-carboxamides; interaction with secondary structure; molecular docking; molecular dynamics simulation.