Design, Synthesis and Biological Evaluation of Chromone Fused ۱,۳,۴-Thiadiazoles as Highly Potent Nontoxic Inhibitors of Enoyl-Acyl Carrier Proteins in M. tuberculosis

A series of ۱۲ novel chromone fused ۱,۳,۴-thiadiazoles were designed and synthesized via an efficient and convenient synthetic route starting from a ۳-formyl chromone. In vitro evaluation of all the derivatives was carried out to demonstrate their inhibitory potential against Mtb. Anti-tubercular evaluation via the MABA assay revealed that compounds ۵b, ۵d, ۵f, ۵ g and ۵ h significantly inhibited the Mycobacterium tuberculosis H۳۷Rv strain, with MICs in the range of ۳.۰-۸.۰ µg ml-۱. Moreover, the experimental results demonstrated the excellent anti-tubercular potential of compounds ۵d and ۵f against Mtb with MICs of ۳.۰ and ۴.۰µg ml-۱. In addition, molecular docking was performed to determine more favorable molecular interactions with the four target enzymes. Molecular docking and binding energy studies revealed the potential of four selected compounds to bind to the enoyl-acyl carrier protein reductase of Mtb which is involved in the biosynthesis of mycolic acid. Interestingly, the binding energies (-۸.۵۰ to -۱۰.۰۸ kcal/mol) of all the selected compounds were found to be greater than that of standard drugs. The chemoinformatics study revealed excellent ADME profiles for all the selected compounds, confirming their importance in the treatment of Mtb.

کلیدواژه ها:

Minimum inhibitory concentration (MIC) ، Molecular Docking ، Topological polar surface area (TPSA) ، Structure-activity relationships (SARs)