2‐Aminoaryl‐3,5‐diaryl pyrazines: Synthesis, biological evaluation against Mycobacterium tuberculosis and docking studies

Rationally designed Mycobacterium tuberculosis (Mtb) inhibitors were synthesized under Buchwald conditions using Pd2(dba)3/xantphos and the compounds were investigated for their biological activity against the Mtb standard strain H37Rv and two other clinically isolated multidrug‐resistant strains with different drug resistance patterns. Compounds 5e, 6e, 7e, and 8e exhibited excellent antituberculosis activity against H37Rv with a minimum inhibitory concentration (MIC) value of 15 μg/ml. Compounds 5a, 6c, 7b, 8a, 8b, and 8d also displayed their potency with a MIC value in the range of 15–25 μg/ml. In addition to the Mtb studies, compounds 4e, 5e, 7e, and 8e were tested for cytotoxicity on HEK‐293 cells and compounds 7e and 8e were identified to have low toxicities of up to 200 and 300 μM, respectively. The synthesized compounds docked with the 2FUM protein of Mtb and the docking studies revealed that compounds 5e, 6e, 7e, and 8e can bind strongly in the active site of the enzyme and showed binding energies of −9.62, −10.7, −11.48, and −12.06 kcal/mol, respectively. Compound 7e forms four hydrogen bonds, whereas compound 8e forms five hydrogen bonds with amino acids, respectively. Based on these results, compounds 7e and 8e might be considered potential lead compounds with good anti‐Mtb potency. Rationally designed Mycobacterium tuberculosis (Mtb) inhibitors were synthesized and investigated for their activity against the Mtb standard strain H37Rv and two other clinically isolated multidrug‐resistant strains with different drug resistance patterns. Compounds 7e and 8e, which were nontoxic at up to 200 µM and showed binding energies to the 2FUM protein of Mtb of −11.48 and −12.06 kcal/mol, respectively, might be considered potential lead compounds with good anti‐Mtb potency.