Synthesis, antibacterial evaluation and in silico studies of novel 2-(benzo[d]thiazol-2-yl)-N-arylacetamides and their derivatives as potential DHFR inhibitors

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Abstract Novel N -arylacetamides 2a – f were synthesized based on benzo[ d ]thiazole scaffold. The compounds 2a – c underwent Knoevenagel condensation through green synthetic method with different aromatic aldehydes and pyrazole-7-carbaldehydes delivered the respective arylidenes with efficient yields. Arylidenes 4 reacted with malononitrile affording the corresponding N -arylpyridones 11a – i . Moreover, the reaction of 2a – c with each of salicylaldehyde and 5-arylazo salicylaldehydes afforded the unexpected coumarins rather than quinolin-5-ones. The structure of coumarin 8 was confirmed by density functional theory (DFT) calculations using basis set B3LYP/6-311 G + + (d,p) to obtain the suitable geometrical structure with molecular orbitals` energies revealing its planar structure and its agreement with experimental data. Besides, the antibacterial activity was tested against different bacterial strains revealing potent activity especially Gram-negative bacteria with excellent minimum inhibition concentration (MIC) value ranging from 31.25 to 250 µg/L. Additionally, compounds 2c and 4m showed enzyme inhibition against dihydrofolate reductase in Escherichia coli with greater potency (IC 50 for 2c = 3.796 µM, IC 50 for 4m = 2.442 µM) than the standard antibiotic trimethoprim (IC 50 = 8.706 µM). Investigation of the physicochemical properties of the newly compounds exhibited their better ADME properties that can be developed for the discovery of new antibacterial agents. Graphical Abstract

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