A series of naphthyridine-3-thiosemicarbazide 7,8(a–e) and the corresponding cyclized analogs, naphthyridine-3-(1,3,4-oxadiazoles) 9,10(a–e) were synthesized through modification of the COOH in nalidixic acid (NA) and its 6-bromo analogue, as new chemical entities (NCE) with enhanced antimicrobial potential. The compounds were screened for antibacterial activity against Gram positive (G+ve) strains (S. aureus, B. cereus); Gram negative (G-ve) (E. coli, K. pneumonia, P. aeruginosa) and Mycobac. smegmatis. Compounds 7 b,c and 9 b,d displayed the highest activity against S. aureus (minimal inhibitory concentration; MIC ∼ 6–7 mM), whereas B. cereus was found to be more susceptible to the brominated oxadiazoles 10 b,d,e (MIC∼ 5.5-5.9 mM). Moreover, 10 b,c,d exhibit similar MIC values against K. pneumonia and M. smegmatis. This demonstrates that bromination of the naphtyridone skeleton results in broader spectrum and enhanced antibacterial profile. In addition, the aryl substituted thioemicarbazides 7 c,d,e showed inhibitory effect of the growth of M. smegmatis at MIC ∼ 5.4-7.1 mM. Molecular docking to DNA-gyrase cleavage complex of S. aureus, Mycobac. (mTB) and Top. IV of K. pneumonia revealed similar binding poses to the co-crystallized quinolone ligands and indicate good correlation of the binding energy (ΔG) with the observed MIC values of the active compounds. Consequently, DNA-gyrase assay was proposed and executed. Most prominent DNA-gyrase inhibition showed by the naphthyridinyl-3-thiosemicarbazides, 7 c and 8 e (IC50: 1.73 and 4.46 μg/mL respectively); and the oxadiazoles 9 b and 10 d (IC50: 3.36 and 3.89 μg/mL respectively). Assessment of drug-likeness characteristics illustrates that the synthesized compounds showed agreement to Lipinsiki's and Veper's parameters. The study could offer an exceptional framework that may lead to the discovery of new potent antimicrobial agents.
