Synthesis and structure-activity relationship studies of 4-arylthiosemicarbazides as topoisomerase IV inhibitors with Gram-positive antibacterial activity. Search for molecular basis of antibacterial activity of thiosemicarbazides.

1-(indol-2-carbonyl)-4-(4-nitrophenyl)-thiosemicarbazide was synthesized and antibacterial and type IIA topoisomerases (DNA gyrase and topoisomerase IV) activity was evaluated. It was found that it shows activity against Gram-positive bacteria with MICs of 50 μg/mL and inhibitory action against topoisomerase IV with an IC(50) of 14 μM. Although modification of its structure resulted in molecules with a lower biological profile, our observations strongly implicate that thiosemicarbazide derivatives participate in at least two different mechanisms of antibacterial activity; one is connected with the inhibition of topoisomerase IV, while the nature of the other cannot be elucidated from the limited data collected thus far. The differences in bioactivity further investigated by the molecular modeling approach and docking studies suggest that inhibitory activity of 4-arylthiosemicarbazides is connected with electronic structure rather than the geometry of the molecule.