Design, synthesis, and antitubercular evaluation of piperazinyl-pyrazolyl-2- hydrazinyl thiazole derivatives: Experimental, DFT and molecular docking insights

Abstract

In the current research, a new series of piperazinyl-pyrazolyl-2-hydrazinyl thiazole derivatives (6a-6i) were synthesized and evaluated for their antitubercular activity against Mycobacterium tuberculosis H37Rv. The compounds were synthesized via a three-component reaction involving 3-methyl-5-(4-methylpiperazin-1-yl)−1-phenyl-1H-pyrazole-4-carbaldehyde, thiosemicarbazide, and substituted phenacyl bromides (5a-5i) in ethanol under reflux conditions. The structures of the compounds were confirmed using ¹H NMR, ¹³C NMR, and FT-IR spectroscopy, which supported the successful formation of the thiazole core. The piperazinyl-pyrazolyl-2-hydrazinyl thiazole derivatives exhibited varying degrees of antitubercular activity, with compound 6c (MIC = 1.6 µg/mL) showing the highest potency, comparable to the standard drugs isoniazid and ethambutol. The most active compounds follow the order as 6c (bromo substituent) > 6d (fluoro substituent) = 6e (methoxy substituent) > 6a (chloro substituent) = 6 g (nitrile substituent) with MIC ranging from (1.6–12.5 µg/mL). Other derivatives also displayed significant activity (MIC = 25–100 µg/mL) in which the compound 6i showed the lowest activity (MIC = 100 µg/mL). Molecular docking studies further supported its biological activity, revealing strong interactions with key residues of the target protein. The DFT analysis demonstrated that substituents such as bromine, methoxy, and fluorine affected the HOMO–LUMO energy gaps (3.89 , 3.80, and 3.88 eV, respectively) and global softness (0.517–0.526 eV^-1). ADME studies confirmed favorable pharmacokinetics for 6c, 6d, and 6e.