X-ray Single-Crystal Analysis, Pharmaco-Toxicological Profile and Enoyl-ACP Reductase-Inhibiting Activity of Leading Sulfonyl Hydrazone Derivatives

Abstract

Taking into consideration the growing resistance towards currently available antimycobacterials, there is still an unmet need for the development of new chemotherapeutic agents to combat the infectious agents. This study presents X-ray single-crystal analysis to verify the structure of leading sulfonyl hydrazone 3b, which has proven its potent antimycobacterial activity against Mycobacterium tuberculosis H37Rv with an MIC value of 0.0716 μM, respectively, low cytotoxicity, and very high selectivity indexes (SI = 2216), and which has been fully characterized by Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS) methods. Furthermore, this study assessed the ex vivo antioxidant activity, acute and subacute toxicity, and in vitro inhibition capacity against enoyl-ACP reductase of hydrazones 3a and 3b, as 3a was identified as the second leading compound in our previous research. Compared to isoniazid, compounds 3a and 3b demonstrated lower acute toxicity for intraperitoneal administration, with LD50 values of 866 and 1224.7 mg/kg, respectively. Subacute toxicity tests, involving the repeated administration of a single dose of the test samples per day, revealed no significant deviations in hematological and biochemical parameters or pathomorphological tissues. The compounds exhibited potent antioxidant capabilities, reducing malondialdehyde (MDA) levels and increasing reduced glutathione (GSH). Enzyme inhibition assays of the sulfonyl hydrazones 3a and 3b with IC50 values of 18.2 µM and 10.7 µM, respectively, revealed that enoyl acyl carrier protein reductase (InhA) could be considered as their target enzyme to exhibit their antitubercular activities. In conclusion, the investigated sulfonyl hydrazones display promising drug-like properties and warrant further investigation.