P010

Tuberculosis (TB) is an infectious disease that continues to pose a significant public health challenge globally. There is an urgent need for new chemotherapeutic agents to address the increasing prevalence of multi-drug resistant tuberculosis (MDR-TB). InhA, the mycobacterial enoyl reductase, stands as one of the few clinically validated targets in tuberculosis drug discovery, prompting extensive efforts to identify direct InhA inhibitors with low toxicity. Here, we present a toxicological profile of two sulfonyl hydrazones, compounds 3g (MIC 0.0763 μM) and 3k (MIC 0.0716 μM), which exhibit potent antimycobacterial activity, low toxicity, and high selectivity index (SI=1819 and 2216, respectively). Additionally, we assessed their in vivo antioxidant activity and in vitro inhibition capacity against enoyl-ACP reductase. Compared to INH, compounds 3g and 3k demonstrated lower acute toxicity for intraperitoneal administration, with LD₅₀ values of 866 and 1224.7 mg/kg, respectively. Subacute toxicity tests, involving the administration of a single dose of the test samples per day over 14 days, 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). Furthermore, 3g and 3k  demonstrated significant enoyl-ACP reductase inhibitory activity, with IC₅₀ values of 18.2 µM and 10.7 µM, respectively. It is suggested that the compounds potentially target InhA. In conclusion, the investigated hydrazones display promising antitubercular drug-like properties and warrant further investigation. This study received support from the Bulgarian National Science Fund (Grant KP-06-H41/3, 2020).