Benzilmonoximethiocarbohydrazide Schiff bases as multifunctional antimalarial and antioxidant scaffolds: synthesis, biological evaluation, and mechanistic insights

A new series of benzilmonoximethiocarbohydrazide (HBMT) Schiff bases was synthesized and structurally characterized with high purity. Four derivatives-HBMT-3M4HB, HBMT-MA3, HBMT-MA6, and HBMT-MA7-were obtained in good yields and evaluated for multifunctional therapeutic potential. All compounds showed significant antimalarial activity against <i>Plasmodium falciparum</i> 3D7, with HBMT-3M4HB being the most potent (IC₅₀ = 1.24 μM), approaching chloroquine. Antioxidant assays revealed that HBMT-3M4HB also exhibited strong radical scavenging and ferric reducing power, surpassing its analogues. Cytotoxicity testing in MCF-7 breast cancer cells indicated selective activity (IC₅₀ = 21.6 μM) with reduced toxicity toward HEK-293 cells. Mechanistic assays suggested apoptosis induction, suppression of pro-inflammatory mediators, and enhancement of antioxidant defense pathways. Complementary computational studies supported the experimental findings, showing favorable electronic properties, stable binding to malarial protein targets, and drug-like pharmacokinetic predictions. Collectively, these results establish HBMT Schiff bases, particularly HBMT-3M4HB, as promising multifunctional scaffolds with combined antimalarial, antioxidant, and selective cytotoxic activities, offering potential for further preclinical development.