Toward multi-target therapy: Design, synthesis and mechanistic profiling of some novel acyl-thiosemicarbazides, as MAO and aromatase inhibitors

Abstract

Monoamine oxidases A and B (MAO-A/MAO-B) catalyze the oxidative deamination of serotonin, norepinephrine, and dopamine, whereas aromatase (CYP19A1) mediates the rate-limiting conversion of androgens into estrogens. Dysregulation across these enzymatic axes links endocrine status to neurochemical balance, with clinical implications in hormone-dependent cancers and mood/cognitive disorders. Motivated by this crosstalk, multi-target-directed ligands (MTDLs) that attenuate both MAO activity and estrogen biosynthesis could address disease complexity while simplifying polypharmacy. Thiosemicarbazides are privileged scaffolds that combine hydrogen-bonding capacity with tunable lipophilicity and π-surface area, making them attractive for engaging the hydrophobic cavities of MAO isoforms and the heme-proximal pocket of aromatase. Here, we report the design, synthesis, and biological evaluation of two matched series of acyl thiosemicarbazides (benzoxazolinone vs. benzimidazole cores). Several compounds achieve sub-micromolar and in multiple cases sub-0.10 μM-potency against MAO-A, MAO-B, and aromatase. Structure-activity relationships (SAR) are delineated, molecular docking and dynamics simulations provide mechanistic insight, and balanced dual and triple-active lead candidates are proposed for further pharmacological investigation.

Keywords: ADME analysis; Aromatase inhibition; Cytotoxicity; Molecular docking; Molecular dynamics; Monoamine oxidases; Thiosemicarbazide.