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

AVCI A., Taşci H., Özkan B. N. S., ÖZENVER N., Tozkoparan B., Kelekçi N. G.

Bioorganic Chemistry, vol.170, 2026 (SCI-Expanded, Scopus) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 170
  • Publication Date: 2026
  • Doi Number: 10.1016/j.bioorg.2026.109489
  • Journal Name: Bioorganic Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Chimica, EMBASE
  • Keywords: ADME analysis, Aromatase inhibition, Cytotoxicity, Molecular docking, Molecular dynamics, Monoamine oxidases, Thiosemicarbazide
  • Anadolu University Affiliated: Yes

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.