Regulation of oxytocin receptor by zinc coumarin derivatives: a mechanistic approach to alleviate anxiety and enhance folliculogenesis in letrozole-induced PCOS in zebrafish model

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, characterized by insulin resistance and mood disturbances. The therapeutic potential of traditional treatments is often limited by side effects, highlighting the need for novel interventions. This study investigated the efficacy of newly synthesized thiosemicarbazone coumarin zinc complexes, TSCO6-Zn (T1) and TSCO13-Zn (T2) were assessed in a letrozole-induced PCOS in-vivo zebrafish model. Synthesis involved Pechmann condensation to form 7-hydroxy-4-methylcoumarin, followed by coordination with zinc. The compounds’ targets were predicted via BindingDB, with molecular docking confirming interactions with PCOS-related proteins. In vivo toxicity was assessed in zebrafish embryos exposed to T1 and T2 (up to 150 µM), examining behavioral assays, body weight, lipid profile, GSI (%) and folliculogenesis. In addition to that, HPLC testosterone quantification and qPCR for gene expression analysis were employed for 20β-hsd, cyp19a1a, dennd1a, tox3, oxtr, mTOR, pik3cd, and drd2a. T1 and T2 markedly reduced anxiety, lowered testosterone, and enhanced follicular maturation, with no toxicity observed up to 50 µM. Docking studies demonstrated a high affinity of T1 and T2 for key metabolic and neurobehavioral targets such as drd2a, oxtr, mTOR, and pik3cd. Significant improvements were noted in body weight, lipid profiles, oxidative stress markers, and normalized gene expressions involved in steroidogenesis and metabolic pathways in letrozole-induced PCOS in the zebrafish. T1 and T2 effectively mitigate metabolic and neurobehavioral disturbances associated with PCOS in the zebrafish model, suggesting their potential as comprehensive therapeutic agents. Their multi-target approach could provide a basis for advanced PCOS treatment strategies.