Steroidal arylidene hybrids with phenolic moieties: Integrated in silico, DFT, and electrochemical evaluation for therapeutic targeting

Abstract

Targeting dual modulators of androgen biosynthesis enzymes, two phenol-substituted steroidal arylidene analogs—Dehydroepiandrosterone-Fn (DHEA-Fn) and Pregnenolone-Fn (PREG-Fn), where “Fn” denotes a phenolic moiety—were structurally characterized and comprehensively evaluated through a multidisciplinary approach integrating spectroscopic, electrochemical, and in silico analyses. Advanced Nuclear Magnetic Resonance (NMR) techniques, including two-dimensional heteronuclear correlation (2D-HETCOR) NMR, confirmed E/Z isomerism in DHEA-Fn and supported precise assignment of regiochemical and stereoelectronic features. Structure-guided molecular docking and molecular mechanics–generalized Born surface area (MM-GBSA) calculations predicted favorable binding to 5α-reductase type 2 and CYP17A1, positioning the compounds as potential dual inhibitors relevant to prostate cancer therapy. DHEA-Fn exhibited a superior docking profile (–10.53 kcal/mol) compared to the positive control Finasteride. Density functional theory (DFT) calculations indicated narrow HOMO–LUMO energy gaps and high electron affinity values, supporting enhanced redox reactivity and antioxidant potential. Electrochemical characterization using cyclic and square wave voltammetry confirmed quasi-reversible redox behavior consistent with the conjugated arylidene–phenol framework. This conjugated arylidene–phenol is proposed to act as a redox-active structural motif (i.e., a moiety capable of reversible electron transfer), potentially influencing bioactivation, oxidative stability, and interactions with redox-sensitive biological targets. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) modeling further predicted excellent oral bioavailability, blood–brain barrier permeability, and no violations of drug-likeness rules. Distinct P-glycoprotein interaction profiles suggest variable CNS efflux, which may influence neuroactivity and systemic distribution. Together, the integration of electrochemical analysis and in silico modeling provides a predictive, mechanism-oriented framework for evaluating the therapeutic viability of steroidal scaffolds. These findings highlight DHEA-Fn and PREG-Fn as rationally designed, multifunctional candidates with favorable physicochemical, electronic, and pharmacological profiles for further development in androgen-related oncology.