Structure-activity relationships of halogenated disinfectants as potent inhibitors of 5α-reductase type 1: Potential impact on neurosteroid synthesis.

Neurosteroids modulate neural function, with their synthesis dependent on 5α-reductase type 1 (SRD5A1). Dysregulation of SRD5A1 has been implicated in neuropsychiatric disorders. Halogenated disinfectants, widely used antimicrobial compounds, may modulate neurosteroidogenesis through SRD5A1 inhibition. This study evaluated the effects of eight halogenated disinfectants on human and rat SRD5A1 activity and characterized their structure-activity relationships. Using human SF126 cell microsomes and rat brain microsomes, all tested compounds significantly inhibited SRD5A1 activity. Hexachlorophene showed the highest potency (IC = 5.50 μM), followed by bromochlorophene (7.10 μM), bithionol (7.33 μM), fenticlor (14.57 μM), dichlorophene (18.34 μM), and clorophene (25.51 μM). Enzyme kinetic analyses revealed mixed/noncompetitive inhibition mechanisms. Rat SRD5A1 showed reduced sensitivity compared to human SRD5A1. In intact cells, all compounds significantly reduced dihydrotestosterone production in a concentration-dependent manner. Molecular docking showed binding to the NADPH site, with binding energies correlating with potency. 3D-QSAR modeling identified hydrogen bond acceptor and hydrophobic features as critical for inhibition. Structure-activity analyses revealed correlations between potency and physicochemical properties including LogP, molecular weight, and halogen content. Cross-species correlation assessment using the arithmetic residuals in K-groups analysis framework provided enhanced analytical validation and confirmed species-specific activity patterns with high-activity compounds clustering consistently across both species. These findings demonstrate that halogenated disinfectants are potent SRD5A1 inhibitors with potential implications for neurosteroid biosynthesis and neuropsychiatric health, providing structural insights for both environmental risk assessment and therapeutic applications.