In-Silico Studies of Novel Aza-Androgen Derivatives; Synthesis, Process Optimization and Characterization of 4-Azaandrost-5-Ene-17 Hydroxy-3-One (Precursor) for Its Commercial Application.

The 4-azasteroid scaffold remains a privileged framework for the design of steroid 5α-reductase inhibitors and related bioactive agents, owing to the pharmacological versatility conferred by A-ring nitrogen substitution. In this study, a series of novel aza-androgen–amino-acid conjugates was designed by functionalizing the C-17 hydroxyl of the 4-azaandrost-5 ene-3-one core with alanine, glycine, leucine, phenylalanine, and lysine to explore variations in polarity, steric bulk, and hydrogen-bonding capacity. The designed conjugates were evaluated in silico for drug-likeness and ADME properties using Swiss ADME, and prioritized compounds were subjected to molecular docking against five biologically relevant targets (5α-reductase type-2, androgen receptor, 17α-hydroxylase, estrogen receptor, and DHFR) using CB-Dock2. Parallelly, the key precursor 4-azaandrost-5-ene-17-hydroxy-3-one was synthesized from androst-4-ene-3,17-dione via a three-step sequence — ozonolytic A-ring cleavage, ammonia-mediated aza-cyclization, and sodium borohydride reduction — and the process was optimized and validated at 50 g scale with yields of 88–94% at each step. All intermediates and the target precursor were characterized by melting point, IR, ¹H/¹³C NMR, and HRMS. The combined computational and synthetic findings establish 4-azaandrost-5-ene-17-hydroxy-3-one as a robust, scalable, and structurally versatile intermediate for generating novel aza-androgen derivatives with predicted target-binding potential.