Bicyclic Monoterpenoid-Based Orthopoxvirus Inhibitors: Design, Synthesis, and Biological Assessment of a Novel Amide Series

Abstract

This study reports the design, synthesis, and comprehensive biological evaluation of a new class of orthopoxvirus inhibitors utilizing natural bicyclic monoterpenoid scaffolds as strategic replacements for synthetic polycyclic cores. A focused library of amides derived from camphor, apocamphane, isocamphane, and nopol-based amines was synthesized and screened for activity against Vaccinia (VACV), Cowpox (CPXV), and Ectromelia (ECTV) viruses. Structure-activity relationship (SAR) analysis identified the importance of a para-substituted electron-withdrawing group on the benzamide moiety, with the apocamphanyl amine series yielding the most potent candidate, compound 13d. Compound 13d exhibited potent in vitro antiviral activity with IC 50 values of 0.32 µM (VACV), 4.43 µM (CPXV), and 3.28 µM (ECTV), coupled with high selectivity indices (up to 1226). Further profiling revealed exceptional metabolic stability of 13d in mouse blood and favorable pharmacokinetics in mice following a single intragastric dose (100 mg/kg), characterized by rapid absorption and a long elimination half-life (T 1/2 ~7.6 h), supportive of once-daily dosing.Computational studies involving pharmacophore analysis, molecular docking, and MD simulations elucidated the binding mode to the p37 phospholipase domain and rationalized the observed SAR, highlighting the critical role of hydrophobic interactions and stereochemistry. These findings validate the bicyclic monoterpenoid platform as a promising strategy for discovering potent, metabolically stable anti-orthopoxvirus agents and establish 13d as a compelling lead candidate for further preclinical development.