New 1,3‐Oxazole and 1,2,4‐Oxadiazole Derivatives as Novel Agents Against Human Rhinovirus and Cytomegalovirus

A library of 16 new five‐functionalized derivatives of 2‐undecyl‐ and 1,2,4‐oxadiazole‐containing 2‐aryl‐4‐cyano‐1,3‐oxazoles was synthesized using α ‐acylamino‐ β , β ‐dichloroacrylonitriles as key building blocks, enabling efficient formation of diverse 1,3‐oxazole, oxadiazole–oxazole, and sulfonamide–oxazole systems. The antiviral potential was evaluated in vitro against rhinovirus 8 (HRV8), cytomegalovirus (HCMV), parainfluenza virus type 3 (HPIV‐3), and zoonotic encephalomyocarditis virus (EMCV). Screening revealed distinct activity profiles: none of the compounds inhibited EMCV or HPIV‐3, while several demonstrated pronounced efficacy against HRV8 and HCMV. In concentration‐dependent assays, compounds 1, 7, 10, 13 , and 14 exhibited potent anti‐HCMV effects (IC 50 = 0.42–4.67 µM). Compound 7 showed remarkable selectivity (SI = 465), outperforming ganciclovir (GCV, SI = 326). Against HRV8, compound 2 was the most active (IC 50 = 1.67 µM, SI = 11), whereas compound 13 displayed weak activity (IC 50 = 21.0 µM, SI = 1). All molecules met drug‐likeness criteria with favorable ADMET‐predicted pharmacokinetic parameters. Molecular docking suggested that derivatives 7, 10, 13 , and 14 may target viral DNA polymerase, with binding energies from –8.8 to –9.7 kcal mol −1 . These findings demonstrate that 1,3‐oxazoles represent a promising chemotype for new antiviral candidates active against HCMV and HRV8.