Design and anti-rhinovirus activity of novel derivatives based on the pleconaril core

Developing drugs to treat rhinovirus (RV) infections remains a serious and unresolved problem. Pleconaril is the most widely studied broad-spectrum RV inhibitor. Fewer than 10 % of circulating RV types are naturally resistant to pleconaril, which is why researchers continue to study it as a basis for creating new, more active molecules. We conducted a comprehensive study on modifying the pleconaril molecule and demonstrated that the isoxazole ring is crucial for determining anti-RV activity. Based on these findings, we aimed to further study the pleconaril core to discover new therapeutic candidates. We synthesized a large series of new pleconaril derivatives with mono- or di-substituted central phenyl rings, modified linkers, and substitutions on the isoxazole or 1,2,4-oxadiazole moieties. We evaluated the cytotoxicity and inhibitory activity of the obtained compounds using RV-A2 and RV-B14 strains in HeLa cells. To explain the differences in inhibitory profiles, we performed molecular dynamics simulations. Results from the structure-activity relationship analysis revealed that the substituents on the isoxazole and 1,2,4-oxadiazole rings, as well as the linker, play a decisive role in the anti-RV activity profile of monomethylated pleconaril derivatives. We demonstrated that the movement of two loops at the entrance of the VP1 binding pocket of the capsid protein and the inhibitor molecules correlates with the stability of the complex, and therefore, with efficacy against RV. Compounds 1q, 1gg, 2g, and 4c were identified as potent new RV inhibitors from this series of compounds. These compounds are promising new candidates for lead optimization and preclinical studies in the development of antiviral drugs against RV.