Design, Synthesis, and Mechanism of Antiviral Acylurea Derivatives Containing a Trifluoromethylpyridine Moiety.

Abstract

Novel acylurea derivatives 7a-7ab were designed and synthesized by linking the active substructures trifluoromethylpyridine and anthranilic diamide via an acylurea bridge. Most of the title compounds exhibited good activity against tobacco mosaic virus (TMV), particularly compound 7x (EC50 of 211.8 μg/mL), which showed much higher curative activity than ningnanmycin (EC50 of 389.8 μg/mL), and compound 7ab, which showed excellent inactivation activity (EC50 of 36.1 μg/mL), similar to ningnanmycin (EC50 of 23.2 μg/mL). The preliminary mechanism of these derivatives was investigated. Autodocking analysis revealed that compounds 7x and 7ab had good affinity for TMV coat protein (TMV CP), with low binding energies (-7.86 and -8.59 kcal/mol) comparable to ningnanmycin (-8.75 kcal/mol). Molecular dynamics simulation showed that compound 7x had a stable system structure with a better binding free energy (-32.94 kcal/mol) than ningnanmycin (-25.62 kcal/mol). Microscale thermophoresis showed that compound 7x bound more strongly to TMV CP (Kd of 19.8 ± 7.3 μM) than ningnanmycin (Kd of 21.2 ± 7.3 μM). Transmission electron microscopy and self-assembly experiments demonstrated that compounds 7x and 7ab significantly obstructed the self-assembly of TMV RNA and TMV CP. This new acylurea derivative has excellent antiviral activity by targeting TMV CP and inhibiting TMV self-assembly and can be considered a candidate for antiviral applications.