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

Abstract

Novel acylurea derivatives <b>7a</b>-<b>7ab</b> 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 <b>7x</b> (EC₅₀ of 211.8 μg/mL), which showed much higher curative activity than ningnanmycin (EC₅₀ of 389.8 μg/mL), and compound <b>7ab</b>, 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 <b>7x</b> and <b>7ab</b> 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 <b>7x</b> 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 <b>7x</b> bound more strongly to TMV CP (<i>K</i>_d of 19.8 ± 7.3 μM) than ningnanmycin (<i>K</i>_d of 21.2 ± 7.3 μM). Transmission electron microscopy and self-assembly experiments demonstrated that compounds <b>7x</b> and <b>7ab</b> 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.