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 (K d of 19.8 ± 7.3 μM) than ningnanmycin (K d 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.

Design, synthesis, and bioactivity of ferulic acid derivatives containing an β-amino alcohol

“…The inhibitory effect of ferulic acid derivatives D1–D24 on TMV was further studied based on the method of literature and the previous work of antiviral activity test [ 1 , 12 , 42 ]. The bioassay results indicated that most of the compounds exhibited moderate to good anti-TMV activity at 500 μg/mL, as shown in Table 5 .…”

“…Plant pathogens, pests and various abiotic stresses cause serious losses to agricultural production, and are significant problems in achieving agricultural sustainability [ 1 ]. So far, more than 1000 plant viruses have been reported [ 2 ].…”

Trifluoromethylpyridine thiourea derivatives: design, synthesis and inhibition of the self‐assembly of tobacco mosaic virus particles

“…Firstly, the substituted 2 H ‐benzo[ d ][1,3]oxazine‐2,4(1 H )‐dione ( 2 ) was easily obtained by treating compound 1 with triphosgene (BTC) in good yields and was subjected to by ring‐opening reaction to give substituted anthranilamide ( 3 ) 14,34 . 3‐Chloro‐5‐(trifluoromethyl) picolinoyl isothiocyanate ( 6 ) was freshly‐prepared by treatment of acyl chloride ( 5 , easily prepared from compound 4 ) 35 . Subsequently, the title compounds (compounds 7a – 7aa ) were easily synthesized via condensation of compound 3 with compound 6 in good yields 35 .…”

“…14,34 3-Chloro-5-(trifluoromethyl) picolinoyl isothiocyanate (6) was freshly-prepared by treatment of acyl chloride (5, easily prepared from compound 4). 35 Subsequently, the title compounds (compounds 7a-7aa) were easily synthesized via condensation of compound 3 with compound 6 in good yields. 35 Synthesized structures were confirmed by 1 H, 13 C, and 19 F NMR and HRMS.…”

1,3,4-Oxadiazole Contained Sesquiterpene Derivatives: Synthesis and Microbiocidal Activity for Plant Disease

“…citri (Xac) reduces the quality and yield of fruits ( Graham et al, 2004 ). Tobacco mosaic virus (TMV) can survive in dry plant debris for up to 100 years, and the associated plant diseases cause economic losses of more than USD 30 billion each year ( Wang et al, 2018 ; Guo et al, 2021 ). At present, pesticides are the main means of controlling crop diseases and insect pests ( Kemmitt et al, 2018 ).…”