RESUMO
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO (NtPPO) and herbicidal activity were evaluated. Among them, compounds B11 (Ki = 9.05 nM) and B20 (Ki = 10.23 nM) showed significantly better inhibitory activity against NtPPO than that against flumiclorac-pentyl (Ki = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to NtPPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.
Assuntos
Amaranthus , Desenho de Fármacos , Inibidores Enzimáticos , Herbicidas , Simulação de Acoplamento Molecular , Oxidiazóis , Ftalimidas , Plantas Daninhas , Protoporfirinogênio Oxidase , Tiadiazóis , Herbicidas/química , Herbicidas/farmacologia , Herbicidas/síntese química , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/síntese química , Relação Estrutura-Atividade , Ftalimidas/química , Ftalimidas/farmacologia , Ftalimidas/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Protoporfirinogênio Oxidase/antagonistas & inibidores , Protoporfirinogênio Oxidase/química , Protoporfirinogênio Oxidase/metabolismo , Amaranthus/química , Amaranthus/efeitos dos fármacos , Proteínas de Plantas/química , Proteínas de Plantas/antagonistas & inibidores , Estrutura Molecular , Nicotiana/químicaRESUMO
A series of ferulic acid dimers were designed, synthesized, and evaluated for anti-TMV activity. Biological assays demonstrated that compounds A6, E3, and E5 displayed excellent inactivating against tobacco mosaic virus (TMV) with EC50 values of 62.8, 94.4, and 85.2 µg mL-1, respectively, which were superior to that of ningnanmycin (108.1 µg mL-1). Microscale thermophoresis indicated that compounds A6, E3, and E5 showed strong binding capacity to TMV coat protein with binding affinity values of 1.862, 3.439, and 2.926 µM, respectively. Molecular docking and molecular dynamics simulation revealed that compound A6 could firmly bind to the TMV coat protein through hydrogen and hydrophobic bonds. Transmission electron microscopy and self-assembly experiments indicated that compound A6 obviously destroyed the integrity of the TMV particles and blocked the virus from infecting the host. This study revealed that A6 can be used as a promising leading structure for the development of antiviral agents by inhibiting TMV self-assembly.