Abstract: Thirty-four new pyrido[4,3- d ]pyrimidine analogs were designed, synthesized, and characterized. The crystal structures for compounds 2c and 4f were measured by means of X-ray diffraction of single crystals. The bioassay results showed that most target compounds exhibited good fungicidal activities against Pyricularia oryzae , Rhizoctonia cerealis , Sclerotinia sclerotiorum , Botrytis cinerea, and Penicillium italicum at 16 μg/mL. Compounds 2l , 2m , 4f , and 4g possessed better fungicidal activities than the commercial fungicide epoxiconazole against B. cinerea . Their half maximal effective concentration (EC 50 ) values were 0.191, 0.487, 0.369, 0.586, and 0.670 μg/mL, respectively. Furthermore, the inhibitory activities of the bioactive compounds were determined against sterol 14α-demethylase (CYP51). The results displayed that they had prominent activities. Compounds 2l , 2m , 4f , and 4g also showed better inhibitory activities than epoxiconazole against CYP51. Their half maximal inhibitory concentration (IC 50 ) values were 0.219, 0.602, 0.422, 0.726, and 0.802 μg/mL, respectively. The results of molecular dynamics (MD) simulations exhibited that compounds 2l and 4f possessed a stronger affinity to CYP51 than epoxiconazole.
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