Design and Synthesis of Pyrimidine Amine Containing Isothiazole Coumarins for Fungal Control

Abstract

Developing new fungicides is always crucial to protecting crops. A series of 4-(3,4-dichloroisothiazol-5-yl)-7-(2-((5-(5-pyrimidin-4-yl)amino)ethoxy)-8-methyl) coumarin derivatives were designed and synthesized by Williamson ether condensation and substitution reactions. Structure determinations were clarified by ¹H NMR, ¹³C NMR, and HRMS, and compound 4h crystallized by the fusion method for further structural confirmation. The in vitro bioassay results showed that the target compounds displayed good fungicidal activity against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Fusarium graminearum, Physalospora piricola, Rhizoctonia solani, and Sclerotinia sclerotiorum. Among them, compounds 4b and 4d showed higher inhibitory activity against R. solani, with EC₅₀ values of 11.3 and 13.7 μg/mL, respectively, and they were more active than the positive control diflumetorim with an EC₅₀ value of 19.8 μg/mL. Molecular docking suggested that compound 4b and diflumetorim may have similar interactions with complex I NADH oxidoreductase. Density functional theory calculation and pesticide-likeness analysis studies gave a rational explanation of their fungicidal activity. These results indicated that compounds 4b and 4d deserved further optimization according to the principle of pesticide-likeness.

Figure 1

Reported fungicides acting on complex I NADH oxidoreductase.

Figure 2

Design of the target compound.

Scheme 1. Synthetic Route of Target Compounds 4a–4j

Reagents and conditions: (i) tert-butyl-2-bromoethyl carbamate, K₂CO₃, DMF, 80 °C, overnight. (ii) CF₃COOH, DCM, r.t., overnight. (iii) Substituted chloro-pyrimidines, K₂CO₃, DMF, 80 °C, 7–8 h.

Figure 3

X-ray crystal structure of compound 4h (CCDC: 2286889).

Figure 4

One-dimensional chain structure (A) and stacking structure (B) of 4h.

Figure 5

Molecular docking of compound 4b (A) and diflumetorim (B) to Mus musculus NADH oxidoreductase (pdb: 6ZR2).

Figure 6

HOMO and LUMO of compounds 4b and 1.