Novel oleanolic acid derivatives containing piperazine pyrimidine moieties: design, synthesis, and antimicrobial...

Natural products are main sources of new chemical entities for pesticide discovery and also important modification substrates for activity enhancement. In this study, a series of novel oleanolic acid derivatives containing piperazine pyrimidine structures were designed and synthesized. Multi NMR and high resolution-mass spectrometry technologies were utilized to characterize the synthesized compounds' structures. Antimicrobial potential of the title compounds was assessed against several phytopathogenic fungi and bacteria, namely Botryosphaeria dothidea, Fusarium sp. in morchella esculenta, Sclerotinia sclerotiorum, Fusarium graminearum, Rhizoctonia solani, Botrytis cinerea in strawberry, Botrytis cinerea in tobacco, Botrytis cinerea in blueberry, Alternaria solani, and Phomopsis sp., and Pseudomonas syringae pv. actinidiae, Xanthomonas oryzae pv. oryzicola, and Xanthomonas axonopodis pv. citri. The results showed that most of these compounds displayed good-to-moderate antimicrobial activities. Among them, compound 4e showed excellent efficacy against B. dothidea with EC₅₀ value of 7.39 μg/mL outperforming pyrimethanil (13.37 μg/mL). In vivo study further confirmed that 4e effectively reduced the incidence of postharvest soft rot in kiwifruit caused by B. dothidea. Mechanistic research revealed that 4e could disrupt cell integrity of B. dothidea causing protein, nucleic acid leakage, and over-generate reactive oxygen species. Furthermore, molecular docking simulation analysis suggested that 4e could readily bound to the isocitrate lyase protein. In addition, compound 4p exhibited promising antibacterial activity superior to the commercial bactericidal thiodiazole copper. The remarkable antimicrobial efficacy of the oleanolic acid derivatives provided great potential for preventing and curing plant diseases.