Structural Modification Of Natural Product Pimprinine And Antifungal Acitivity Study Of Its Derivatives

Natural product based lead discovery for pesticide development is a hotspot in the field of agrochemicals in recent years. In this thesis, the biologically active natural product pimprinine was selected as lead compound, its structural modification was investigated in detail, with the hope to discover novel analogues with improved activities that can be used as the fungicide candidates. Detailed research contents are asfollows:1. The structures, synthesis and biological activities of Pimprinine and its analogues were systematically summarized in this thesis.2. We have designed and synthesized 191 new Pimprinine derivatives which can be divided in 5 different structure types, all of the target compounds have been characterized by 1H NMR,13C NMR and HRMS (or elemental analysis), and some of them were further confirmed by X-ray single crystal diffraction.3. The mainly modification strategies of the Pimprinine structure are as follows:(1). The synthesis of natural product Streptochlorin and its derivatives through introducing a halogen atom (Cl, Br) to the 4-site of the oxazole ring or introducing different substituents to the indole nitrogen;(2). Novel analogues were prepared by introducing a substituent to the indole ring of Streptochlorin backbone;(3). Replacement of the indole ring of Streptochlorin with a biological active heteroaromatic ring, such as pyridine, benzofuran, benzothiophene,1,3-benzodioxole, naphthol and quinoline and so on;(4). Replacement of the oxazole ring of pimprinine with an oxadiazole ring, three types of target compounds were obtained by this structural optimization methodology;(5). Two types of Pimprinine derivatives were synthesized by replacing the oxazole ring of pimprinine with 1,3,4-oxadiazole-2-thioether and introducing a methylene bridge between these two rings.4.In this thesis, three simple and efficient synthetic protocols have been developed by using some low cost and easily-accessible starting materials, and further used to synthesize a series of novel analogues of natural product pimprinine, including a 4-step synthetic route for Streptochlorin and its derivatives with indole as the starting material, and two synthetic routes for 1,3,4-oxadiazole-containing or 1,3,4-oxadiazole-2-thioether-containing Pimprinine derivatives with 3-indoleformic acid or 3-indoleacetic acid as the starting materials.5. All the synthesized target compounds were screened for their antifungal activity against seven fungi species namely Phytophthora infestans, Septoria triticiUromyces viciae-fabae, Pythium dissimile, Alternaria solani, Botryotinia fuckeliana and Gibbere11a zeae by Syngenta company. The bioassays results showed that compounds Ⅱ-30, Ⅱ-32h, Ⅱ-32i, Ⅱ-32j, Ⅱ-32m, Ⅱ-32o, Ⅱ-33h, Ⅱ-33i, 11-331 exhibited effective control and good spectrum of antifungal activity against Pythium dissimile, Alternaria solani, Botryotinia fuckeliana and displayed 99% inhibitory at the highest rate screened, however, the antifungal activity lacks potency, rarely extending to the lower rates tested; Some indole ring substituented Streptochlorin derivatives showed good antifungal activity, such as compounds Ⅲ-19, Ⅲ-24c, Ⅲ-24d, Ⅲ-26a,Ⅲ-32, and Ⅲ-32 is the most active compound, showing 99% inhibitory against Uromyces viciae-fabae, Alternaria solani and Botryotinia fuckeliana at at the highest rate screened; While those analogues with a heterocyclic ring instead of the indole ring of Streptochlorin were totally inactive except some showed weak activity; The antifungal spectrum is generally improved by substituting an ethyl group onto the indole ring nitrogen(V-6), or by introducing a methylene bridge between the indole and the oxadiazole rings(V-9), for example, compound V-6e exhibiting 99% inhibition against Pythium dissimile and Uromyces viciae-fabae, but the activity of this series compounds were still not good enough; Biological activity of the 1,3,4-oxadiazole-containing Pimprinine derivatives are still on testing.6. This thesis summarized the primary structure and antifugal acitivty relationship of Pimprinine derivatives, which offered a guide for further design and synthesis of Pimprinine derivatives with higher bioactivity.