Design,Synthesis,and Biological Activity Evaluation Of Novel Quinoline And Quinazolinone Derivatives

Quinolines and quinazolinones,which are widely found in natural products in nature,are two important classes of nitrogen-containing heterocycles in the development of medicinal chemistry and have been developed into a variety of drugs with rich pharmacological activities as privileged scaffolds for drug research.For example,antimalarial drugs chloroquine,hydroxychloroquine and mefloquine based on quinoline core and skeletal muscle relaxant afloqualone,antifungal agent abaconazole and sedative-hypnotic drug mecloqualone based on quinazolinone core.Due to their superior biopharmacological properties,quinoline and quinazolinone skeletons are also widely used in the prevention and treatment of agricultural diseases,such as the commercial pesticide molecules ethoxyquin,8-hydroxyquinoline,proquinazid,quinoxyfen and fluquinconazole are all derived from quinoline and quinazolinone skeletons.During the screening of antifungal activity of various alkaloids in the early stage of our research group,it was found that quinoline and quinazolinone compounds have potential anti-phytopathogenic fungal activity.Based on that,quinoline and quinazolinone were treated as the targets of modification and optimization in this study.We designed and synthesized several series of quinoline and quinazolinone derivatives,and studied the structure-activity relationship of target compounds against phytopathogenic fungi.In addition,we further explored the mechanism of highly active compounds in inhibiting phytopathogenic fungi,which provided a theoretical basis and laid the foundation for further development and application of quinoline and quinazolinone.The main research contents are described as follows:1.Design,synthesis,and biological activity evaluation of 8-hydroxyquinoline metal complexesBased on the preliminary screening,we selected 10 8-hydroxyquinolines with different substitutions as ligand molecules,designed and synthesized four types of 8-hydroxyquinoline divalent metal ion complexes(Zn²⁺,Mn²⁺,Ni²⁺,Mg²⁺),and determined the antifungal activity of the synthesized target compounds against four plant pathogenic fungi to explore the structure-activity relationship for further structure optimization studies.In the antifungal activity screening,compound 1e showed the best in vitro antifungal activity with an EC₅₀ value of 0.09μg/m L against Sclerotinia sclerotiorum,and pot experiments showed that this compound possessed better curative activity than that of positive control azoxystrobin at 80,40,and 20μg/m L.We further investigated the inhibition mechanism of compound 1e against S.sclerotiorum.The results of scanning electron microscopy showed that compound 1e disrupted the biofilm system of S.sclerotiorum mycelia,and caused the increase of mycelial cell membrane permeability and the release of contents,which affected the normal physiological and biochemical functions of S.sclerotiorum,resulting in the death of mycelium.In addition,the compound can effectively inhibit the formation and germination of the sclerotia of S.sclerotiorum,which has some positive significance to reduce the production and spread of S.sclerotiorum infection.2.Design,synthesis,and biological activity evaluation of 5-nitro-8-hydroxyquinoline derivativesBased on the analysis of the structure-activity relationship of the previous working compounds,we chose 5-nitro-8-hydroxyquinoline as the lead compound for the structural design and synthesis of its 7-position derivatives,and the synthesized compounds were screened for anti-phytopathogenic fungal activity and analyzed for structure-activity relationship.In the antifungal activity assay,the lead compound 5-nitro-8-hydroxyquinoline（compound 1）showed the most effective in vitro inhibitory activity against the five tested strains.We further determined the antifungal and antibacterial spectral of compound 1,it showed that the compound possessed better inhibiting activity than some commercial agents against a variety of fungi and bacteria commonly found in agriculture.In addition,pot experiments showed that compound 4c exhibited superior in vivo curative activity to that of compound 1 and the positive control azoxystrobin against S.sclerotiorum,and scanning electron microscopy revealed that compounds 1 and 4c caused mycelial deformation of S.sclerotiorum,thus leading to mycelial death of S.sclerotiorum.3.Design,synthesis and evaluation of anti-phytopathogenic fungal activity of2,8-bis（trifluoromethyl）quinazolinone derivatives.The research content of this part was based on the parent nucleus of 2,8-bis（trifluoromethyl）-quinazolinone with potential antifungal activity discovered by our group in the previous research,the structure design and synthesis of its 4-position derivatives were carried out,and the synthesized target compounds were screened for their anti-phytopathogenic fungal activity to find quinazolinone derivatives with effective in vitro antifungal activity.