Synthesis Of Novel CYP51 Inhibitors And Biological Evaluation Of Antifungal Activities Based On Tetrahydronaphthalene

In recent years, the treatment of fungal infection gains lots of attention. The incidence of systemic fungal infections has increased dramatically and patients with AIDS and becomes a major cause of morbidity and mortality in immunocompromised individuals such as patients undergoing anticancer chemotherapy, serious damage to the body’s normal flora symbiotic relationship. Currently limited antifungal, liver toxicity, inefficiency and resistance, seriously affect the use and development of antifungal drugs. Looking for high efficiency, broad-spectrum and safe antifungal agents become a very pressing issue.This article introduced the Polyene, Azoles, Spine albomycin antifungal agents and their characteristics and application in clinical based on their structure. Most synthesized antifungal lead compounds on recent researching are heterocyclic compounds. New type of heterocyclic lead compounds modified or altered structure for the azole and non-azole drugs. Many different types of antifungal lead compounds with enhanced structure are also on researching. This article selected new antifungal agents with small adverse reactions, strong activity and broad spectrum for clinical use, based on rational design, structure modification and enhancement of Quinazolinone and Benzopyran. Application of lead compounds played a great role in promoting the development of new antifungal agents. The research will achieve greater breakthroughs for new antifungal agents with small adverse reactions, strong activity and broad spectrum.Objective:Design and synthesis new type of Quinazolinone and Benzopyran lead compounds via computer technology support. Select the best reaction conditions for synthesis via variance analysis of Orthogonal test, perform topical antifungal test with synthesized lead compounds, therefore select new compounds with potential inhibitory effect. And lay the foundation for future Tetrahydronaphthalene compound optimization and structure-activity relationships.Method:1.Research on total synthesis of Quinazolinone:By using methyl aniline, Propionic anhydride and Amines as materials, generate corresponding quinazolinone derivative compound with multi-step reaction. Orthogonal test analysis from the time, temperature, amount of condensing agent DCC three aspects, the optimal process route. The synthesized Quinazolinone lead compounds in vitro antifungal test, measured antifungal activity.2.Research synthesis of Benzopyran derivatives:Tetrahydronaphthalene design and synthesis of benzopyran derivatives based on nuclear structure, determine its antifungal activity.Result:1.There are eighteen different compounds generated, none of them showed up on any article or research,proved by using 1H NMR,MS,and13 C NMR test.2.After orthogonal experimental design and analysis:(1) Compound 1 was synthesized by esterification ammonolysis compound 2,the reaction yield of primary and secondary factors affecting:reaction time>reaction temperature>Compound 1 and solid-liquid ratio of propionic anhydride.The optimum reaction for 5 hours at 160 ℃,compound 1 with propionic anhydride liquid ratio of 1:8.(2) Compound 2 obtained by the ammonolysis reaction of compound 3,the primary and secondary factors affect the yield of the reaction: reaction time>reaction temperature>condensing agent and the feed ratio of the reactants. That is 30℃ under optimum reaction 24 hours, condensing agent and reactant feed ratio 1.5:1. 3. Tested lead compounds have potential antifungal activity for five different kinds of clinical pathogenic fungi. Best active compound 7A2.Compounds 6A1, 6A2, 6A4, 6A5, 7A1,7A2,7A3 and 7A4 had higher antifungal activity than fluconazole against Cryptococcus neoformans and Candida tropicalis.Compounds 6A1,6A2,6A5,7A2 and 7A3 had better potency against a broad range of fungal pathogen, which gave us the suggestion to further design and synthesize their derivatives.Conclusion: This experiment successfully generated eighteen new types of Tetrahydronaphthalene antifungal agents,Some compounds have good antifungal activity.Lays the foundation for future research on Quinazolinone’s and Benzopyran’s structure modification, enhancement and structure-activity relationships.