Design, Synthesis And Biological Evaluation Of Novel Quinazoline-2,4-diones As Potential Chitin Synthase Inhibitors

Fungal infection especially deep infection has threatened the human health seriously. With the extensive use of antifungal drugs, more and more resistant strains emerged, looking for new antifungal agents become imperative. Chitin synthase inhibitor which was as a new type of antifungal agents has injected new vitality for the modern antifungal research work. Quinazoline-2,4-diones displayed various pharmacological activities including antibacterial, anti-cancer, anti-viral, blood-pressure, lowering blood sugar, anti-inflammatory, anesthetic etc. There are plurality quinazoline-2,4-diketones and derivatives have been developed to applied to clinical.Based on the current situation in the researches of chitin synthase and quinazoline-2,4-diones, we designed and synthesized a series of novel quinazoline-2,4-diones derivatives as chitin synthase inhibitors. The antibacterial activities in vitro of all target compounds and the chitin synthase inhibitory activities of some compounds were investigated. The structure-activity relationship was explored preliminarily. The main work was summarized as following:1. Preparation of novel quinazoline-2,4-dione amides I:starting from methyl anthranilate, the key intermediate3-(2-hydroxy-3-(methylamino)propyl)-1-methy lquinazoline-2.4-dione55was obtained via multistep reactions such as substitution reaction, hydrolysis reaction, cyclization, ring-opening reaction and so on. The target compounds59a-s were synthesized from reacting intermediate55with various intermediates57a-s.2. Preparation of novel quinazoline-2,4-dione amides â…¡:starting from methyl anthranilate, the key intermediate64and the target compounds67a-j were obtained via multistep reactions such as N-alkylation, cyclization, substitution reaction, ring-opening reaction and so on.3. Preparation of novel quinazoline-2,4-dione amides â…¢:starting from intermediate53,the target compounds75a-m were obtained via multistep reactions such as substitution reaction, Condensation reaction and so on.4.The condition for preparation of intermediate and target compounds were explored, and the optimal reaction condition was obtained.5. Eight seven compounds were synthesized in this thesis and more than fifty were new compounds. The structures of all obtained compounds were confirmed by1H NMR,13C NMR or MS spectrum.6. All target compounds were tested antimicrobial activity in vitro. The antimicrobial activities assays showed that all synthesized quinazoline-2,4-diones derivatives displayed different inhibitory activities for the all tested microorganisms, some compounds showed equivalent or superior inhibitory activities in comparison with the reference drugs. The compounds of series I and series II showing no inhibitory effect on the tested bacteria indicated that these compounds inhibit selectively the tested fungi.7. The chitin synthase inhibitory activity of some target compounds was studied. The chitin synthase inhibition activity assays indicated that the compounds with good solubility showed better inhibitory activity on chitin synthase and some of them showed superior inhibitory activities in comparison with the reference drugs.8. The preliminary structure-activity relationship showed that the compounds containing aromatic amine showed better anti-microbial activities on the tested microorganisms than those containing aliphatic amines. Overall, the electronic effects of aromatic ring played an important role in biological activities with the electron with drawing substituent showed more potent anti-microbial activities. The compounds with better antifungal activities in vitro showed better inhibition on chitin synthase, but they were not all proportional to each other. The compounds containing aromatic amine showed better inhibition on chitin synthase than the compounds containing aliphatic amines. The electronic effects of aromatic ring had a great influence on the chitin synthase inhibition, the compounds with electron with drawing substituent showed better inhibition than the compounds with electron donating substituent. The location of the substituents on the benzene had a certain degree influence on the inhibition. The para-substituents showed better inhibition on chitin synthase than orth-substituents.