Design,synthesis And Antimicrobial Evaluation Of Novel Imide Spiro-derivatives

During the past decades,invasive fungal infection morbidity and mortality rose sharply.Deep fungal infection is a serious threat to the health of people,however,due to the abuse of antifungal drugs,the situation that many strains generate drug resistance is caused.In this case,exploring new antifungal drugs has become a top priority.Chitin synthase has played an important role in the biosynthesis processes of chitin that is the indispensable part of the cell walls of fungi,which does not exist in the body of mammals,so it becomes a unique antifungal drugs target.Spiro-compounds are widely applied in the field of materials,and have biological activity in the aspects of antifungal,diminishing inflammation,anticancer,etc.In this paper,chitin synthase is regarded as targets,and based on the structure characteristics of the reported chitin synthase inhibitors,a series of imide spiro-compounds are designed and synthesized as antifungal compounds.Then the in vitro antibacterial activities of these compounds are tested and their inhibition activities against the chitin synthase are tested by high-throughput screening method.The main works are summarized as follows:1.Synthesis of imide spiro-compounds 111a-n: starting from malononitrile and bromine ethyl acetate,the key intermediate 2-(2-bromoethyl)-7-ethyl-2,7-diazaspiro[4.4]nonane-1,3,6,8-tetraone(105)was obtained via multistep reactions such as substitution,cyclization,et.The intermediates 109a-n was prepared by multi-step reaction using 4-piperidinecarboxylic acid as a raw material through protection,amidation and deprotection.The compound 105 reacted with compounds 109a-n to give compound 110a-n,which was then acidified with concentrated hydrochloric acid to give final products 111a-n.2.Synthesis of imidium spiro ring L-hydroxyproline derivatives 116a-v: methyl 4-hydroxypyrrolidine-2-carboxylate 113 was prepared from L-hydroxyproline as starting material,then the intermediate 105 reacted with the compound 113 to give 1-(2-(7-ethyl-1,3,6,8-tetraoxo-2,7-diazaspiro[4.4]nonan-2-yl)ethyl)-4-hydroxypyrrolidine-2-carboxylate 114.Compounds 115a-v were synthesized from reacting intermediate 114 with various carboxylic acids,which were then acidified to form the target products 116a-v.3.The conditions for synthesis of intermediates and target compounds were explored,and the optimum was obtained.4.Seventy-one compounds were synthesized in this paper,among these compounds thirty-nine are new compounds.5.In this paper,the synthesized intermediates and target products were confirmed by 1H NMR and 13 C NMR.MIC of the target compounds are acquired by testing antifungal and antibacterial activity in vitro.6.The chitin synthase inhibition activity of some target compounds was tested.