Design,synthesis And Activity Evaluation Of KDO Synthase Inhibitor Prodrugs

Bacterial resistance to existing antibiotics is developing rapidly,so the development of new therapeutic drugs is imperative.2-Keto-3-deoxyoctanoic acid(KDO)is one of the core structures of lipopolysaccharide(LPS)in the outer membrane of Gram-negative bacteria,which is a common structure in Gram-negative bacteria but not in mammals.CMP-KDO synthase(3-deoxy-d-monno-octulosonate cytidylyltransferase)is the key enzyme in the biosynthetic process of KDO.Inhibition of the activity of this enzyme could stop bacterial growth.Therefore,effective CMP-KDO synthase inhibitors are expected to be new antimicrobial agents against Gram-negative bacteria.However,many compounds with good inhibitory activity against CMP-KDO synthase did not exhibit antibacterial activity.due to their inability to cross the membrane into the bacteria.In order to solve the problem that such active molecules with in vitro enzyme activity cannot enter into bacteria cells,four types of prodrugs were designed based on prodrug strategy using self-immolative groups.Then they were synthesized and their anti-Gram-negative bacteria activity was tested.The results of antibacterial activity test showed that compound 2-6 showed certain antibacterial activity in tested bacteria.This indicates that the reducing substance in bacteria can trigger the fragmentation of the self-immolative group in the prodrug,thus realizing the release of the active drug.