Design,Synthesis And Biological Activity Of Heterocyclic Bioisosteric Analogues As Novel Peptide Deformylase Inhibitors

Peptide deformylase is a metalloproteinase that is widely involved in protein synthesis in prokaryotes and mitochondria and chloroplasts of eukaryotes.The peptide deformylase of prokaryotes is a novel antibacterial drug target,whose inhibitors are expected to be new antibiotics against‘super bacteria’.In recent years,researchers have found that another human peptide deformylase is overexpressed in a variety of cancer cells.Inhibition of Hs PDF can effectively inhibit proliferation of cancer cells.Thus,Hs PDF is considered as a novel antitumor target,and its inhibition agents and mechanisms are also being studied.However,there is currently no listed drug of PDF inhibitors due to safety and efficacy issues.This paper was based on the previous researches of our group to synthesize a new class of PDF inhibitors with high efficiency and low toxicity.So that,we retained the structural characteristics of the lead compounds and replaced the amide bond of PDF inhibitors with bioisosteres.We designed and synthesized a new class PDF inhibitors containing heterocycles,testing their antibacterial activity in vitro and analyzing the SAR.We found that those heterocyclic compounds with aromatic P₃’side chain possess better antibacterial activity and have a certain antibacterial effect on Gram-negative bacteria.We determined their inhibitory activity on Hs PDF.We also performed in vitro cell proliferation assay to determine their antitumor activity on various cancer cells.The results showed that most of the compounds possess good anticancer activity.In addition,we chose 27 for acute toxicity experiments,and the preliminary results showed that it has low toxicity in vivo.We will conduct further in vivo experiments to evaluate the efficacy and safety of these compounds.