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Published on: August 1, 2018
Design, Synthesis, and Biological Evaluation of 1,3,4-Thiadiazole Derivatives as Novel Potent Peptide Deformylase
Shouning Yang1, Yaru Wang1, Yujie Yang1
1State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, NMPA Key Laboratory for Research and Evaluation of Innovative Drug, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China.
Abstract:
The prevalence of drug-resistant bacteria is a major challenge throughout the world, especially with respect to Gram-negative bacteria, such as drug-resistant Acinetobacter baumannii, which are regarded as the greatest bacterial threat to human health by the World Health Organization (WHO). In this work, 1,3,4-thiadiazole was introduced into the main skeleton of the classical peptidomimetic peptide deformylase (PDF) inhibitor in pursuit of highly efficient and broad-spectrum bacteriostatic drugs. Upon detailed structure-activity relationship study, PDF inhibitors that possess satisfactory activity against both Gram-positive and Gram-negative bacteria as well as a lower potential for methemoglobin toxicity were screened out. The mechanism of the empowered antibacterial activity against Gram-negative bacteria was also investigated. Finally, for the first time, remarkable protective efficacy against drug-resistant A. baumannii in a mouse model was achieved by a PDF inhibitor (compound 43). These findings can pave a way to new approaches to the development of novel broad-spectrum PDF inhibitors.
