2. Academic Validation
  3. Discovery of N-(1-(6-Oxo-1,6-dihydropyrimidine)-pyrazole) Acetamide Derivatives as Novel Noncovalent DprE1 Inhibitors against Mycobacterium tuberculosis

Discovery of N-(1-(6-Oxo-1,6-dihydropyrimidine)-pyrazole) Acetamide Derivatives as Novel Noncovalent DprE1 Inhibitors against Mycobacterium tuberculosis

  • J Med Chem. 2024 Jan 17. doi: 10.1021/acs.jmedchem.3c01703.
Liu Yang 1,  Xueping Hu 2,  Yang Lu 1,  Ruolan Xu 1,  Yaping Xu 1,  WanLi Ma 3 4,  Md Shah Alam 3 4 5 6,  Tianyu Zhang 3 4 5 6,  Xin Chai 1,  Yixuan Lei 1,  Qing Ye 1,  Xiaowu Dong 1,  Yu Kang 1,  Jinxin Che 1,  Tingjun Hou 1,  Dan Li 1 7
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao 266237, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 China-New Zealand Joint Laboratory of Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China.
  • 6 Guangdong-Hong Kong-Macau Joint Laboratory of Respiratory Infectious Diseases, Guangzhou 510530, China.
  • 7 Jinhua Institute of Zhejiang University, Jinhua ,Zhejiang321000, China.
PMID: 38232131 DOI: 10.1021/acs.jmedchem.3c01703
Abstract

Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is a promising target for treating tuberculosis (TB). Currently, most novel DprE1 inhibitors are discovered through high-throughput screening, while computer-aided drug design (CADD) strategies are expected to promote the discovery process. In this study, with the aid of structure-based virtual screening and computationally guided design, a series of novel scaffold N-(1-(6-oxo-1,6-dihydropyrimidine)-pyrazole) acetamide derivatives with significant antimycobacterial activities were identified. Among them, compounds LK-60 and LK-75 are capable of effectively suppressing the proliferation of Mtb with MICMtb values of 0.78-1.56 μM, comparable with isoniazid and much superior to the phase II candidate TBA-7371 (MICMtb = 12.5 μM). LK-60 is also the most active DprE1 inhibitor derived from CADD so far. Further studies confirmed their high affinity to DprE1, good safety profiles to gut microbiota and human cells, and synergy effects with either rifampicin or ethambutol, indicating their broad potential for clinical applications.

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