2. Academic Validation
  3. Exploration and Biological Evaluation of 1,3-Diamino-7 H-pyrrol[3,2- f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors

Exploration and Biological Evaluation of 1,3-Diamino-7 H-pyrrol[3,2- f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors

  • J Med Chem. 2023 Oct 26;66(20):13946-13967. doi: 10.1021/acs.jmedchem.3c00891.
Zihao Zhu 1,  Cantong Chen 1,  Jie Zhang 1,  Fangfang Lai 1,  Jing Feng 1,  Guangxu Wu 2,  Jie Xia 1,  Wenxuan Zhang 1,  Zunsheng Han 1,  Chi Zhang 1,  Qingyun Yang 1,  Yuchen Wang 1,  Bo Liu 1,  Tianlei Li 1,  Song Wu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Department of Pharmacy, The People Hospital of Liupanshui City, Guizhou, Liupanshui 553000, China.
PMID: 37698518 DOI: 10.1021/acs.jmedchem.3c00891
Abstract

Dihydrofolate reductase (DHFR), a core enzyme of folate metabolism, plays a crucial role in the biosynthesis of purines and thymidylate for cell proliferation and growth in both prokaryotic and eukaryotic cells. However, the development of new DHFR inhibitors is challenging due to the limited number of scaffolds available for drug development. Hence, we designed and synthesized a new class of DHFR inhibitors with a 1,3-diamino-7H-pyrrol[3,2-f]quinazoline derivative (PQD) structure bearing condensed rings. Compound 6r exhibited therapeutic effects on mouse models of systemic Infection and thigh Infection caused by methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. Moreover, methyl-modified PQD compound 8a showed a strong efficacy in a murine model of breast Cancer, which was better than the effects of taxol. The findings showcased in this study highlight the promising capabilities of novel DHFR inhibitors in addressing Bacterial infections as well as breast Cancer.

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