The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates
| Autor: | Xi Lu, Xiaohong Sang, Han Wu, Wei Hong, Jing Pang, Peng Wang, Yue Li, Ouyang Yifan, Tongying Nie, Hong-Tong Chen, Xue Li, Yu Huang, Yu Sun, Congran Li, Xinxin Hu, Luyao Dong, Ian C. Paterson, Guoqing Li, Xinyi Yang, Xuefu You, Yun Lu, Jian-Dong Jiang, Dong Wenting, Hao Wang, Xiukun Wang |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Acinetobacter baumannii
Methicillin-Resistant Staphylococcus aureus DHPS Microbial Sensitivity Tests Thymidylate synthase Vancomycin-Resistant Enterococci Structure-Activity Relationship chemistry.chemical_compound Folic Acid Enterobacteriaceae Drug Discovery Dihydrofolate reductase medicine Quinazoline Pharmacology Dose-Response Relationship Drug Molecular Structure biology Sulfamethoxazole Organic Chemistry General Medicine Antimicrobial Trimethoprim Anti-Bacterial Agents Biochemistry chemistry biology.protein Folic Acid Antagonists Dihydropteroate synthase medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 228:113979 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2021.113979 |
| Popis: | The shortage of new antibiotics makes infections caused by gram-negative (G−) bacteria a significant clinical problem. The key enzymes involved in folate biosynthesis represent important targets for drug discovery, and new antifolates with novel mechanisms are urgently needed. By targeting to dihydrofolate reductase (DHFR), a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (PQZ) compounds were designed, and exhibited potent antibacterial activities in vitro, especially against multi-drug resistant G− strains. Multiple experiments indicated that PQZ compounds contain a different molecular mechanism against the typical DHFR inhibitor, trimethoprim (TMP), and the thymidylate synthase (TS) was identified as another potential but a relatively weak target. A significant synergism between the representative compound, OYYF-175, and sulfamethoxazole (SMZ) was observed with a strong cumulative and significantly bactericidal effect at extremely low concentrations (2 μg/mL for SMZ and 0.03 pg/mL for OYYF-175), which could be resulted from the simultaneous inhibition of dihydropteroate synthase (DHPS), DHFR and TS. PQZ compounds exhibited therapeutic effects in a mouse model of intraperitoneal infections caused by Escherichia coli (E. coli). The co-crystal structure of OYYF-175-DHFR was solved and the detailed interactions were provided. The inhibitors reported represent innovative chemical structures with novel molecular mechanism of action, which will benefit the generation of new, efficacious bactericidal compounds. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect