The discovery of 1, 3-diamino-7H-pyrrol3, 2-f]quinazoline compounds as potent antimicrobial antifolates
Document Type
Article
Publication Date
1-1-2022
Abstract
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-pyrrol3,2-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 mu g/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. (C) 2021 Elsevier Masson SAS. All rights reserved.
Keywords
1, 3-Diamino-7H-pyrrol3, 2-f]quinazoline compounds, Folate pathway inhibitors, Dihydrofolate reductase, Thymidylate synthase, Antibacterial activity
Divisions
OralBiology
Funders
Foundation of Minzu University of China [Grant No; 104-202000070349],Innovative Group's Project of National Ethnic Affairs Commission of the People's Republic of China [Grant No; 104-202000070350],National Mega-project for Innovative Drugs [Grant No; 2019ZX09721001],National Science and Technology Infrastructure of China,Peking Union Medical College Youth Fund [Grant No; 33320140177, 3332016139],Key Research and Development Program of Ningxia [Grant No; 2018BFG02004],National Natural Science Foundation of China [Grant No; 81273427, 81361138020, 81773582, 81960623, 82173694],Chinese Academy of Meteorological Sciences [Grant No; 2016-I2M-3-014, 2021-1-12M- 039],Chinese Academy of Medical Sciences,Peking Union Medical College,Fundamental Research Funds for the Central Universities [Grant No; 2019-PT350-004, 2020-PT310-003]
Publication Title
European Journal of Medicinal Chemistry
Volume
228
Publisher
Elsevier
Publisher Location
65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE