The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates

Li, Yue; Ouyang, Yifan; Wu, Hanjiang; Wang, Peng; Huang, Yu; Li, Xue; Chen, Hongtong; Sun, Yu; Hu, Xinxin; Wang, Xiukun; Li, Guoqing; Lu, Yuanyao; Li, Congran; Lü, Xi; Pang, Jing; Nie, Tongying; Sang, Xiaohong; Dong, Luyao; Dong, Wenting; Jiang, Jian‐Dong; Paterson, Ian C.; Yang, Xinyi; Hong, Wei; Wang, Hao; You, Xuefu

doi:10.1016/j.ejmech.2021.113979

Cited by 12 publications

(11 citation statements)

References 34 publications

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“…The preparation and characterization of OYYF-171, -172, and -175 can be referred to in our previous publication [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…Based on the structure of NSC-339579, a series of PQZ compounds were designed and synthesized. Antibacterial studies showed that these compounds exhibited potent broad-spectrum in vitro antibacterial activities [ 11 ]. In view of the urgency of developing antimicrobial candidates against A. baumannii , especially MDR strains, as described above, we further investigated the in vitro activity of the PQZ compounds OYYF-171, -172, and -175 ( Figure 2 ) against A. baumannii including MDR isolates, in this study.…”

Section: Introductionmentioning

confidence: 99%

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The Anti-Multidrug-Resistant Acinetobacter baumannii Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds

Chen

Zhang

et al. 2022

Molecules

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As a major public health problem, the prevalence of Acinetobacter baumannii (A. baumannii) infections in hospitals due to the pathogen’s multiple-antibiotic resistance has attracted extensive attention. We previously reported a series of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline (PQZ) compounds, which were designed by targeting Escherichia coli dihydrofolate reductase (ecDHFR), and exhibited potent antibacterial activities. In the current study, based on our molecular-modeling study, it was proposed that PQZ compounds may function as potent A. baumannii DHFR (abDHFR)-inhibitors as well, which inspired us to consider their anti-A. baumannii abilities. We further found that three PQZ compounds, OYYF-171, -172, and -175, showed significant antibacterial activities against A. baumannii, including multidrug-resistant (MDR) strains, which are significantly stronger than the typical DHFR-inhibitor, trimethoprim (TMP), and superior to, or comparable to, the other tested antibacterial agents belonging to β-lactam, aminoglycoside, and quinolone. The significant synergistic effect between the representative compound OYYF-171 and the dihydropteroate synthase (DHPS)-inhibitor sulfamethoxazole (SMZ) was observed in both the microdilution-checkerboard assay and time-killing assay, which indicated that using SMZ in combination with PQZ compounds could help to reduce the required dosage and forestall resistance. Our study shows that PQZ is a promising scaffold for the further development of folate-metabolism inhibitors against MDR A. baumannii.

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“…The preparation and characterization of OYYF-171, -172, and -175 can be referred to in our previous publication [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Anti-Multidrug-Resistant Acinetobacter baumannii Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds

Chen

Zhang

et al. 2022

Molecules

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“…The significant enzymes associated with folate synthesis are promising candidate molecules, and novel antifolates with innovative mechanisms are desperately required. A criteria of 1,3‐diamino‐7 H ‐pyrrol[3,2‐f]quinazoline (PQZ) molecules ( 26 , Figure 4) were recently developed, synthesized, and reported to have significant dihydrofolate reductase (DHFR) inhibitory activity as well as promising antibacterial activity in vitro, particularly versus multi‐drug‐resistant Gram‐negative bacteria strains (Li et al, 2022). Numerous tests revealed that the investigated compounds have a distinct molecular mechanism when compared to the standard trimethoprim (TMP), DHFR inhibitor, and thymidylate synthase (TS) was found as further prospective but weak target.…”

Section: Biological Actionsmentioning

confidence: 99%

A comprehensive review of recent advances in the biological activities of quinazolines

Gomaa

2022

Chem Biol Drug Des

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Quinazoline heterocycles are critical in the development of medications.Quinazoline derivatives have been intensively researched, providing a wide range of compounds with diverse biological roles. The quinazoline nucleus has garnered a lot of attention in medical chemistry in recent years. It was assumed to be a pharmacophore component in the development of physiologically interesting drugs. This review is an attempt to increase the potential of quinazoline by highlighting a wide range of advancements demonstrated by numerous derivatives of the quinazoline moiety, as well as focusing on diverse pharmacological actions of the quinazoline moiety. This review compiles recent studies on the quinazoline moiety described in the literature by researchers.

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“…26,27 PQD has a unique molecular structure that allows it to interact with different biological targets in cells, making it a potential candidate for the development of new drugs. A deluge of PQD inhibitors has been discovered including PQD-1, 28 NSC-309401, 29 SCH-79797, 30,31 IRS-16, 32 EN-2, 33 NSX-339579, 34 AMPQD, 35 and OYYF-175 36 (Figure 2A). Most studies have focused on investigating the various substituent groups in the aromatic side chain.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Interestingly, the biphenyl moiety (IRS-16) can kill both Gram-positive and Gram-negative bacteria by simultaneously targeting folate metabolism and membrane integrity, but this dual-targeting synergistic mechanism is only on the IRS-16 scaffold. Recently, Wang and co-workers 36 showed that a new PQD analogue (OYYF-175) exhibited nanomolar antibacterial efficacy against multidrug-resistant Gram-negative strains with a significant synergistic effect between DHFR with thymidylate synthase.…”

Section: ■ Introductionmentioning

confidence: 99%

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

Zhu,

Chen,

Zhang

et al. 2023

J. Med. Chem.

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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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The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates

Cited by 12 publications

References 34 publications

The Anti-Multidrug-Resistant Acinetobacter baumannii Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds

The Anti-Multidrug-Resistant Acinetobacter baumannii Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds

A comprehensive review of recent advances in the biological activities of quinazolines

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

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