7-烷基-N(2)-取代的 3-去氮鸟嘌呤。合成、DNA 聚合酶 III 抑制和抗菌活性。
7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity.
机构信息
GLSynthesis Inc., One Innovation Drive, Worcester, MA 01605, USA.
出版信息
Bioorg Med Chem Lett. 2011 Jul 15;21(14):4197-202. doi: 10.1016/j.bmcl.2011.05.093. Epub 2011 May 30.
Abstract
Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N(2)-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N(2)-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10μg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice.
摘要
已经合成了几种 2-苯胺基和 2-苯甲氨基-3-去氮-6-氧嘌呤[3-去氮鸟嘌呤]，并选择了一些 8-甲基和 8-氮杂类似物。7-取代的 N(2)-(3-乙基-4-甲基苯基)-3-去氮鸟嘌呤是革兰氏阳性菌 DNA 聚合酶（pol）IIIC 的有效且选择性抑制剂，而 7-取代的 N(2)-(3,4-二氯苄基)-3-去氮鸟嘌呤是革兰氏阳性菌的 pol IIIC 和 pol IIIE 的有效抑制剂，但对革兰氏阴性菌的 pol IIIE 抑制作用较弱。这两类强效酶抑制剂均能抑制革兰氏阳性菌的生长（MIC 为 2.5-10μg/ml），对革兰氏阴性菌大肠杆菌无活性。一些衍生物在金黄色葡萄球菌感染的小鼠中具有中等的保护活性。
相似文献
1
7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity.7-烷基-N(2)-取代的 3-去氮鸟嘌呤。合成、DNA 聚合酶 III 抑制和抗菌活性。
Bioorg Med Chem Lett. 2011 Jul 15;21(14):4197-202. doi: 10.1016/j.bmcl.2011.05.093. Epub 2011 May 30.
2
Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth.取代6-苯胺基尿嘧啶的合成及其对DNA聚合酶IIIC和革兰氏阳性菌生长的抑制作用。
J Med Chem. 2003 Jun 19;46(13):2731-9. doi: 10.1021/jm020591z.
3
Biological characterization of novel inhibitors of the gram-positive DNA polymerase IIIC enzyme.革兰氏阳性DNA聚合酶IIIC酶新型抑制剂的生物学特性
Antimicrob Agents Chemother. 2005 Mar;49(3):987-95. doi: 10.1128/AAC.49.3.987-995.2005.
4
Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils.3-取代-6-(3-乙基-4-甲基苯胺基)尿嘧啶的合成及抗菌活性
J Med Chem. 2005 Nov 3;48(22):7063-74. doi: 10.1021/jm050517r.
5
Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria.DNA聚合酶III抑制剂作为抗革兰氏阳性真细菌的新型抗菌剂。
Antimicrob Agents Chemother. 1999 Aug;43(8):1982-7. doi: 10.1128/AAC.43.8.1982.
6
Design and synthesis of novel antibacterial agents with inhibitory activity against DNA polymerase III.对DNA聚合酶III具有抑制活性的新型抗菌剂的设计与合成。
Bioorg Med Chem Lett. 2001 Aug 20;11(16):2185-8. doi: 10.1016/s0960-894x(01)00407-3.
7
Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors.混合抗菌剂。DNA聚合酶-拓扑异构酶抑制剂。
J Med Chem. 2006 Feb 23;49(4):1455-65. doi: 10.1021/jm0510023.
8
Improved synthesis of antibacterial 3-substituted 6-anilinouracils.抗菌3-取代6-苯胺基尿嘧啶的合成改进
Bioorg Med Chem Lett. 2008 Jun 1;18(11):3215-8. doi: 10.1016/j.bmcl.2008.04.061. Epub 2008 Apr 26.
9
Active site directed inhibitors of replication-specific bacterial DNA polymerases.复制特异性细菌DNA聚合酶的活性位点定向抑制剂。
Bioorg Med Chem Lett. 2005 Feb 1;15(3):729-32. doi: 10.1016/j.bmcl.2004.11.016.
10
Antimicrobials targeted to the replication-specific DNA polymerases of gram-positive bacteria: target potential of dnaE.针对革兰氏阳性菌复制特异性DNA聚合酶的抗菌药物：dnaE的靶点潜力
Infect Disord Drug Targets. 2012 Oct;12(5):327-31. doi: 10.2174/187152612804142279.
引用本文的文献
1
Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research.对抗抗菌药物耐药性：抗菌研究中的创新药物
Angew Chem Int Ed Engl. 2025 Mar 3;64(10):e202414325. doi: 10.1002/anie.202414325. Epub 2025 Feb 10.
2
A Review of Antibacterial Candidates with New Modes of Action.具有新型作用机制的抗菌候选药物综述。
ACS Infect Dis. 2024 Oct 11;10(10):3440-3474. doi: 10.1021/acsinfecdis.4c00218. Epub 2024 Jul 17.
3
Antibiotics in the clinical pipeline as of December 2022.截至 2022 年 12 月处于临床研发管线中的抗生素。
J Antibiot (Tokyo). 2023 Aug;76(8):431-473. doi: 10.1038/s41429-023-00629-8. Epub 2023 Jun 8.
4
Novel Antibiotics Targeting Bacterial Replicative DNA Polymerases.靶向细菌复制性DNA聚合酶的新型抗生素
Antibiotics (Basel). 2020 Nov 4;9(11):776. doi: 10.3390/antibiotics9110776.
5
Investigational Treatment Agents for Recurrent Infection (rCDI).复发性感染（rCDI）的研究性治疗药物
J Exp Pharmacol. 2020 Oct 9;12:371-384. doi: 10.2147/JEP.S242959. eCollection 2020.
6
Antibiotics in the clinical pipeline in October 2019.2019 年 10 月处于临床研发管线中的抗生素。
J Antibiot (Tokyo). 2020 Jun;73(6):329-364. doi: 10.1038/s41429-020-0291-8. Epub 2020 Mar 10.
7
The Macromolecular Machines that Duplicate the Escherichia coli Chromosome as Targets for Drug Discovery.作为药物发现靶点的复制大肠杆菌染色体的大分子机器
Antibiotics (Basel). 2018 Mar 14;7(1):23. doi: 10.3390/antibiotics7010023.
8
Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis.靶向DNA复制与修复以开发抗结核病新型疗法
Front Mol Biosci. 2017 Nov 14;4:75. doi: 10.3389/fmolb.2017.00075. eCollection 2017.
9
DNA Replication in Mycobacterium tuberculosis.结核分枝杆菌中的 DNA 复制。
Microbiol Spectr. 2017 Mar;5(2). doi: 10.1128/microbiolspec.TBTB2-0027-2016.
10
DNA replication proteins as potential targets for antimicrobials in drug-resistant bacterial pathogens.作为耐药性细菌病原体抗菌药物潜在靶点的DNA复制蛋白
J Antimicrob Chemother. 2017 May 1;72(5):1275-1284. doi: 10.1093/jac/dkw548.
本文引用的文献
1
Active site directed inhibitors of replication-specific bacterial DNA polymerases.复制特异性细菌DNA聚合酶的活性位点定向抑制剂。
Bioorg Med Chem Lett. 2005 Feb 1;15(3):729-32. doi: 10.1016/j.bmcl.2004.11.016.
2
Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth.取代6-苯胺基尿嘧啶的合成及其对DNA聚合酶IIIC和革兰氏阳性菌生长的抑制作用。
J Med Chem. 2003 Jun 19;46(13):2731-9. doi: 10.1021/jm020591z.
3
DNA polymerases of low-GC gram-positive eubacteria: identification of the replication-specific enzyme encoded by dnaE.低GC含量革兰氏阳性真细菌的DNA聚合酶：由dnaE编码的复制特异性酶的鉴定
J Bacteriol. 2002 Jul;184(14):3834-8. doi: 10.1128/JB.184.14.3834-3838.2002.
4
Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria.DNA聚合酶III抑制剂作为抗革兰氏阳性真细菌的新型抗菌剂。
Antimicrob Agents Chemother. 1999 Aug;43(8):1982-7. doi: 10.1128/AAC.43.8.1982.
5
6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III: antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3.基于6-苯胺基尿嘧啶的枯草芽孢杆菌DNA聚合酶III抑制剂：基于尿嘧啶N3取代的抗聚合酶和抗菌构效关系
J Med Chem. 1999 Jun 3;42(11):2035-40. doi: 10.1021/jm980693i.
6
Compilation, alignment, and phylogenetic relationships of DNA polymerases.DNA聚合酶的汇编、比对及系统发育关系
Nucleic Acids Res. 1993 Feb 25;21(4):787-802. doi: 10.1093/nar/21.4.787.
7
Non-peptide angiotensin II receptor antagonists: synthesis and biological activity of a series of novel 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine derivatives.非肽类血管紧张素II受体拮抗剂：一系列新型4,5-二氢-4-氧代-3H-咪唑并[4,5-c]吡啶衍生物的合成与生物活性
J Med Chem. 1994 May 27;37(11):1632-45. doi: 10.1021/jm00037a014.
8
Inhibitors of Bacillus subtilis DNA polymerase III. 6-Anilinouracils and 6-(alkylamino)uracils.枯草芽孢杆菌DNA聚合酶III的抑制剂。6-苯胺基尿嘧啶和6-（烷基氨基）尿嘧啶。
J Med Chem. 1980 Jan;23(1):34-8. doi: 10.1021/jm00175a007.
9
10
Synthesis and antiviral and enzymatic studies of certain 3-deazaguanines and their imidazolecarboxamide precursors.某些3-脱氮鸟嘌呤及其咪唑甲酰胺前体的合成、抗病毒和酶学研究。
J Med Chem. 1978 Dec;21(12):1212-8. doi: 10.1021/jm00210a008.
Zotero 插件