1,4-苯并恶嗪类 MenB 抑制剂的合成及 SAR 研究：抗结核分枝杆菌的新型抗菌药物。
Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: novel antibacterial agents against Mycobacterium tuberculosis.
机构信息
Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
出版信息
Bioorg Med Chem Lett. 2010 Nov 1;20(21):6306-9. doi: 10.1016/j.bmcl.2010.08.076. Epub 2010 Aug 21.
Abstract
Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.
摘要
甲萘醌是许多病原体电子传递链的必需组成部分，因此甲萘醌生物合成途径中的酶是开发新型抗菌药物的潜在药物靶点。为了鉴定针对 MenB 的先导化合物，即结核分枝杆菌的 1,4-二羟基-2-萘酰基辅酶 A 合酶，进行了高通量筛选。在该筛选中鉴定出了几种 1,4-苯并恶嗪，随后的 SAR 研究发现了具有优异抗结核分枝杆菌 H37Rv 活性的化合物，MIC 值低至 0.6μg/ml。因此，1,4-苯并恶嗪骨架是开发抗结核药物的有前途的基础。
相似文献
1
Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: novel antibacterial agents against Mycobacterium tuberculosis.
Bioorg Med Chem Lett. 2010 Nov 1;20(21):6306-9. doi: 10.1016/j.bmcl.2010.08.076. Epub 2010 Aug 21.
2
Highly active antimycobacterial derivatives of benzoxazine.
Bioorg Med Chem. 2010 Dec 1;18(23):8178-87. doi: 10.1016/j.bmc.2010.10.017. Epub 2010 Oct 19.
3
Highly active potential antituberculotics: 3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dihiones substituted in ring-B by halogen.
Arch Pharm (Weinheim). 2008 Dec;341(12):800-3. doi: 10.1002/ardp.200800004.
4
CoA Adducts of 4-Oxo-4-Phenylbut-2-enoates: Inhibitors of MenB from the M. tuberculosis Menaquinone Biosynthesis Pathway.
ACS Med Chem Lett. 2011 Nov 10;2(11):818-823. doi: 10.1021/ml200141e.
5
Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents.
Eur J Med Chem. 2018 Jul 15;155:754-763. doi: 10.1016/j.ejmech.2018.06.033. Epub 2018 Jun 18.
6
Synthesis, Biological Evaluation and Molecular Docking Studies of New Pyrazolines as an Antitubercular and Cytotoxic Agents.
Infect Disord Drug Targets. 2019;19(3):310-321. doi: 10.2174/1871526519666181217120626.
7
Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads.
Bioorg Chem. 2021 Sep;114:105110. doi: 10.1016/j.bioorg.2021.105110. Epub 2021 Jun 21.
8
Substituted 4-methylquinolines as a new class of anti-tuberculosis agents.
Bioorg Med Chem Lett. 2003 Mar 24;13(6):1051-4. doi: 10.1016/s0960-894x(03)00074-x.
9
Synthesis and screening of (E)-1-(β-D-galactopyranosyl)-4-(aryl)but-3-ene-2-one against Mycobacterium tuberculosis.
Bioorg Med Chem Lett. 2011 Jul 1;21(13):3947-50. doi: 10.1016/j.bmcl.2011.05.037. Epub 2011 May 15.
10
Synthesis and discovery of new bisadducts derived from heterocyclic aldehydes and active methylene compounds as potent antitubercular agents.
Acta Pol Pharm. 2013 Mar-Apr;70(2):221-8.
引用本文的文献
1
Synthesis, Antimycobacterial Activity, and Computational Insight of Novel 1,4-Benzoxazin-2-one Derivatives as Promising Candidates against Multidrug-Resistant Mycobacterium Tuberculosis.
ChemMedChem. 2025 Jul 18;20(14):e202500073. doi: 10.1002/cmdc.202500073. Epub 2025 Jun 10.
2
Phytochemical and antibacterial properties of calyces Hibiscus sabdariffa L.: an in vitro and in silico multitarget-mediated antibacterial study.
BMC Complement Med Ther. 2025 Feb 18;25(1):62. doi: 10.1186/s12906-025-04794-1.
3
Unraveling bacterial stress responses: implications for next-generation antimicrobial solutions.
World J Microbiol Biotechnol. 2024 Jul 29;40(9):285. doi: 10.1007/s11274-024-04090-z.
4
Design and Synthesis of Novel Antioxidant 2-Substituted-5,7,8-Trimethyl-1,4-Benzoxazine Hybrids: Effects on Young and Senescent Fibroblasts.
Antioxidants (Basel). 2024 Jun 29;13(7):798. doi: 10.3390/antiox13070798.
5
GC-MS Analysis, Antibacterial, and Anticancer Activities of L. Methanolic Extract: In Vitro and In Silico Studies.
Microorganisms. 2023 Jun 16;11(6):1601. doi: 10.3390/microorganisms11061601.
6
Synthesis, Biological Evaluation and Computational Studies of New Hydrazide Derivatives Containing 1,3,4-Oxadiazole as Antitubercular Agents.
Int J Mol Sci. 2022 Dec 4;23(23):15295. doi: 10.3390/ijms232315295.
7
Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism.
RSC Adv. 2018 Jan 29;8(10):5099-5105. doi: 10.1039/c7ra12950e.
8
Advances in Key Drug Target Identification and New Drug Development for Tuberculosis.
Biomed Res Int. 2022 Feb 25;2022:5099312. doi: 10.1155/2022/5099312. eCollection 2022.
9
Acid- and Base-Mediated Hydrolysis of Dichloroacetamide Herbicide Safeners.
Environ Sci Technol. 2022 Jan 4;56(1):325-334. doi: 10.1021/acs.est.1c05958. Epub 2021 Dec 17.
10
Application of Networking Approaches to Assess the Chemical Diversity, Biogeography, and Pharmaceutical Potential of Verongiida Natural Products.
Mar Drugs. 2021 Oct 18;19(10):582. doi: 10.3390/md19100582.
本文引用的文献
1
Bulky 1,4-benzoxazine derivatives with antifungal activity.
Bioorg Med Chem. 2009 Jun 1;17(11):3838-46. doi: 10.1016/j.bmc.2009.04.051. Epub 2009 May 3.
2
Bacillus anthracis o-succinylbenzoyl-CoA synthetase: reaction kinetics and a novel inhibitor mimicking its reaction intermediate.
Biochemistry. 2008 Nov 25;47(47):12434-47. doi: 10.1021/bi801311d.
3
Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis.
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5963-6. doi: 10.1016/j.bmcl.2008.07.130. Epub 2008 Aug 12.
4
Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis.
J Med Chem. 2008 Mar 27;51(6):1695-705. doi: 10.1021/jm701129j. Epub 2008 Feb 27.
5
Discovery of 1,4-dihydroxy-2-naphthoate [corrected] prenyltransferase inhibitors: new drug leads for multidrug-resistant gram-positive pathogens.
J Med Chem. 2007 Aug 23;50(17):3973-5. doi: 10.1021/jm070638m. Epub 2007 Jul 21.
6
Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors.
Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4. doi: 10.1016/j.bmcl.2004.11.011.
7
Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 2: the synthesis and biological activities of RPR127963 an orally bioavailable inhibitor.
Bioorg Med Chem Lett. 2003 Sep 15;13(18):3097-100. doi: 10.1016/s0960-894x(03)00655-3.
8
Crystal structure of Mycobacterium tuberculosis MenB, a key enzyme in vitamin K2 biosynthesis.
J Biol Chem. 2003 Oct 24;278(43):42352-60. doi: 10.1074/jbc.M307399200. Epub 2003 Aug 8.
9
Essential Bacillus subtilis genes.
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4678-83. doi: 10.1073/pnas.0730515100. Epub 2003 Apr 7.
10
Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives.
J Med Chem. 2002 Dec 5;45(25):5604-6. doi: 10.1021/jm020310n.
Zotero 插件