新型细菌拓扑异构酶抑制剂OSUAB-0284的十克规模合成
Decagram-Scale Synthesis of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284.
作者信息
West Jason S, Mann Chelsea A, Mitton-Fry Mark J
机构信息
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
出版信息
Org Process Res Dev. 2025 Mar 26;29(4):1136-1151. doi: 10.1021/acs.oprd.5c00033. eCollection 2025 Apr 18.
Abstract
Medicinal chemistry efforts identified OSUAB-0284 () as a preclinical candidate to treat staphylococcal infections, especially those caused by methicillin-resistant (MRSA). Herein, we describe a fit-for-purpose route that enabled the production of >20 g of API for toxicology studies and further preclinical characterization. Process improvements include a 16-fold increase in yield over the longest sequence, a 21-fold increase in efficiency for the cost-limiting reagent, and reduction of chromatography to one silica plug across an 18-step route.
摘要
药物化学研究确定了OSUAB-0284（）作为治疗葡萄球菌感染的临床前候选药物，尤其是耐甲氧西林（MRSA）引起的感染。在此，我们描述了一种适用的路线，该路线能够生产超过20克的活性药物成分用于毒理学研究和进一步的临床前表征。工艺改进包括在最长的合成序列中收率提高了16倍，成本限制试剂的效率提高了21倍，并且在一条18步的路线中将色谱步骤减少到一个硅胶柱。
相似文献
1
Decagram-Scale Synthesis of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284.
Org Process Res Dev. 2025 Mar 26;29(4):1136-1151. doi: 10.1021/acs.oprd.5c00033. eCollection 2025 Apr 18.
2
Methicillin-resistant (MRSA) and anti-MRSA activities of extracts of some medicinal plants: A brief review.
AIMS Microbiol. 2019 Apr 15;5(2):117-137. doi: 10.3934/microbiol.2019.2.117. eCollection 2019.
3
Actions of a Novel Bacterial Topoisomerase Inhibitor against Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks.
Int J Mol Sci. 2023 Jul 28;24(15):12107. doi: 10.3390/ijms241512107.
4
Novel inhibition of sortase A by plantamajoside: implications for controlling multidrug-resistant infections.
Appl Environ Microbiol. 2025 Jan 31;91(1):e0180424. doi: 10.1128/aem.01804-24. Epub 2024 Dec 31.
5
Next-Generation Sequence Analysis Reveals Transfer of Methicillin Resistance to a Methicillin-Susceptible Staphylococcus aureus Strain That Subsequently Caused a Methicillin-Resistant Staphylococcus aureus Outbreak: a Descriptive Study.
J Clin Microbiol. 2017 Sep;55(9):2808-2816. doi: 10.1128/JCM.00459-17. Epub 2017 Jul 5.
6
Therapeutic potential of bacteriophages for staphylococcal infections and selected methods for in vitro susceptibility testing of staphylococci.
Epidemiol Mikrobiol Imunol. 2020 Winter;69(1):10-18.
7
Methicillin-resistant Staphylococcus aureus: a controversial food-borne pathogen.
Lett Appl Microbiol. 2017 Jun;64(6):409-418. doi: 10.1111/lam.12735. Epub 2017 May 3.
8
Temporal trends of skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus in Gabon.
Antimicrob Resist Infect Control. 2024 Jun 25;13(1):68. doi: 10.1186/s13756-024-01426-0.
9
The origin of a methicillin-resistant Staphylococcus aureus isolate at a neonatal ward in Sweden-possible horizontal transfer of a staphylococcal cassette chromosome mec between methicillin-resistant Staphylococcus haemolyticus and Staphylococcus aureus.
Clin Microbiol Infect. 2008 Nov;14(11):1048-56. doi: 10.1111/j.1469-0691.2008.02090.x.
10
Multilocus Sequence Typing and Staphylococcal Protein A Typing Revealed Novel and Diverse Clones of Methicillin-Resistant Staphylococcus aureus in Seafood and the Aquatic Environment.
J Food Prot. 2017 Mar;80(3):476-481. doi: 10.4315/0362-028X.JFP-16-260.
本文引用的文献
1
Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials.
Lancet. 2024 Feb 24;403(10428):741-755. doi: 10.1016/S0140-6736(23)02196-7. Epub 2024 Feb 8.
2
Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with Efficacy against MRSA.
J Med Chem. 2021 Oct 28;64(20):15214-15249. doi: 10.1021/acs.jmedchem.1c01250. Epub 2021 Oct 6.
3
Two Decades of Successful SAR-Grounded Stories of the Novel Bacterial Topoisomerase Inhibitors (NBTIs).
J Med Chem. 2020 Jun 11;63(11):5664-5674. doi: 10.1021/acs.jmedchem.9b01738. Epub 2020 Feb 17.
4
Synthetic and Organocatalytic Studies of Quinidine Analogues with Ring-Size Modifications in the Quinuclidine Moiety.
Chemistry. 2016 Sep 26;22(40):14247-56. doi: 10.1002/chem.201601917. Epub 2016 Aug 17.
5
Novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram positive activity and improved safety profile.
J Med Chem. 2015 Jan 22;58(2):927-42. doi: 10.1021/jm501590q. Epub 2014 Dec 23.
6
Facile reductive amination of aldehydes with electron-deficient anilines by acyloxyborohydrides in TFA: application to a diazaindoline scale-up.
J Org Chem. 2009 May 1;74(9):3587-90. doi: 10.1021/jo900157z.
7
Efficient access to azaindoles and indoles.
Org Lett. 2006 Jul 20;8(15):3307-10. doi: 10.1021/ol061232r.
8
Ozonolysis applications in drug synthesis.
Chem Rev. 2006 Jul;106(7):2990-3001. doi: 10.1021/cr040682z.
9
Homeopathic ligand-free palladium as a catalyst in the heck reaction. A comparison with a palladacycle.
Org Lett. 2003 Sep 4;5(18):3285-8. doi: 10.1021/ol035184b.
10
[The hydroxylamino lysis of N-substituted phthalimide, a method for the prepartion of peptides and N-hydroxypeptides].
Justus Liebigs Ann Chem. 1968;712:208-13. doi: 10.1002/jlac.19687120125.
Zotero 插件