Soumitra Guin, Kathryn M. Alden, Damian J. Krysan* and Marvin J. Meyers*,
{"title":"甲氟喹类似物立体异构体的合成与抗真菌活性","authors":"Soumitra Guin, Kathryn M. Alden, Damian J. Krysan* and Marvin J. Meyers*, ","doi":"10.1021/acsmedchemlett.4c00031","DOIUrl":null,"url":null,"abstract":"<p ><i>Cryptococcal neoformans</i> and <i>Candida albicans</i> are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal therapy highlights the need for new drugs. In our previous work, we demonstrated that an analogue of the clinically used antimalarial mefloquine, (8-chloro-2-(4-chlorophenyl)quinolin-4-yl)(piperidin-2-yl)methanol (<b>4377</b>), has both antifungal activity and the ability to penetrate the central nervous system. Herein we describe the synthesis and antifungal assay of all four stereoisomers of <b>4377</b>. All four stereoisomers retain potent antifungal activity with the <i>erythro</i> enantiomers having MIC values of 1 and 4 μg/mL against <i>C. neoformans</i> and <i>C. albicans,</i> respectively, and <i>threo</i> enantiomers, MIC values of 2 and 8 μg/mL, respectively. These results indicate that the stereochemistry of the piperidine methanol group is not critical for the antifungal properties of <b>4377</b> and gives guidance to future medicinal chemistry optimization efforts.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis and Antifungal Activity of Stereoisomers of Mefloquine Analogs\",\"authors\":\"Soumitra Guin, Kathryn M. Alden, Damian J. Krysan* and Marvin J. Meyers*, \",\"doi\":\"10.1021/acsmedchemlett.4c00031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p ><i>Cryptococcal neoformans</i> and <i>Candida albicans</i> are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal therapy highlights the need for new drugs. In our previous work, we demonstrated that an analogue of the clinically used antimalarial mefloquine, (8-chloro-2-(4-chlorophenyl)quinolin-4-yl)(piperidin-2-yl)methanol (<b>4377</b>), has both antifungal activity and the ability to penetrate the central nervous system. Herein we describe the synthesis and antifungal assay of all four stereoisomers of <b>4377</b>. All four stereoisomers retain potent antifungal activity with the <i>erythro</i> enantiomers having MIC values of 1 and 4 μg/mL against <i>C. neoformans</i> and <i>C. albicans,</i> respectively, and <i>threo</i> enantiomers, MIC values of 2 and 8 μg/mL, respectively. These results indicate that the stereochemistry of the piperidine methanol group is not critical for the antifungal properties of <b>4377</b> and gives guidance to future medicinal chemistry optimization efforts.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00031\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00031","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
新型隐球菌和白色念珠菌是全球最常见的威胁生命的真菌感染病因。尽管目前有抗真菌疗法,但与这些感染相关的高死亡率凸显了对新药的需求。在之前的研究中,我们证明了临床上常用的抗疟药甲氟喹的类似物(8-氯-2-(4-氯苯基)喹啉-4-基)(哌啶-2-基)甲醇(4377)具有抗真菌活性和穿透中枢神经系统的能力。在此,我们介绍了 4377 全部四种立体异构体的合成和抗真菌检测。所有四种立体异构体都具有很强的抗真菌活性,其中红对映体对新变形杆菌和白僵菌的 MIC 值分别为 1 和 4 μg/mL,而苏对映体的 MIC 值分别为 2 和 8 μg/mL。这些结果表明,哌啶甲醇基团的立体化学对 4377 的抗真菌特性并不重要,为今后的药物化学优化工作提供了指导。
Synthesis and Antifungal Activity of Stereoisomers of Mefloquine Analogs
Cryptococcal neoformans and Candida albicans are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal therapy highlights the need for new drugs. In our previous work, we demonstrated that an analogue of the clinically used antimalarial mefloquine, (8-chloro-2-(4-chlorophenyl)quinolin-4-yl)(piperidin-2-yl)methanol (4377), has both antifungal activity and the ability to penetrate the central nervous system. Herein we describe the synthesis and antifungal assay of all four stereoisomers of 4377. All four stereoisomers retain potent antifungal activity with the erythro enantiomers having MIC values of 1 and 4 μg/mL against C. neoformans and C. albicans, respectively, and threo enantiomers, MIC values of 2 and 8 μg/mL, respectively. These results indicate that the stereochemistry of the piperidine methanol group is not critical for the antifungal properties of 4377 and gives guidance to future medicinal chemistry optimization efforts.
期刊介绍:
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.