Jamie L. Breunig, M. Alejandro Valdes-Pena, Andrew W. Ratchford and Joshua G. Pierce*,
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引用次数: 0
摘要
新的抗菌支架非常稀缺，因此亟需开发新型疗法。在本研究中，我们报告了一种通过 9 个步骤聚合合成左旋炔诺酮 A 和一系列靶向类似物的方法。所设计的化合物允许在左炔诺酮 A 的 2,3-吡咯烷二酮周围加入非天然脲基二肽分子以及 4 位和 5 位取代基。左炔诺酮 A 对 MRSA 具有适度的抗菌活性（32 μg/mL），而活性最高的类似物的活性略有提高（8-16 μg/mL）。此外，几种莱奥olic酸 A 类似物显示出良好的抗生物膜活性，最显著的是其 MBEC:MIC 比值为 1∼。总之，这项工作代表了天然产物的初步 SAR 以及在生物活性吡咯烷二酮背景下进一步优化这些生物活性支架的框架。
Total Synthesis and Microbiological Evaluation of Leopolic Acid A and Analogues
New antimicrobial scaffolds are scarce, and there is a great need for the development of novel therapeutics. In this study, we report a convergent 9-step synthesis of leopolic acid A and a series of targeted analogues. The designed compounds allowed for incorporation of non-natural ureido dipeptide moieties and 4- and 5-position substituents around the 2,3-pyrrolidinedione of leopolic acid A. Leopolic acid A displayed modest antimicrobial activity (32 μg/mL) against MRSA, while the most active analogues displayed slightly improved activity (8–16 μg/mL). Additionally, several of the leopolic acid A analogues displayed promising antibiofilm activity, most notably having an MBEC:MIC ratio of ∼1. Overall, this work represents an initial SAR of the natural product and a framework for further optimization of these bioactive scaffolds within the context of bioactive pyrrolidinediones.
期刊介绍：
ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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