具有改善脑内暴露的含硅恶唑烷酮类抗生素的设计、合成与鉴定
Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure.
作者信息
Seetharamsingh B, Ramesh Remya, Dange Santoshkumar S, Khairnar Pankaj V, Singhal Smita, Upadhyay Dilip, Veeraraghavan Sridhar, Viswanadha Srikant, Vakkalanka Swaroop, Reddy D Srinivasa
机构信息
CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
Daiichi Sankyo India Pharma Pvt. Ltd. , Gurgaon, Haryana 122015, India.
出版信息
ACS Med Chem Lett. 2015 Oct 26;6(11):1105-10. doi: 10.1021/acsmedchemlett.5b00213. eCollection 2015 Nov 12.
Abstract
Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders.
摘要
对于由对药物敏感性降低的病原体引起的脑部感染，治疗选择有限。最近关于利奈唑胺用于治疗脑部感染的潜在用途的报道促使我们围绕该骨架设计新型化合物。在此，我们描述了各种含硅恶唑烷酮抗生素的设计与合成。我们在临床前物种中的研究结果表明，引入硅对于提高脑部药物暴露量非常有用。有趣的是，该系列中的三种化合物与利奈唑胺相比显示出高达30倍的更高脑/血浆比率，从而表明它们在脑部相关疾病中的治疗潜力。
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