Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure.

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Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure.

ACS Med Chem Lett. 2015 Nov 12;6(11):1105-1110

Authors: Seetharamsingh B, Ramesh R, Dange SS, Khairnar PV, Singhal S, Upadhyay D, Veeraraghavan S, Viswanadha S, Vakkalanka S, Reddy DS

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.

PMID: 26617962 [PubMed - as supplied by publisher]