title: Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure.
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.
authors.affiliation: CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: B
authors.initials: B
authors.lastname: Seetharamsingh
authors.affiliation: CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Remya
authors.initials: R
authors.lastname: Ramesh
authors.affiliation: CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Santoshkumar S
authors.initials: SS
authors.lastname: Dange
authors.affiliation: CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Pankaj V
authors.initials: PV
authors.lastname: Khairnar
authors.affiliation: Daiichi Sankyo India Pharma Pvt. Ltd. , Gurgaon, Haryana 122015, India.
authors.forename: Smita
authors.initials: S
authors.lastname: Singhal
authors.affiliation: Daiichi Sankyo India Pharma Pvt. Ltd. , Gurgaon, Haryana 122015, India.
authors.forename: Dilip
authors.initials: D
authors.lastname: Upadhyay
authors.affiliation: Incozen Therapeutics Pvt. Ltd. , Alexandria Knowledge Park, Turkapally, Rangareddy 500078, India.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Veeraraghavan
authors.affiliation: Incozen Therapeutics Pvt. Ltd. , Alexandria Knowledge Park, Turkapally, Rangareddy 500078, India.
authors.forename: Srikant
authors.initials: S
authors.lastname: Viswanadha
authors.affiliation: Incozen Therapeutics Pvt. Ltd. , Alexandria Knowledge Park, Turkapally, Rangareddy 500078, India.
authors.forename: Swaroop
authors.initials: S
authors.lastname: Vakkalanka
authors.affiliation: CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: D Srinivasa
authors.initials: DS
authors.lastname: Reddy
keywords: Antibacterial; brain exposure; linezolid; oxazolidinone; sila analogue