Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents

  • Eur J Med Chem. 2016 Oct 21:122:723-730. doi: 10.1016/j.ejmech.2016.07.009.
Remya Ramesh  1 ,  Rahul D Shingare  1 ,  Vinod Kumar  2 ,  Amitesh Anand  3 ,  Swetha B  4 ,  Sridhar Veeraraghavan  5 ,  Srikant Viswanadha  5 ,  Ramesh Ummanni  6 ,  Rajesh Gokhale  3 ,  D Srinivasa Reddy  7
Affiliations
  • 1. CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
  • 2. CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India.
  • 3. CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
  • 4. CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India.
  • 5. Incozen Therapeutics Pvt. Ltd., Alexandria Knowledge Park, Turkapally, Rangareddy, 500078, India.
  • 6. CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
  • 7. CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India. Electronic address: [email protected].
PMID: 27476117 DOI: 10.1016/j.ejmech.2016.07.009
Abstract

The structural similarity between an MmpL3 inhibitor BM212, and a Cannabinoid Receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.

Keywords
BM212; Drug repurposing; MmpL3 inhibitor; Rimonabant; Sila analogue; Tuberculosis.