Design, Synthesis and SAR of Antitubercular Benzylpiperazine Ureas.


Identification: Khan-Afreen


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Design, Synthesis and SAR of Antitubercular Benzylpiperazine Ureas.
Authors: Sohal Satish‡, Rohan Chitral‡, Amitkumar Kori‡, Basantkumar Sharma‡, Jayashree Puttur‡, Afreen A. Khan║, Deepali Desle║, Kavita Raikuvar║, Aaron Korkegian╪, Elvis A. F. Martis║, Krishna R. Iyer║, Evans C. Coutinho║, Tanya Parish╪ and Santosh Nandan‡*

Affiliations: ‡Ambernath Organics Pvt. Ltd., 222, The Summit Business Bay, Andheri (E), Mumbai 400 093. India.
║Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098. India.
╪TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, Seattle, WA 98102, USA.

Abstract: N-Furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to a molecule with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC50 ~ 80μM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with our molecule, fifty-five analogs were synthesized and screened against  for MIC90, against Mtb H37Rv.  The SAR suggests that the piperazine ring, benzyl urea and piperonyl moieties are essential signatures of this series.  Active compounds in this series are metabolically stable; have low cellular toxicity and are valuable leads for optimization.  Molecular docking suggests these molecules occupy the Q0 site of QcrB like Q203.

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