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Design, synthesis and SAR of antitubercular benzylpiperazine ureas

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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 molecule (I) with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC50 ~ 80 μM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with (I), fifty-five analogs were synthesized and screened against Mtb. 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.

Graphic Abstract

Bioisosteric replacement of N-furfuryl piperazine-1-carboxamides yielded molecule (I) a novel lead with satisfactory PD, metabolism, and toxicity profiles.

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Acknowledgements

We thankfully acknowledge the National Facility for Biopharmaceuticals, G N Khalsa College, Mumbai, for antibacterial activity results; Maratha Mandal’s Central Research Laboratory, Belgaum, for cytotoxicity results; SAIF, Panjab University, Chandigarh, for HRMS analysis, Mrs. Varsha Vhadge, Ambernath Organics Pvt. Ltd, Mumbai, for HPLC purity results and Dr. M. K Rangnekar Memorial testing laboratory, Bombay College of Pharmacy, Mumbai, for FTIR analysis.

Funding

Financial support for this work was provided by Ambernath Organics Pvt. Ltd. and the Amrut Mody Research Foundation at Bombay College of Pharmacy.

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Authors and Affiliations

  1. Ambernath Organics Pvt. Ltd., 222, The Summit Business Bay, Andheri (E), Mumbai, 400 093, India

    Sohal Satish, Rohan Chitral, Amitkumar Kori, Basantkumar Sharma, Jayashree Puttur & Santosh Nandan

  2. Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India

    Afreen A. Khan, Deepali Desle, Kavita Raikuvar, Elvis A. F. Martis, Krishna R. Iyer & Evans C. Coutinho

  3. TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, Seattle, WA, 98102, USA

    Aaron Korkegian & Tanya Parish

Authors
  1. Sohal Satish
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  2. Rohan Chitral
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  14. Santosh Nandan
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Contributions

SS and AAK wrote the paper and synthesized the molecules. RC, AK, BS synthesized the molecules. JP oversaw the synthesis and analysis. DD, KR, KRI performed metabolism studies. EAFM performed computational studies. AK and TP antimycobacterial assay (H37Rv strain). ECC and SN designed and oversaw the study.

Corresponding author

Correspondence to Santosh Nandan.

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Satish, S., Chitral, R., Kori, A. et al. Design, synthesis and SAR of antitubercular benzylpiperazine ureas. Mol Divers 26, 73–96 (2022). https://doi.org/10.1007/s11030-020-10158-3

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  • DOI: https://doi.org/10.1007/s11030-020-10158-3

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