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Design, synthesis, molecular docking, and biological activity of pyrazolo[3,4-b]pyridines as promising lead candidates against Mycobacterium tuberculosis

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Abstract

Pyrazolo[3,4-b]pyridine is a medicinally privileged structure. We have achieved a new and facile synthesis of a combinatorial library of its tetra- and persubstituted derivatives by trifluoracetic acid catalyzed condensation of a group of 5-aminopyrazoles and a group of α-oxoketene dithioacetals. Furthermore, we demonstrated structural modification of the products via reductive desulfurization, hydrolysis of the ester, and Suzuki coupling of the bromo derivative with aryl boronic acids. Some products were subjected to in vitro Microplate Alamar Blue assay (MABA) assay against M. tuberculosis H37Rv strain and in silico analysis by binding to Pantothenate Synthetase from M. tuberculosis (MTBPS). The results indicated that the pyazolo[3,4-b]pyridine with N(1)CH3, C(3)C6H5, C(4) pCH3C6H5, C(5)CO2Et, C(6)SMe substitutions exhibits promising antituberculotic activity.

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Data related to this study are available from the corresponding author upon request.

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Acknowledgements

We thank Professor D. Sriram. Ph.D. Senior Professor, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad- 500 078. (Email: dsriram@hyderabad.bits-pilani.ac.in) for conducting anti-tuberculosis studies. We thank DST-FIST, UGC SAP DRS-2, and CIF, PU for facilities and spectral recordings. RG thanks CSIR for SRF and UGC-PU for JRF. JM thanks Sharda University, Greater Noida for support.

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Authors and Affiliations

  1. Department of Chemistry, Pondicherry University, Puducherry, 605 014, India

    H. Surya Prakash Rao, R. Gunasundari & Lakshmi Narayana Adigopula

  2. Teadus Pharma Private Limited, TSIIC Industrial Estate, Prashanth Nagar, Hyderabad, Telangana, 500072, India

    H. Surya Prakash Rao

  3. Department of Biotechnology, Sharda School of Engineering and Technology, Sharda University, Greater Noida, India

    Jayaraman Muthukumaran

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Contributions

HSPR supervised the findings of this work and conceived the studies. He was involved in planning and supervised the work. RG and LNA were involved the synthesis. JM performed the in silico studies. HSPR aided in interpreting the results obtained from synthesis, in silico and in vitro studies. HSPR, RG, LNA, and JM prepared the first draft of the manuscript. HSPR and JM revised the manuscript into its final version, to which all the authors gave approval.

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Rao, H.S.P., Gunasundari, R., Adigopula, L.N. et al. Design, synthesis, molecular docking, and biological activity of pyrazolo[3,4-b]pyridines as promising lead candidates against Mycobacterium tuberculosis. Med Chem Res 33, 177–200 (2024). https://doi.org/10.1007/s00044-023-03173-0

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