2. Academic Validation
  3. Synthesis and in-vitro anti-HIV-1 evaluation of novel pyrazolo[4,3-c]pyridin-4-one derivatives

Synthesis and in-vitro anti-HIV-1 evaluation of novel pyrazolo[4,3-c]pyridin-4-one derivatives

  • Eur J Med Chem. 2019 Dec 1:183:111714. doi: 10.1016/j.ejmech.2019.111714.
Sanjay Kumar 1,  Shiv Gupta 1,  Leila Fotooh Abadi 2,  Shraddha Gaikwad 2,  Dipen Desai 2,  Kamlesh Kumar Bhutani 1,  Smita Kulkarni 3,  Inder Pal Singh 4
Affiliations

Affiliations

  • 1 Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, 160062, Punjab, India.
  • 2 Department of Virology, ICMR-National AIDS Research Institute (NARI), Bhosari, Pune, 411026, Maharashtra, India.
  • 3 Department of Virology, ICMR-National AIDS Research Institute (NARI), Bhosari, Pune, 411026, Maharashtra, India. Electronic address: skulkarni@icmr.org.in.
  • 4 Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, 160062, Punjab, India. Electronic address: ipsingh@niper.ac.in.
PMID: 31557609 DOI: 10.1016/j.ejmech.2019.111714
Abstract

In our continuing efforts to find novel anti-HIV compounds, we have synthesized sixteen novel pyrazolo[4,3-c]pyridin-4-one derivatives. All the synthesized compounds were screened for anti-HIV activity against HIV-1VB59 (R5, subtype C). Compounds 12a-12c and 12e were also tested against HIV-1UG070 (X4, subtype D) in TZM-bl cell line. Compound 12c was found to be the most active against HIV-1VB59 and HIV-1UG070 with IC50 value 3.67 μM and 2.79 μM, and therapeutic indices 185 and 243, respectively. The lead compound 12c inhibited the HIV-192/BR/018 (R5, subtype B) and drug resistant isolates, NIH-119 (X4/R5, subtype B) and NARI-DR (R5, subtype C) effectively. The activity of the lead compound was further confirmed by PBMC assays. The molecular docking data showed that the most active compound 12c binds in the non-nucleoside binding pocket of HIV-1 Reverse Transcriptase, which was confirmed by the ToA assay. Thus the study indicated that 12c may be considered as a NNRTI and further explored as a lead for anti-HIV drug development.

Keywords

ADMET; Anti–HIV–1; Pyrazolo[4,3–c]pyridin–4–one; QED; TZM–bl.

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