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

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. [Display omitted] •Novel Pyrazolo[4,3–c]pyridin–4–one derivatives designed and synthesized.•QED and in silico ADMET properties predicted.•Evaluated for anti-HIV-1 activity.•Lead compound was further confirmed by PBMC assay.•The compound was shown to act through inhibition of reverse transcriptase.