Identification of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase

Eur J Med Chem. 2023 Feb 5:247:115045. doi: 10.1016/j.ejmech.2022.115045. Epub 2022 Dec 23.

Abstract

Here, we reported a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP). The anti-HIV-1 activity results demonstrated that compound 9e (EC50 = 2.04-61.1 nM) displayed robust potencies against a panel of HIV-1 NNRTIs-resistant strains, being comparable to that of etravirine (ETR). Moreover, 9e displayed much lower cytotoxicity (CC50 = 59.2 μM) and higher SI values (4605) toward wild-type HIV-1 strain. The HIV-1 RT enzyme inhibitory activity clarified the binding target of 9e was HIV-1 RT (IC50 = 0.019 μM). Furthermore, the molecular modeling study was also investigated to give a reasonable explanation of the preliminary SARs. Further test indicated that 9e possessed significantly improved water solubility under pH 7.0 and 7.4 conditions. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features. Consequently, compound 9e showed the highest activity and low cytotoxicity, which could be used as a lead for further modification to obtain potent HIV-1 NNRTIs.

Keywords: HIV-1; Molecular modeling study; NNIBP; NNRTI adjacent site; NNRTIs.

MeSH terms

  • Anti-HIV Agents* / chemistry
  • Anti-HIV Agents* / pharmacology
  • Drug Design
  • HIV Reverse Transcriptase
  • HIV-1*
  • Molecular Structure
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • reverse transcriptase, Human immunodeficiency virus 1
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase