Structure-guided design of novel biphenyl-quinazoline derivatives as potent non-nucleoside reverse transcriptase inhibitors featuring improved anti-resistance, selectivity, and solubility

Bioorg Chem. 2024 Jun:147:107340. doi: 10.1016/j.bioorg.2024.107340. Epub 2024 Apr 5.

Abstract

In pursuit of enhancing the anti-resistance efficacy and solubility of our previously identified NNRTI 1, a series of biphenyl-quinazoline derivatives were synthesized employing a structure-based drug design strategy. Noteworthy advancements in anti-resistance efficacy were discerned among some of these analogs, prominently exemplified by compound 7ag, which exhibited a remarkable 1.37 to 602.41-fold increase in potency against mutant strains (Y181C, L100I, Y188L, F227L + V106A, and K103N + Y181C) in comparison to compound 1. Compound 7ag also demonstrated comparable anti-HIV activity against both WT HIV and K103N, albeit with a marginal reduction in activity against E138K. Of significance, this analog showed augmented selectivity index (SI > 5368) relative to compound 1 (SI > 37764), Nevirapine (SI > 158), Efavirenz (SI > 269), and Etravirine (SI > 1519). Moreover, it displayed a significant enhancement in water solubility, surpassing that of compound 1, Etravirine, and Rilpivirine. To elucidate the underlying molecular mechanisms, molecular docking studies were undertaken to probe the critical interactions between 7ag and both WT and mutant strains of HIV-1 RT. These findings furnish invaluable insights driving further advancements in the development of DAPYs for HIV therapy.

Keywords: Anti-resistance; HIV-1; NNRTI; Quinazoline; Solubility.

MeSH terms

  • Anti-HIV Agents* / chemical synthesis
  • Anti-HIV Agents* / chemistry
  • Anti-HIV Agents* / pharmacology
  • Biphenyl Compounds* / antagonists & inhibitors
  • Biphenyl Compounds* / chemistry
  • Biphenyl Compounds* / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Resistance, Viral / drug effects
  • HIV Reverse Transcriptase* / antagonists & inhibitors
  • HIV Reverse Transcriptase* / metabolism
  • HIV-1* / drug effects
  • HIV-1* / enzymology
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • Quinazolines* / chemical synthesis
  • Quinazolines* / chemistry
  • Quinazolines* / pharmacology
  • Reverse Transcriptase Inhibitors* / chemical synthesis
  • Reverse Transcriptase Inhibitors* / chemistry
  • Reverse Transcriptase Inhibitors* / pharmacology
  • Solubility*
  • Structure-Activity Relationship

Substances

  • biphenyl
  • NNRTI MKC-442