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Rational Design of Broad-Spectrum Non-Nucleoside Reverse Transcriptase Inhibitors via Pharmacophore-Oriented

Kun Zhang1,2, Yuhan Lin3, Ling Dong1,2

  • 1Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Shanghai Engineering Research Center of Industrial Asymmetric Catalysis of Chiral Drugs, State Key Laboratory of Green Chemical Synthesis and Conversion, Fudan University, Shanghai 200433, China.

Journal of Medicinal Chemistry
|March 30, 2026
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Summary
This summary is machine-generated.

Researchers developed novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using rilpivirine as a lead. Compound A24 shows potent activity against drug-resistant HIV-1, with improved safety and pharmacokinetic profiles, positioning it for further development.

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Area of Science:

  • Medicinal Chemistry
  • Virology
  • Drug Discovery

Background:

  • HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are crucial for antiretroviral therapy.
  • Development of new NNRTIs is needed to combat drug resistance and improve safety profiles.
  • Rilpivirine (RPV) serves as a lead compound for novel NNRTI development.

Purpose of the Study:

  • To design and synthesize novel NNRTI analogs based on the rilpivirine pharmacophore.
  • To evaluate the antiviral activity, cytotoxicity, and drug-resistance profiles of the synthesized compounds.
  • To optimize lead compounds for improved pharmacokinetic properties and reduced toxicity.

Main Methods:

  • Pharmacophore-oriented molecular generation using the PhoreGen platform.
  • Synthesis and structural diversification of rilpivirine analogs.
  • In vitro evaluation of anti-HIV-1 activity (EC50) and cytotoxicity (CC50).
  • Molecular docking, drug-likeness, and synthetic feasibility assessments.
  • Structure-activity relationship (SAR) studies and pharmacokinetic profiling (CYP inhibition, hERG toxicity, metabolic stability).

Main Results:

  • Compound No.102 (A19) showed potent activity against WT HIV-1 (EC50 = 3.15 nM) with low cytotoxicity.
  • Structure-activity relationship optimization led to compound A24, active against drug-resistant HIV-1 mutants (EC50 = 2.07-28.8 nM).
  • A24 demonstrated significantly reduced cytotoxicity (CC50 = 82.3 μM) and enhanced potency against specific mutants compared to RPV.
  • A24 exhibited favorable pharmacokinetics, including attenuated CYP inhibition, reduced hERG-related toxicity, and improved metabolic stability.

Conclusions:

  • Compound A24 is a promising NNRTI candidate with potent activity against drug-resistant HIV-1.
  • A24 possesses an improved safety and pharmacokinetic profile compared to the lead compound rilpivirine.
  • The developed NNRTI scaffold holds potential for further clinical development in HIV-1 treatment.