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Updated: Jul 20, 2025
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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
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Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability
Ya-Li Sang1,2,3, Christophe Pannecouque4, Erik De Clercq4
1Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China.
Acta Pharmaceutica Sinica. B
|July 31, 2023
Summary
Researchers improved the metabolic stability of an anti-HIV drug by adding a hydroxymethyl side chain. The new compound, 9g, shows significantly enhanced stability and potent activity against drug-resistant HIV-1 strains with good safety profiles.
Area of Science:
- Medicinal Chemistry
- Virology
- Pharmacology
Background:
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are crucial in HIV-1 treatment.
- Compound 5, a recently identified NNRTI, exhibited poor metabolic stability (t1/2 = 96 min).
- Improving metabolic stability is key for developing effective and long-lasting anti-HIV therapies.
Purpose of the Study:
- To enhance the metabolic stability of NNRTI 5.
- To synthesize novel methylol-biphenyl-diarylpyrimidines with improved pharmacokinetic properties.
- To evaluate the anti-HIV-1 activity, drug resistance profile, cytotoxicity, and safety of the new compounds.
Main Methods:
- Chemical synthesis of novel methylol-biphenyl-diarylpyrimidine derivatives.
- In vitro metabolic stability assays using human liver microsomes.
- Antiviral activity testing against wild-type (WT) and drug-resistant HIV-1 strains (EC50 determination).
- Cytotoxicity assays (CC50 determination) and selectivity index (SI) calculation.
- Molecular docking studies to elucidate binding interactions.
- Inhibition assays for CYP enzymes and hERG channels.
- Acute toxicity studies in mice.
Main Results:
- A series of novel methylol-biphenyl-diarylpyrimidines were synthesized.
- Compound 9g demonstrated significantly improved metabolic stability (t1/2 = 2754 min), a 29-fold increase compared to compound 5.
- Compound 9g exhibited potent picomolar inhibition of WT HIV-1 (EC50 = 0.9 nmol/L) and low nanomolar activity against five resistant strains.
- Compound 9g showed low cytotoxicity (CC50 = 264 μmol/L) and a high selectivity index (SI = 256,438).
- Molecular docking revealed enhanced binding stability of 9g due to a new hydrogen bond interaction.
- Compound 9g displayed no significant inhibition of CYP enzymes or hERG, and no toxicity in mice at a high dose (2 g/kg).
Conclusions:
- The introduction of a hydroxymethyl side chain effectively enhanced the metabolic stability of the NNRTI.
- Compound 9g represents a promising candidate for a new generation of anti-HIV-1 drugs due to its potent activity, improved pharmacokinetics, and favorable safety profile.
- These findings support the further development of this class of compounds for HIV treatment.
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