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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Published on: May 9, 2025

Cyclization-Inspired Structural Optimization: Designing Potent Non-nucleoside Reverse Transcriptase Inhibitors with

Yin-Xiang Zhang¹, Christophe Pannecouque², Erik De Clercq²

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

|January 9, 2026

Summary

This summary is machine-generated.

A novel bicyclic tetrahydropteridine derivative, compound 16a, shows potent activity against HIV-1, including resistant strains. This promising drug candidate offers improved safety and solubility compared to existing treatments.

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Nucleoside Triphosphates - From Synthesis to Biochemical Characterization

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Published on: April 3, 2014

Area of Science:

Medicinal Chemistry
Organic Synthesis
Pharmacology

Background:

Etravirine (ETR) and rilpivirine (RPV) are non-nucleoside reverse transcriptase inhibitors (NNRTIs) used to treat HIV-1 infection.
Improving the safety and selectivity of NNRTIs is crucial for enhancing patient outcomes and overcoming drug resistance.

Purpose of the Study:

To develop novel bicyclic tetrahydropteridine derivatives with improved safety and selectivity profiles compared to ETR.
To evaluate the in vitro and in vivo properties of these new compounds as potential anti-HIV agents.

Main Methods:

A cyclization strategy was employed to synthesize novel bicyclic tetrahydropteridine derivatives by replacing the pyrimidine ring of ETR with a dihydropteridin-6(5H)-one scaffold.
Antiviral activity against wild-type (WT) and mutant HIV-1 strains was assessed using EC50 values.
Cytotoxicity was determined by CC50 values, and selectivity index (SI) was calculated.
Aqueous solubility, metabolic stability (CYP enzyme sensitivity), hERG channel inhibition, and acute in vivo toxicity were evaluated.

Main Results:

Compound 16a demonstrated potent activity against WT HIV-1 (EC50 = 3 nM) and seven mutant strains (EC50 = 14-77 nM), comparable to ETR.
16a exhibited negligible cytotoxicity (CC50 = 196.46 μM) and a high SI (65,789), significantly surpassing ETR and RPV.
16a showed improved aqueous solubility, minimal sensitivity to CYP enzymes, no hERG channel inhibition, and no acute toxicity in vivo.

Conclusions:

Compound 16a represents a highly promising non-nucleoside reverse transcriptase inhibitor candidate.
The novel bicyclic tetrahydropteridine scaffold offers significant advantages in terms of potency, safety, and pharmacokinetic properties.
16a warrants further investigation for the treatment of HIV-1 infection.