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

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Summary

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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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.