Probing the Dominant Motifs within the Hydrophobic Channel Yields Oxadiazole-Containing Diarylpyrimidine Derivatives...

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• Developing effective non-nucleoside reverse transcriptase inhibitors (NNRTIs) is crucial for combating HIV-1.
• Existing NNRTIs face challenges with drug resistance and suboptimal pharmacokinetic profiles.
• Novel compounds targeting the NNRTI-binding pocket are needed to overcome these limitations.

Purpose of the Study:

• To design, synthesize, and evaluate novel diarylpyrimidine derivatives as potential anti-HIV-1 agents.
• To identify compounds with improved activity against drug-resistant HIV-1 strains.
• To assess the drug-like properties and safety of lead compounds.

Main Methods:

• Strategic design and synthesis of diarylpyrimidine derivatives.
• In vitro evaluation of inhibitory activity against wild-type and mutant HIV-1 reverse transcriptase.
• Determination of resistance factors (RF) for mutant strains.
• Molecular simulation studies to understand binding interactions.
• Assessment of pharmacokinetic properties and acute toxicity (LD50).

Main Results:

• Compound 18e demonstrated potent inhibition against wild-type and NNRTI-resistant HIV-1 strains, with EC50 values in the nanomolar range.
• 18e exhibited improved antiresistance profiles against Y188L and RES056 mutant strains compared to ETR.
• Molecular simulations confirmed the importance of the 1,3,4-oxadiazolylpyridine motif for binding to reverse transcriptase.
• 18e displayed favorable pharmacokinetic properties (T1/2 = 2.35 h, F = 14.4%) and low toxicity (LD50 < 2000 mg/kg).

Conclusions:

• The novel diarylpyrimidine derivative 18e is a potent anti-HIV-1 agent with significant potential.
• 18e demonstrates superior antiresistance capabilities and favorable drug-like characteristics.
• The findings position 18e as a promising drug candidate for the treatment of HIV-1 infection.