Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase...

Area of Science:

• Medicinal Chemistry
• Virology
• Pharmacology

Background:

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are crucial in HIV treatment.
• Drug resistance necessitates the development of novel NNRTIs with enhanced efficacy.
• Previous NNRTI 4 showed promise but required further optimization.

Purpose of the Study:

• To design and synthesize novel biphenyl-DAPY derivatives to overcome NNRTI resistance.
• To evaluate the anti-HIV-1 potency and safety profiles of the new compounds.
• To identify lead candidates with improved therapeutic potential.

Main Methods:

• Fragment-hopping strategy employed for novel compound design.
• Synthesis of biphenyl-DAPY derivatives (compounds 8a-v).
• In vitro evaluation of anti-HIV-1 activity against wild-type and mutant strains, cytotoxicity, and pharmacokinetic properties.

Main Results:

• Most synthesized compounds (8a-v) demonstrated significantly improved anti-HIV-1 potency compared to NNRTI 4.
• Compound 8r exhibited exceptional potency against wild-type HIV-1 (EC50 = 2.3 nM) and resistant mutants (e.g., K103N, E138K).
• Compound 8r displayed reduced cytotoxicity and a higher selectivity index than etravirine and rilpivirine, with favorable pharmacokinetics and low toxicity.

Conclusions:

• Novel biphenyl-DAPY analogues represent a promising class of NNRTIs.
• Compound 8r demonstrates high potency, safety, and oral bioavailability, suggesting its potential for HIV therapy.
• These findings support the development of biphenyl-DAPY analogues as next-generation anti-HIV drugs.