N-Phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine as a New Class of HIV-1 Non-nucleoside Reverse Transcriptase...

Area of Science:

• Medicinal Chemistry
• Virology
• Neuroscience

Background:

• Highly active antiretroviral therapy (HAART) transformed HIV treatment but can lead to comorbidities like HIV-associated neurocognitive disorders (HAND).
• HAND presents as cognitive and motor function impairment, posing a significant challenge in long-term HIV management.

Purpose of the Study:

• To discover and synthesize novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) specifically designed to avoid HAND.
• To evaluate the antiviral efficacy, safety, and neurotoxic potential of a new class of N-phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine derivatives.

Main Methods:

• Synthesis of a novel series of N-phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine compounds.
• Antiviral activity testing against wild-type HIV-1 and resistant mutants in TZM cells.
• In vitro cytotoxicity and neurotoxicity assessments in mouse neurons.
• In vivo toxicity and brain penetration studies in mouse models.

Main Results:

• The lead compound, 12126065, demonstrated potent antiviral activity against wild-type HIV-1 (EC50 = 0.24 nM) with low in vitro cytotoxicity (CC50 = 4.8 μM).
• 12126065 retained activity against clinically relevant HIV mutants and showed no in vivo acute or subacute toxicity.
• The compound exhibited good in vivo brain penetration and minimal neurotoxicity in mouse neurons (TC50 >100 μM).

Conclusions:

• The novel N-phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine class represents a promising strategy for developing HIV-1 NNRTIs with reduced neurotoxic potential.
• Compound 12126065 is a highly effective and safe candidate for further development, potentially mitigating HAND in HIV patients.