N -Phenyl-1-(phenylsulfonyl)-1 H -1,2,4-triazol-3-amine as a New Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor.
Thomas R LaneVadim MakarovJulie A E NelsonRick B MeekerGiuseppina SannaOlga RiabovaElena KazakovaNatalia MonakhovaAndrey TsedilinFabio UrbinaThane JonesAshley SuchySean EkinsPublished in: Journal of medicinal chemistry (2023)
Highly active antiretroviral therapy (HAART) has revolutionized human immunodeficiency virus (HIV) healthcare, turning it from a terminal to a potentially chronic disease, although some patients can develop severe comorbidities. These include neurological complications, such as HIV-associated neurocognitive disorders (HAND), which result in cognitive and/or motor function symptoms. We now describe the discovery, synthesis, and evaluation of a new class of N -phenyl-1-(phenylsulfonyl)-1 H -1,2,4-triazol-3-amine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) aimed at avoiding HAND. The most promising molecule, 12126065, exhibited antiviral activity against wild-type HIV-1 in TZM cells (EC 50 = 0.24 nM) with low in vitro cytotoxicity (CC 50 = 4.8 μM) as well as retained activity against clinically relevant HIV mutants. 12126065 also demonstrated no in vivo acute or subacute toxicity, good in vivo brain penetration, and minimal neurotoxicity in mouse neurons up to 10 μM, with a 50% toxicity concentration (TC 50 ) of >100 μM, well below its EC 50 .
Keyphrases
- antiretroviral therapy
- human immunodeficiency virus
- hiv infected
- hiv positive
- hiv infected patients
- hiv aids
- hepatitis c virus
- hiv testing
- healthcare
- men who have sex with men
- wild type
- end stage renal disease
- hepatitis b virus
- bipolar disorder
- small molecule
- chronic kidney disease
- early onset
- liver failure
- south africa
- physical activity
- ejection fraction
- endoplasmic reticulum stress
- resting state
- extracorporeal membrane oxygenation
- induced apoptosis
- depressive symptoms
- prognostic factors
- cell death
- brain injury
- functional connectivity