Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV-1 NNRTIs.
Yanying SunZhenzhen ZhouNa WangFabao ZhaoYing LiuXiaoxuan XuXiaohan WangZhenbang GouErik De ClercqChristophe PannecouquePeng ZhanDongwei KangXinyong LiuPublished in: Journal of medicinal chemistry (2024)
NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC 50 = 0.009-17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile ( T 1/2 = 5.09 h, F = 108.96%) compared that of DOR ( T 1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD 50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.
Keyphrases
- antiretroviral therapy
- molecular docking
- hiv infected
- hiv infected patients
- hiv positive
- human immunodeficiency virus
- hiv aids
- hiv testing
- molecular dynamics simulations
- hepatitis c virus
- men who have sex with men
- liver failure
- sars cov
- transcription factor
- south africa
- oxidative stress
- small molecule
- high throughput
- drug induced
- cancer therapy
- mesenchymal stem cells
- aortic dissection
- acute respiratory distress syndrome
- loop mediated isothermal amplification