Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs.
Ting-Ting LiChristophe PannecouqueErik De ClercqChun-Lin ZhuangFen-Er ChenPublished in: Molecules (Basel, Switzerland) (2020)
Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds B4 (EC50 = 6 nM) and B6 (EC50 = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC50 values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC50 = 0.08 μM). The preliminary structure-activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.
Keyphrases
- antiretroviral therapy
- hiv infected
- hiv positive
- hiv testing
- human immunodeficiency virus
- lymph node metastasis
- molecular docking
- room temperature
- hiv aids
- hepatitis c virus
- men who have sex with men
- wild type
- hiv infected patients
- squamous cell carcinoma
- photodynamic therapy
- small molecule
- molecular dynamics simulations
- randomized controlled trial
- systematic review
- ionic liquid