Structure-Based Optimization of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants.
Dongwei KangZengjun FangBoshi HuangXueyi LuHeng ZhangHaoran XuZhipeng HuoZhongxia ZhouZhao YuQing MengGaochan WuXiao DingYe TianDirk DaelemansErik De ClercqChristophe PannecouquePeng ZhanXinyong LiuPublished in: Journal of medicinal chemistry (2017)
This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016 , 59 , 7991 - 8007 ). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure-activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 infection.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- wild type
- human immunodeficiency virus
- hiv aids
- hepatitis c virus
- men who have sex with men
- induced apoptosis
- drug induced
- acute lymphoblastic leukemia
- small molecule
- oxidative stress
- south africa
- sars cov
- liver failure
- cell cycle arrest
- dna methylation
- molecular docking
- endoplasmic reticulum stress
- intensive care unit
- gene expression
- cell death
- cell proliferation
- electronic health record
- structure activity relationship