title: Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains.
abstract: Novel 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs), and their biological activity was evaluated. Most of the compounds, especially 26 and 22, bearing a 3-isopropyl and 3-iodine group, respectively, exhibited highly potent activity against wild-type HIV-1 strains and those resistant to reverse transcriptase inhibitors (RTIs). The diastereoisomers of 26-trans and 26-cis were synthesized separately and confirmed with HPLC and NOESY spectra. The 26-trans isomers had an activity about 400-fold more potent than that of 26-cis. The pair of 26-trans enantiomers, one of the most potent inhibitors with EC50 of 4 nM and selectivity index (SI) of 75000, was highly effective against a panel of RTIs-resistant strains with single (Y181C and K103N) or double (A17) mutations in reverse transcriptase. The results suggest that these novel pyridinone derivatives have the potential to be further developed as new antiretroviral drugs with improved antiviral efficacy and drug resistance profile.
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences.
authors.forename: Amin
authors.initials: A
authors.lastname: Li
authors.forename: Yabo
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Wang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Cao
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Ran
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Kang
authors.initials: K
authors.lastname: Qiao
authors.forename: Weisi
authors.initials: W
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Tian
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Liu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Du
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Junyi
authors.initials: J
authors.lastname: Liu
mesh_terms: D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase