title: Enantioselective inhibition of reverse transcriptase (RT) of HIV-1 by non-racemic indole-based trifluoropropanoates developed by asymmetric catalysis using recyclable organocatalysts.
abstract: Herein, we report the development of efficient inhibitors of reverse transcriptase (RT) of HIV-1 based on indole-alkyl trifluoropyruvate derivatives by a TZM-bl cell assay. The inhibitory activities of the two enantiomers and the corresponding racemic mixture have been compared. TZM-bl cells exhibited strong enantioselective discrimination for the (R)-configuration, among these indole derivatives, the most active compound R-12, with a 5-NO2 substituent, gave the best result when tested in the TZM-bl cells on HIV virus type HIV-1IIIB, with an EC50 value of 0.019 μM, CC50 value of 210.697 μM and SI (selectivity index, CC50/EC50) value of 11,089, respectively. The cell test showed that, in most cases, the R-enantiomer was superior to the Rac-mixture, which was better than the corresponding S-enantiomer. The results indicated that the R-enantiomer is the most favorable configuration as an efficient HIV-1 inhibitor. Molecular modeling studies suggested a structural basis for the enantioselectivity of RT towards this class of molecules.
authors.affiliation: State Key Laboratory of Virology, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.forename: Wenjie
authors.initials: W
authors.lastname: Ouyang
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Po
authors.initials: P
authors.lastname: Tien
authors.forename: Shuwen
authors.initials: S
authors.lastname: Wu
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D054879:Halogenation; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D019380:Anti-HIV Agents; D007211:Indoles; D011422:Propionates; D018894:Reverse Transcriptase Inhibitors; C030374:indole; D054303:HIV Reverse Transcriptase