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Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV ‐1 RN ase H inhibitors
Author(s) -
Gao Ping,
Wang Xueshun,
Sun Lin,
Cheng Xiqiang,
Poongavanam Vasanthanathan,
Kongsted Jacob,
Álvarez Mar,
Luczkowiak Joanna,
Pannecouque Christophe,
De Clercq Erik,
Lee KuoHsiung,
Chen ChinHo,
Liu Huiqing,
MenéndezArias Luis,
Liu Xinyong,
Zhan Peng
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13455
Subject(s) - rnase h , reverse transcriptase , enzyme , ic50 , chemistry , integrase , in vitro , human immunodeficiency virus (hiv) , biochemistry , virology , biology , rna , dna , gene
Abstract Human immunodeficiency virus ( HIV ) reverse transcriptase ( RT )‐associated ribonuclease H ( RN ase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. In this work, we report the design, synthesis, and biologic evaluation of a novel series of galloyl derivatives with HIV ‐1 RN ase H inhibitory activity. Most of them showed IC 50 s at sub‐ to low‐micromolar concentrations in enzymatic assays. The most potent compound was II ‐25 that showed an IC 50 of 0.72 ± 0.07 μM in RN ase H inhibition assays carried out with the HIV ‐1 BH 10 RT . II ‐25 was 2.8 times more potent than β‐thujaplicinol in these assays. Interestingly, II ‐25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure–activity relationships ( SAR ) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds.