Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent

被引:103
作者
Campiani, G
Aiello, F
Fabbrini, M
Morelli, E
Ramunno, A
Armaroli, S
Nacci, V
Garofalo, A
Greco, G
Novellino, E
Maga, G
Spadari, S
Bergamini, A
Ventura, L
Bongiovanni, B
Capozzi, M
Bolacchi, F
Marini, S
Coletta, M
Guiso, G
Caccia, S
机构
[1] Univ Salerno, Fac Farm, Dipartimento Sci Farmaceut, I-84084 Fisciano, Salerno, Italy
[2] Univ Siena, Dipartimento Farm Chim Tecnol, I-53100 Siena, Italy
[3] Univ Calabria, I-87036 Arcavacata Di Rende, Italy
[4] Univ Naples Federico II, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy
[5] CNR, Ist Genet Biochim & Evoluzionist, I-27100 Pavia, Italy
[6] Univ Roma Tor Vergata, DSP&BC, I-00133 Rome, Italy
[7] Univ Roma Tor Vergata, DMS&SB, I-00133 Rome, Italy
[8] Ist Ric Farmacol Mario Negri, I-20157 Milan, Italy
关键词
D O I
10.1021/jm0010365
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the ethyl spacer, and structure-activity relationships are discussed in terms of the possible interaction with the RT binding site. Although the new QXPTs analogues show potent antiviral activity, none of the compounds tested overcome the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic antiviral agents, which in general have very low oral bioavailability. Through an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic series of antivirals. Replacing the ethylthioureidic moiety with a hydrazine linker led to a new antiviral lead, offering promising pharmacological and pharmacokinetic properties in terms of antiviral activity and oral bioavailability.
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页码:305 / 315
页数:11
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