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rdf:type |
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|
lifeskim:mentions |
umls-concept:C0121925,
umls-concept:C0205314,
umls-concept:C0205549,
umls-concept:C0220781,
umls-concept:C0243072,
umls-concept:C0268563,
umls-concept:C0282519,
umls-concept:C0439849,
umls-concept:C0445223,
umls-concept:C0600115,
umls-concept:C0679622,
umls-concept:C1552599,
umls-concept:C1704787,
umls-concept:C1707689,
umls-concept:C1883254,
umls-concept:C1957438,
umls-concept:C2603343
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pubmed:issue |
5
|
|
pubmed:dateCreated |
2003-2-20
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|
pubmed:abstractText |
A novel series of potent, selective HIV-1 N-acylthiocarbamate (ATC) nonnucleoside reverse transcriptase inhibitors (NNRTIs) is described. The title compounds were synthesized through a highly convergent, one-pot procedure. In cell-based assays, the lead compound (17c) prevented the HIV-1 multiplication with an EC(50) of 8 microM. The lead optimization strategy was developed by single or multiple modifications of the three molecular portions, in which 17c was notionally divided. Molecular modeling studies led to the synthesis of O-(2-phthalimidoethyl)-N-(p-substituted phenyl)-N-acylthiocarbamates, which showed in vitro activities against HIV-1 in the low nanomolar range. Nevertheless, the title compounds retained low potency against HIV-1 strains carrying mutations (K103R, Y181C, and K103N/Y181C) responsible for NNRTI resistance. The hypothetical docking model of RT/17c and RT/25c, derived from X-ray crystallographic structure of a PETT derivative in complex with HIV-1 RT, revealed that the model structures of ATCs do not approximate the NNRTI butterfly-like conformation. Analysis of these hypotetical complexes helps to rationalize some SARs and resistance data.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
27
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pubmed:volume |
46
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
768-81
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:12593657-Cell Line,
pubmed-meshheading:12593657-Computer-Aided Design,
pubmed-meshheading:12593657-HIV Reverse Transcriptase,
pubmed-meshheading:12593657-HIV-1,
pubmed-meshheading:12593657-Humans,
pubmed-meshheading:12593657-Ligands,
pubmed-meshheading:12593657-Models, Molecular,
pubmed-meshheading:12593657-Mutation,
pubmed-meshheading:12593657-Quantitative Structure-Activity Relationship,
pubmed-meshheading:12593657-Reverse Transcriptase Inhibitors,
pubmed-meshheading:12593657-Thiazoles,
pubmed-meshheading:12593657-Thiocarbamates,
pubmed-meshheading:12593657-Thiourea,
pubmed-meshheading:12593657-Virus Replication
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pubmed:year |
2003
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pubmed:articleTitle |
Design, synthesis, SAR, and molecular modeling studies of acylthiocarbamates: a novel series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors structurally related to phenethylthiazolylthiourea derivatives.
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pubmed:affiliation |
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. ranise@unige.it
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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