| Arylthiopyrrole (AThP) derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis, structure-activity relationships, and docking studies (part 1). | |
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MedLine Citation:
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PMID: 17089433 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3-5, which are related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008-53 microM. Even if compounds 3-5 are generally less potent than S-1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S-1153. Compound 4e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC(50)=8 and 3 nM, respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT. In fact, compounds 3-5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4k and 5a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5e showed an approximate 240-fold decrease in activity against Y181I, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4e, 4j, 4k and 5e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure-activity relationships and resistance data. |
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Authors:
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Roberto Di Santo; Roberta Costi; Marino Artico; Gaetano Miele; Antonio Lavecchia; Ettore Novellino; Alberto Bergamini; Reynel Cancio; Giovanni Maga |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: ChemMedChem Volume: 1 ISSN: 1860-7179 ISO Abbreviation: - Publication Date: 2006 Dec |
Date Detail:
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Created Date: 2006-12-06 Completed Date: 2007-03-19 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 101259013 Medline TA: ChemMedChem Country: Germany |
Other Details:
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Languages: eng Pagination: 1367-78 Citation Subset: IM |
Affiliation:
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Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. roberto.disanto@uniroma1.it |
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| MeSH Terms | |
Descriptor/Qualifier:
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Binding Sites Cell Line Computer Simulation Crystallography, X-Ray Drug Design HIV Reverse Transcriptase / antagonists & inhibitors* Humans Ligands Microbial Sensitivity Tests Models, Molecular Molecular Structure Pyrroles / chemical synthesis*, chemistry, pharmacology* Reverse Transcriptase Inhibitors / chemical synthesis*, chemistry, pharmacology* Stereoisomerism Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Ligands; 0/Pyrroles; 0/Reverse Transcriptase Inhibitors; EC 2.7.7.49/HIV Reverse Transcriptase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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