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Design, synthesis, and structure-activity relationship of a novel series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans as HIV-1 entry inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 Dec 10; Vol. 52 (23), pp. 7631-9. - Publication Year :
- 2009
-
Abstract
- We previously identified two small molecules targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole 12 (NB-2) and N-(3-carboxy-4-chloro)phenylpyrrole 13 (NB-64), that inhibit HIV-1 infection at low micromolar levels. On the basis of molecular docking analysis, we designed a series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans. Compared with 12 and 13, these compounds have bigger molecular size (437-515 Da) and could occupy more space in the deep hydrophobic pocket on the gp41 NHR trimer. Fifteen 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans (11a-o) were synthesized by Suzuki-Miyaura cross-coupling followed by a Knoevenagel condensation and tested for their anti-HIV-1 activity and cytotoxicity on MT-2 cells. We found that all 15 compounds had improved anti-HIV-1 activity and 3 of them (11a, 11b, and 11d) exhibited inhibitory activity against replication of HIV-1(IIIB) and 94UG103 at <100 nM range, more than 20-fold more potent than 12 and 13, suggesting that these compounds can serve as leads for development of novel small molecule HIV fusion inhibitors.
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents metabolism
Cell Line
Drug Design
Furans chemical synthesis
Furans metabolism
HIV Envelope Protein gp41 chemistry
HIV Envelope Protein gp41 metabolism
Models, Molecular
Molecular Weight
Protein Conformation
Structure-Activity Relationship
Anti-HIV Agents chemistry
Anti-HIV Agents pharmacology
Furans chemistry
Furans pharmacology
HIV-1 drug effects
HIV-1 physiology
Virus Internalization drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19746983
- Full Text :
- https://doi.org/10.1021/jm900450n