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

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 seri...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-12, Vol.52 (23), p.7631-7639
Main Authors: Katritzky, Alan R, Tala, Srinivasa R, Lu, Hong, Vakulenko, Anatoliy V, Chen, Qi-Yin, Sivapackiam, Jothilingam, Pandya, Keyur, Jiang, Shibo, Debnath, Asim K
Format: Article
Language:English
Subjects:
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - chemistry
Anti-HIV Agents - metabolism
Anti-HIV Agents - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Cell Line
Drug Design
Furans - chemical synthesis
Furans - chemistry
Furans - metabolism
Furans - pharmacology
HIV Envelope Protein gp41 - chemistry
HIV Envelope Protein gp41 - metabolism
HIV-1 - drug effects
HIV-1 - physiology
Medical sciences
Models, Molecular
Molecular Weight
Pharmacology. Drug treatments
Protein Conformation
Structure-Activity Relationship
Virus Internalization - drug effects
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Summary: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-1IIIB and 94UG103 at
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900450n