Structure--activity relationship studies of 1-(4-chloro-2,5-dimethoxyphenyl)-3-(3-propoxypropyl)thiourea, a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type-1
| Autor: | Michal Weitman, Dan Thomas Major, Alon Herschhorn, Abraham Nudelman, Keti Lerman, Amnon Hizi |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Pharmacology
Infectivity Molecular Structure Chemistry Organic Chemistry Mutant Thiourea Stereoisomerism General Medicine Reverse transcriptase HIV Reverse Transcriptase Chemical library Nucleoside Reverse Transcriptase Inhibitor chemistry.chemical_compound Structure-Activity Relationship Biochemistry Docking (molecular) Drug Discovery HIV-1 Structure–activity relationship Reverse Transcriptase Inhibitors |
| Zdroj: | European journal of medicinal chemistry. 46(2) |
| ISSN: | 1768-3254 |
| Popis: | The reverse transcriptase (RT) of the human immunodeficiency virus type-1 (HIV-1) is still a prime target for drug development due to the continuing need to block drug-resistant RT mutants by new inhibitors. We have previously identified 1-(4-chloro-2,5-dimethoxyphenyl)-3-(3-propoxypropyl)thiourea, compound 1 , as a potent RT inhibitor from an available chemical library. Here, we further modified this compound to study structure–activity relationships when replacing various groups in the molecule. Different functional groups were systematically introduced on the aromatic ring and the aliphatic chain of the compound was modified. The effect of these modifications on viral infectivity was then evaluated. The most potent compound found was propyl 4-(amino- N -(4-chloro-2,5-dimethoxyphenyl)methanethioamino)butanoate, 45c , which inhibited infectivity with a calculated IC 50 of about 1.1 μM. Docking studies identified potential important interactions between the top scoring ligands and HIV-1 RT, and the predicted relative affinity of the ligands was found to be in agreement with the experimental results. |
| Databáze: | OpenAIRE |
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