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

Michal Weitman; Keti Lerman; Abraham Nudelman; Dan Thomas Major; Amnon Hizi; Alon Herschhorn

doi:10.1016/j.ejmech.2010.11.003

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

Eur J Med Chem. 2011 Feb;46(2):447-67. doi: 10.1016/j.ejmech.2010.11.003. Epub 2010 Nov 10.

Authors

Michal Weitman¹, Keti Lerman, Abraham Nudelman, Dan Thomas Major, Amnon Hizi, Alon Herschhorn

Affiliation

¹ Chemistry Department, Bar Ilan University, Ramat Gan 52900, Israel.

PMID: 21159409
DOI: 10.1016/j.ejmech.2010.11.003

Abstract

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 IC50 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.

MeSH terms

HIV Reverse Transcriptase / antagonists & inhibitors*
HIV-1 / drug effects*
HIV-1 / enzymology*
Molecular Structure
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Stereoisomerism
Structure-Activity Relationship
Thiourea / analogs & derivatives*
Thiourea / chemical synthesis
Thiourea / chemistry
Thiourea / pharmacology

Substances

1-(4-chloro-2,5-dimethoxyphenyl)-3-(3-propoxypropyl)thiourea
Reverse Transcriptase Inhibitors
HIV Reverse Transcriptase
Thiourea