title: 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.
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.
authors.affiliation: Chemistry Department, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Weitman
authors.forename: Keti
authors.initials: K
authors.lastname: Lerman
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: Dan Thomas
authors.initials: DT
authors.lastname: Major
authors.forename: Amnon
authors.initials: A
authors.lastname: Hizi
authors.forename: Alon
authors.initials: A
authors.lastname: Herschhorn
mesh_terms: D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C558514:1-(4-chloro-2,5-dimethoxyphenyl)-3-(3-propoxypropyl)thiourea; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013890:Thiourea