TY - JOUR
T1 - 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
AU - Weitman, Michal
AU - Lerman, Keti
AU - Nudelman, Abraham
AU - Major, Dan Thomas
AU - Hizi, Amnon
AU - Herschhorn, Alon
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
KW - HIV-1
KW - Reverse transcriptase
KW - Thioureas
UR - http://www.scopus.com/inward/record.url?scp=79151473381&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2010.11.003
DO - 10.1016/j.ejmech.2010.11.003
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AN - SCOPUS:79151473381
SN - 0223-5234
VL - 46
SP - 447
EP - 467
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 2
ER -