Pyrimidine Thioethers: A Novel Class of HIV-1 Reverse Transcriptase Inhibitors with Activity Against BHAP-Resistant HIV

A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 41; no. 20; pp. 3793 - 3803
Main Authors:	Nugent, Richard A, Schlachter, Stephen T, Murphy, Michael J, Cleek, Gary J, Poel, Toni J, Wishka, Donn G, Graber, David R, Yagi, Yoshihiko, Keiser, Barbara J, Olmsted, Robert A, Kopta, Laurie A, Swaney, Steven M, Poppe, Susan M, Morris, Joel, Tarpley, W. Gary, Thomas, Richard C
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 24-09-1998
Subjects:	AIDS/HIV Amino Acid Substitution Animals Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Cell Line Delavirdine - pharmacology Drug Resistance, Microbial HIV Reverse Transcriptase - antagonists & inhibitors HIV Reverse Transcriptase - genetics HIV-1 - drug effects HIV-1 - enzymology Human immunodeficiency virus 1 Leucine - genetics Medical sciences Mice Pharmacology. Drug treatments Proline - genetics pyrimidine thioethers Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Reverse Transcriptase Inhibitors - chemical synthesis Reverse Transcriptase Inhibitors - chemistry Reverse Transcriptase Inhibitors - pharmacology Structure-Activity Relationship Sulfides - chemical synthesis Sulfides - chemistry Sulfides - pharmacology RNA-directed DNA polymerase HIV-1 virus Enzyme Nitrogen heterocycle Transferases Non nucleoside compound Retroviridae Enzyme inhibitor Lentivirus Delavirdine Virus Resistance Organic thiocarbamimidate Nucleotidyltransferases Structure activity relation Chlorine Organic compounds Six membered ring Vinylic compound Antiviral Carboxamide Reversibility Human immunodeficiency virus Chemical synthesis Pyrimidine nucleoside
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Summary:	A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.
Bibliography:	ark:/67375/TPS-6Q2HRK63-D istex:0BC512A0F9DAFD50B53DC7903786225D5BA63B60 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm9800806