101. Novel 1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine Derivatives as Non-Nucleoside Reverse Transcriptase Inhibitors That Inhibit Human Immunodeficiency Virus Type 1 Replication
- Author
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S. Vega, S. T. Ingate, Myriam Witvrouw, J. A. Diaz, E. Arranz, E. De Clercq, Jan Balzarini, and Christophe Pannecouque
- Subjects
Thiadiazines ,Bicyclic molecule ,Chemistry ,Stereochemistry ,Substituent ,Virus Replication ,Chemical synthesis ,HIV Reverse Transcriptase ,Reverse transcriptase ,Cell Line ,Nucleoside Reverse Transcriptase Inhibitor ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,HIV-1 ,Benzyl group ,Humans ,Reverse Transcriptase Inhibitors ,Molecular Medicine ,Moiety ,Structure–activity relationship - Abstract
The 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) represent a recently discovered chemical class of non-nucleoside reverse transcriptase inhibitors that selectively block human immunodeficiency virus type 1 replication. In a search for a better understanding of their mode of binding and with the aim of obtaining novel lead compounds, a second series of TTD derivatives was synthesized and evaluated for antiviral activity. The design of the new compounds was based on a variety of chemical modifications which were carried out in the original prototype 20a (QM 96521). Substitution of a halogen at the meta position of the N-2 benzyl group resulted in an improvement of the antiviral activity by 1 order of magnitude. Compounds bearing at the N-4 position a cyanomethyl, propargyl, or benzyl substituent were found to be the most potent of the series. Modifying the thieno[3,4-e] ring fused to the 1,2,4-thiadiazine moiety to other heterocyclic ring systems decreased the potency. The results obtained in this investigation have provided new indications for the design of even more effective TTDs.
- Published
- 1998