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.
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.
Instituto de Química Médica, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain, and Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
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Arranz
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Díaz
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Ingate
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Witvrouw
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Pannecouque
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Balzarini
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De Clercq
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Vega
D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D018894:Reverse Transcriptase Inhibitors; D013829:Thiadiazines; D054303:HIV Reverse Transcriptase