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Title: 1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives: a new class of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors with anti-HIV-1 activity
Authors: Witvrouw, Myriam ×
Arranz, M E
Pannecouque, Christophe
Declercq, R
Jonckheere, H
Schmit, J C
Vandamme, Anne-Mieke
Diaz, J A
Ingate, S T
Desmyter, Jan
Esnouf, R
Van Meervelt, Luc
Vega, S
Balzarini, Jan
De Clercq, Erik #
Issue Date: Mar-1998
Series Title: Antimicrobial Agents and Chemotherapy vol:42 issue:3 pages:618-23
Abstract: We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-l,1,3-trioxo-2H,4H- thieno [3,4-e] [1,2,4] thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (IIIB)] replication in MT-4 cells at a concentration of 0.09 microM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3'-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/ MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (IIIB) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.
ISSN: 0066-4804
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
Laboratory of Clinical and Epidemiological Virology (Rega Institute)
Biochemistry, Molecular and Structural Biology Section
Molecular Virology and Gene Therapy
× corresponding author
# (joint) last author

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