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.
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] [...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Journal article |
Language: | English |
Published: |
1998
|
_version_ | 1797051382190047232 |
---|---|
author | Witvrouw, M Arranz, M Pannecouque, C Declercq, R Jonckheere, H Schmit, J Vandamme, A Diaz, J Ingate, S Desmyter, J Esnouf, R Van Meervelt, L Vega, S Balzarini, J De Clercq, E |
author_facet | Witvrouw, M Arranz, M Pannecouque, C Declercq, R Jonckheere, H Schmit, J Vandamme, A Diaz, J Ingate, S Desmyter, J Esnouf, R Van Meervelt, L Vega, S Balzarini, J De Clercq, E |
author_sort | Witvrouw, M |
collection | OXFORD |
description | 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. |
first_indexed | 2024-03-06T18:18:44Z |
format | Journal article |
id | oxford-uuid:058af157-69b8-4b17-9f52-04501bad9a1b |
institution | University of Oxford |
language | English |
last_indexed | 2024-03-06T18:18:44Z |
publishDate | 1998 |
record_format | dspace |
spelling | oxford-uuid:058af157-69b8-4b17-9f52-04501bad9a1b2022-03-26T08:57:46Z1,1,3-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.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:058af157-69b8-4b17-9f52-04501bad9a1bEnglishSymplectic Elements at Oxford1998Witvrouw, MArranz, MPannecouque, CDeclercq, RJonckheere, HSchmit, JVandamme, ADiaz, JIngate, SDesmyter, JEsnouf, RVan Meervelt, LVega, SBalzarini, JDe Clercq, EWe 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. |
spellingShingle | Witvrouw, M Arranz, M Pannecouque, C Declercq, R Jonckheere, H Schmit, J Vandamme, A Diaz, J Ingate, S Desmyter, J Esnouf, R Van Meervelt, L Vega, S Balzarini, J De Clercq, E 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. |
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. |
title_full | 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. |
title_fullStr | 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. |
title_full_unstemmed | 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. |
title_short | 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. |
title_sort | 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 |
work_keys_str_mv | AT witvrouwm 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT arranzm 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT pannecouquec 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT declercqr 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT jonckheereh 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT schmitj 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT vandammea 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT diazj 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT ingates 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT desmyterj 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT esnoufr 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT vanmeerveltl 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT vegas 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT balzarinij 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity AT declercqe 113trioxo2h4hthieno34e124thiadiazinettdderivativesanewclassofnonnucleosidehumanimmunodeficiencyvirustype1hiv1reversetranscriptaseinhibitorswithantihiv1activity |