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.
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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. myriam.witvrouw@uz.kuleuven.ac.be
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: M E
authors.initials: ME
authors.lastname: Arranz
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: R
authors.initials: R
authors.lastname: Declercq
authors.forename: H
authors.initials: H
authors.lastname: Jonckheere
authors.forename: J C
authors.initials: JC
authors.lastname: Schmit
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: J A
authors.initials: JA
authors.lastname: Diaz
authors.forename: S T
authors.initials: ST
authors.lastname: Ingate
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: R
authors.initials: R
authors.lastname: Esnouf
authors.forename: L
authors.initials: L
authors.lastname: Van Meervelt
authors.forename: S
authors.initials: S
authors.lastname: Vega
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D016049:Didanosine / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D019829:Nevirapine / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D015215:Zidovudine; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D016049:Didanosine