1,1,3-Trioxo-2
 H
 ,4
 H
 -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

Witvrouw, Myriam; Arranz, María Esther; Pannecouque, Christophe; Declercq, Ruben; Jonckheere, Heidi; Schmit, Jean-Claude; Vandamme, Anne-Mieke; Díaz, J. A.; Ingate, S. T.; Desmyter, Jan; Esnouf, Robert; Meervelt, Luc Van; Vega, Salvador; Balzarini, Jan; Clercq, Erik De

doi:10.1128/aac.42.3.618

Cited by 45 publications

(22 citation statements)

References 48 publications

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“…found to be moderately active at inhibiting HIV-1 (IIIB) replication in MT-4 cells at concentrations down to 0.09 µM[73]. The most potent compound, QM96521, (2-benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine) had a resistance profile similar to that observed with nevirapine.…”

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confidence: 56%

A Review of Recent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Research Activity

Corbett¹

2002

CMCAIA

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This non-nucleoside reverse transcriptase inhibitor review covers the patent and published literature from January, 1998-August, 2001. Major advances have been made in the past decade in discovering non-nucleoside reverse transcriptase inhibitors that are effective in inhibiting replication of wild-type virus. Attention is now focused upon the discovery of agents that are effective in inhibiting replication of virus' with singly and doubly mutated HIV-1 reverse transcriptase. Notable advances in the discovery of such broad spectrum therapeutics are SG-153 and the quinazolines DPC961 and DPC083. Attempts at discovering other broad spectrum anti-viral agents are presented herein.

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confidence: 56%

A Review of Recent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Research Activity

Corbett¹

2002

CMCAIA

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“…9). Not only do the positions of the fused rings overlap, but the cyclopropyl group of nevirapine (which has a spatial counterpart in all RT-NNRTI structures reported) is mimicked by the N4-cyanomethyl group of QM96521 [51].…”

Section: Thienothiadiazines and Their Bioisosteresmentioning

confidence: 96%

“…All of them were found to inhibit HIV-1 (IIIB) replication in MT-4 cells at a low concentration ranging from 0.09 μM to 0.1μM, without cytotoxicity at relative higher concentration (higher SI value) ( Table 7). Furthermore, these lead compounds have capability against different HIV-1 strains, including strains that were resistant to AZT and certain NNRTIs [51][52][53].…”

Section: Thienothiadiazines and Their Bioisosteresmentioning

confidence: 99%

“…These two factors received special attention to exploit the second generation of TTD derivatives. The -systems connected at the N 2 and N 4 positions, respectively, might satisfy the structural requirements in the optimization of HIV-1 RT inhibition [51]. Because a disubstituted thiadiazine has a structurally "butterfly-like" conformation, it should be much more suitable for filling the space in the NNRTI binding pocket (NNIBP) [54,55].…”

Section: Thienothiadiazines and Their Bioisosteresmentioning

confidence: 99%

“…The 1,1,3-Trioxo-2H,4H-Thieno [3,4-e] [1,2,4]Thiadiazine (TTD) represents a newly emerging class of HIV-1 NNRTIs that selectively block HIV-1 replication at the reverse transcription process [51].…”

Section: Thienothiadiazines and Their Bioisosteresmentioning

confidence: 99%

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Recent Advances in Antiviral Activity of Benzo/Heterothiadiazine Dioxide Derivatives

Zhan¹,

Liu²,

Clercq

2008

CMC

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Benzo/heterothiadiazine dioxides have been identified as important fused heterocyclic systems possessing a broad spectrum of biological activities and potential pharmacological applications. Recently, a large number of structurally novel compounds derived from these heterocycle scaffolds were identified as antiviral agents. Especially, substituted benzo/heterothiadiazine dioxide derivatives have been shown to inhibit the replication of HCMV, VZV, HCV and HIV. Of particular interest, some potent HCV polymerase inhibitors possess a benzothiadiazine dioxide scaffold, which is critical for the anti-HCV potency through strong hydrogen bond formation of the SO(2)NH group with the active site of the enzyme, as shown by X-ray crystallography. Also, some compounds belonging to the benzothiadiazine dioxide class have been found to be potent antiviral agents against HCMV and VZV. Moreover, some novel heterothiadiazine dioxide derivatives have been synthesized and evaluated as potential HIV inhibitors with lower toxicity and/or increased activity against drug-resistant virus strains. No systematic review is available in the literature on these thiadiazine derivatives in the design of potent antiviral inhibitors. In this article, we review the recent advances in the antiviral profile of this kind of compounds, as well as the impact of structural modifications and the structure-activity relationship (SAR).

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Novel compounds in preclinical/early clinical development for the treatment of HIV infections

Clercq

2000

Rev. Med. Virol.

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An Erratum has been published for this article in http://www3.interscience.wiley.com/cgi-bin/abstract/73502086/START Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), (ii) non‐nucleoside reverse transcriptase inhibitors (NNRTIs) and (iii) protease inhibitors (PIs). In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulphates, polysulphonates, polyoxometalates, zintevir, negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 [bicyclams (AMD3100), polyphemusins (T22), TAK‐779]; (iii) virus–cell fusion, through binding to the viral glycoprotein gp41 [T‐20 (DP‐178), siamycins, betulinic acid derivatives]; (iv) viral assembly and disassembly, through NCp7 zinc finger‐targeted agents [2,2′‐dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as L‐chicoric acid; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (peptoid CGP64222, fluoroquinolone K‐12, Streptomyces product EM2487). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess, respectively, improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI‐resistant HIV strains, or, in the case of PIs, a different, non‐peptidic scaffold. Given the multitude of molecular targets with which anti‐HIV agents can interact, one should be cautious in extrapolating from cell‐free enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L‐chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus–cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively. Copyright © 2000 John Wiley & Sons, Ltd.

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1,1,3-Trioxo-2 H ,4 H -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

Cited by 45 publications

References 48 publications

A Review of Recent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Research Activity

A Review of Recent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Research Activity

Recent Advances in Antiviral Activity of Benzo/Heterothiadiazine Dioxide Derivatives

Novel compounds in preclinical/early clinical development for the treatment of HIV infections

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