Triazole derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase—Structure–activity relationships and crystallographic analysis

Kirschberg, Thorsten; Balakrishnan, Mini; Huang, Wei; Hluhanich, Rebecca; Kutty, Nilima; Liclican, Albert; McColl, Damian J.; Squires, Neil; Lansdon, E.B.

doi:10.1016/j.bmcl.2007.11.127

Cited by 37 publications

(20 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many of the identified inhibitors showed antiviral activity although the extent to which this was mediated by inhibition of RNase H is unclear as the compounds also inhibited RT DNA polymerase. Interestingly, both computational studies and crystallography show that triazoles bind in the NNRTI binding pocket in the RT DNA polymerase domain [48,49,50]. There are no structural data for interaction of triazole inhibitors with the RT RNase H domain.…”

Section: Inhibitors Of Hiv-1 Rt Rnase Hmentioning

confidence: 99%

Inhibitors of HIV-1 Reverse Transcriptase—Associated Ribonuclease H Activity

Ilina

LaBarge

Sarafianos

et al. 2012

Biology

View full text Add to dashboard Cite

HIV-1 enzyme reverse transcriptase (RT) is a major target for antiviral drug development, with over half of current FDA-approved therapeutics against HIV infection targeting the DNA polymerase activity of this enzyme. HIV-1 RT is a multifunctional enzyme that has RNA and DNA dependent polymerase activity, along with ribonuclease H (RNase H) activity. The latter is responsible for degradation of the viral genomic RNA template during first strand DNA synthesis to allow completion of reverse transcription and the viral dsDNA. While the RNase H activity of RT has been shown to be essential for virus infectivity, all currently used drugs directed at RT inhibit the polymerase activity of the enzyme; none target RNase H. In the last decade, the increasing prevalence of HIV variants resistant to clinically used antiretrovirals has stimulated the search for inhibitors directed at stages of HIV replication different than those targeted by current drugs. HIV RNase H is one such novel target and, over the past few years, significant progress has been made in identifying and characterizing new RNase H inhibitor pharmacophores. In this review we focus mainly on the most potent low micromolar potency compounds, as these provide logical bases for further development. We also discuss why HIV RNase H has been a difficult target for antiretroviral drug development.

show abstract

Section: Inhibitors Of Hiv-1 Rt Rnase Hmentioning

confidence: 99%

Inhibitors of HIV-1 Reverse Transcriptase—Associated Ribonuclease H Activity

Ilina

LaBarge

Sarafianos

et al. 2012

Biology

View full text Add to dashboard Cite

show abstract

“…In turn, many 1,2,4-triazole derivatives exhibit antimicrobial [19–20], antifungal [21], antitumor [22], analgesic [23], anti-inflammatory [24], psychoactive [25–27], anticonvulsant [28], diuretic [29], and anti-HIV [30] activity. 1,2,4-Triazole derivatives also represent the most important group of herbicides and fungicides [31].…”

Section: Introductionmentioning

confidence: 99%

Chemoenzymatic synthesis and biological evaluation of enantiomerically enriched 1-(β-hydroxypropyl)imidazolium- and triazolium-based ionic liquids

Borowiecki¹,

Milner-Krawczyk²,

Plenkiewicz³

2013

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

SummaryRacemic 1-(β-hydroxypropyl)azoles were prepared by solvent-free direct regioselective ring opening of 1,2-propylene oxide with imidazole or 1,2,4-triazole. Lipase-catalyzed transesterification of alcohols with vinyl acetate resulted in kinetic enantiomers resolution. Separated (S)-enantiomers of (+)-1-(1H-imidazol-1-yl)propan-2-ol and (+)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol were quaternized with alkyl bromides or iodides, yielding novel optically active ionic liquids. Racemic salts were tested against a wide range of microorganisms.

show abstract

“…Triazole derivatives, and in particular 3,4,5-trisubstituted-1,2,4-4H-triazoles (TTs), have been recently described as a novel class of potent NNRTIs [15,16]. In 2006 Girardet and coworkers discussed a series of TTs bearing an amide function at the linker group, positioned between the sulfur atom (at the triazole position 3) and the R1 substituent ( Fig.…”

Section: Introductionmentioning

confidence: 99%

3,4,5-Trisubstituted-1,2,4-4H-triazoles as WT and Y188L mutant HIV-1 non-nucleoside reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses

2010

View full text Add to dashboard Cite

3,4,5-Trisubstituted-1,2,4-4H-triazoles (TTs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Two series of triazoles have been studied, one of which was also screened against the Y188L mutant. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) has been used to elucidate the atomic details of the RT/TT interactions and to identify the most important features impacting the TT antiretroviral activity. Two 3D-QSAR CoMFA and CoMSIA models were derived, using the TT pEC₅₀ values measured against wild-type (WT) HIV-1 (model A) and the Y188L mutant form (model B), respectively, as the dependent variable. The final model A CoMSIA (r(ncv)² = 0.97, r(cv)² = 0.89, SEE = 0.314, and r(pred)² = 0.82) and model B CoMSIA (r(ncv)² = 0.91, r(cv)² = 0.61, SEE = 0.236, and r(pred)² = 0.73) analyses were more predictive. The results allowed us to obtain useful information for the design of new compounds with improved potency towards WT HIV-1 or that are potentially active against the Y188L mutant.

show abstract

Triazole derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase—Structure–activity relationships and crystallographic analysis

Cited by 37 publications

References 17 publications

Inhibitors of HIV-1 Reverse Transcriptase—Associated Ribonuclease H Activity

Inhibitors of HIV-1 Reverse Transcriptase—Associated Ribonuclease H Activity

Chemoenzymatic synthesis and biological evaluation of enantiomerically enriched 1-(β-hydroxypropyl)imidazolium- and triazolium-based ionic liquids

3,4,5-Trisubstituted-1,2,4-4H-triazoles as WT and Y188L mutant HIV-1 non-nucleoside reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses

Contact Info

Product

Resources

About