Tetrazole thioacetanilides: Potent non-nucleoside inhibitors of WT HIV reverse transcriptase and its K103N mutant

Muraglia, Ester; Kinzel, Olaf; Laufer, Ralph; Miller, Michael D.; Moyer, Gregory; Munshi, Vandna; Orvieto, Federica; Palumbi, Maria Cecilia; Pescatore, Giovanna; Rowley, Michael; Williams, Peter; Summa, Vincenzo

doi:10.1016/j.bmcl.2006.02.024

Cited by 84 publications

(38 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 Tetrazole and its derivatives have received much attention in recent years due to their widespread applications in biology. For instance, sulfanyltetrazole derivative (I) was identified as a potent, broad spectrum NNRTI lead of HIV-1 replication 4,5 and Cilostazol (II) which is a selective PDE3 phosphodiesterase inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Regioselective synthesis and preliminary cytotoxic activity properties of tetrazole appendage N-substituted piperazine derivatives

Dileep¹,

Katiki²,

Rao³

et al. 2017

Org. Commun.

View full text Add to dashboard Cite

A series of 1-(4-substituted)-4-(3-((1-(substituted)-1H-tetrazol-5-yl)thio)propyl)piperazine derivatives were (6a-t) synthesized by KF-Al 2 O 3 mediated S-alkylation of 5-thio-substituted tetrazole with 1-(3-chloropropyl)-4-(4-substituted)piperazine. The structures of the newly synthesized compounds were characterized by NMR and MS spectral data. Further, the regioselective formation of C-S bond was unambiguously confirmed by single crystal Xray diffraction. All the synthesized compounds were screened for their in vitro cytotoxic activities against two cancer cell lines: DU-145 (prostate cancer) and HeLa (cervical cancer). These cell lines were utilized in MTT assays and the obtained results were compared to doxorubicin, and their IC 50 values were determined. Among the compounds tested, 6f, 6j, 6m, 6n, 6o, 6q, 6r and 6t showed considerable potent activity, while the compound 6p exhibited significant potent activity against DU-145 and HeLa cancer cell lines compare to standard Doxorubicin.

show abstract

Section: Introductionmentioning

confidence: 99%

Regioselective synthesis and preliminary cytotoxic activity properties of tetrazole appendage N-substituted piperazine derivatives

Dileep¹,

Katiki²,

Rao³

et al. 2017

Org. Commun.

View full text Add to dashboard Cite

show abstract

“…(2) The aryl group linked to the tetrazole core fits into the important hydrophobic pocket, where many key resistant mutations take place, which include Y188L, Y181C, F227C, and L100I. (3) The tetrazole portion of these inhibitors could simply be acting as a scaffold that orients the pharmacophores into the proper geometry for binding (O'Meara et al, 2007;Muraglia et al, 2006;Gagnon et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Otherwise, molecular modeling of the lead compound also reveals that the anilide phenyl group is positioned near the binding pocket opening controlled by the Pro236 loop, which adjusts position based on the size of the NNRTI inhibitor bound (O'Meara et al 2007;Muraglia et al, 2006;Gagnon et al, 2007), so lengthening of this flexible link should be tolerated.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anti-HIV activity evaluation of novel N′-arylidene-2-[1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio]acetohydrazides

Zhan

Liu

et al. 2009

Med Chem Res

View full text Add to dashboard Cite

A series of novel N 0 -arylidene-2-[1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio] acetohydrazides was synthesized and evaluated, as nonnucleoside reverse transcriptase inhibitors (NNRTIs), for their in vitro HIV-1 and HIV-2 activity using the IIIB strain and ROD strain, respectively. The activity was monitored by the inhibition of the virusinduced cytopathic effect in the human T-lymphocyte (MT-4) cells. All of the new compounds were structurally confirmed by spectral analyses. Compounds 5q and 5r showed EC 50 of 29.62 lM (CC 50 of 169.24 ± 23.83lM) and 31.62 lM (CC 50 [ 309.06 lM), and resulting in selectivity index of 6 and [9, respectively. However, all newly synthesized derivatives were not active against HIV-2 replication.

show abstract

“…[5][6][7][8][9][10][11] Especially, 1,2,4-triazole derivatives VRX-480733 12 and RDEA806 13 were selected as candidates for further studies. RDEA806, a promising new drug candidate undergoing phase IIa clinical trial (by Ardea Biosciences Company), was highly effective against mutant HIV-1 strains and exhibited reduced clinical adverse reactions and serum half-life for once-daily dosing (Fig.…”

Section: 4mentioning

confidence: 99%

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

et al. 2013

View full text Add to dashboard Cite

In continuation of our endeavors to develop new, potent, selective, and less toxic anti-HIV agents, we describe our structure-based bioisosterism design, synthetic strategy, and structure-activity relationship (SAR) studies that led to the identification of pyridazinylthioacetamides, a novel class of NNRTIs, isosteres of arylazolylthioacetanilide derivatives. Nearly all of the tested compounds inhibited HIV-1 strain IIIB replication in the lower micromolar concentration range (EC 50 : 0.046-5.46 mM). Notably, the most promising compound 8k exhibited extremely potent inhibitory activity against HIV-1 replication with an EC 50 value of 0.046 mM, CC 50 of 99.9 mM and the viral selectivity index amounted to 2149.These values were much better than those of NVP (EC 50 ¼ 0.09 mM) and DDC (EC 50 ¼ 1.04 mM).Compound 8k also exhibited moderate inhibition of enzymatic activity with an IC 50 value of 4.06 mM, which was of the same order of magnitude as that of NVP (2.74 mM). Docking calculations were also performed to investigate the binding mode of compound 8k into the non-nucleoside binding site of HIV-1 RT and to rationalize some SARs.

show abstract

Tetrazole thioacetanilides: Potent non-nucleoside inhibitors of WT HIV reverse transcriptase and its K103N mutant

Cited by 84 publications

References 7 publications

Regioselective synthesis and preliminary cytotoxic activity properties of tetrazole appendage N-substituted piperazine derivatives

Regioselective synthesis and preliminary cytotoxic activity properties of tetrazole appendage N-substituted piperazine derivatives

Synthesis and anti-HIV activity evaluation of novel N′-arylidene-2-[1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio]acetohydrazides

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

Contact Info

Product

Resources

About