2-Amino diphenylsulfides as new inhibitors of trypanothione reductase

Fernández-Gómez, Rodolfo; Moutiez, Mireille; Aumercier, Marc; Bethegnies, G.; Luyckx, M.; Ouaissi, Ali; Tartar, André; Sergheraert, Christian

doi:10.1016/0924-8579(95)00029-x

Cited by 29 publications

(29 citation statements)

References 19 publications

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“…If the piperazine ring is quaternized with a terminal benzyl moiety, the Figure 1. Known ligands of trypanothione reductase: the natural substrate trypanothione disulfide (1), and the competitive inhibitors mepacrine (2; K ic = 19 mm), [28] diaryl sulfide 3 (K ic = 27 mm), [18] and the benzylammonium compound 4 (K ic = 9 mm). [20,22] Figure 2.…”

Section: Designmentioning

confidence: 99%

“…H 2 O (10 mL) was added, and the mixture was diluted with saturated aqueous Na 2 CO 3 (30 mL), extracted with EtOAc (3 40 mL), dried (MgSO 4 ), filtered, and concentrated. Purification by RP HPLC (C 18 …”

Section: -Methoxy-7-nitroacridine (17)mentioning

confidence: 99%

“…Ligands equipped with tricyclic scaffolds, such as acridine or phenothiazine cores, as well as "ring-opened" 2-aminodiphenyl sulfide-based structures (such as 3) are known to interact with TR. [10,[16][17][18] Formation of dimeric structures through large amine linkers or introduction of a permanent positive charge (as in 4) further increases the inhibitory potency. [19,20] Computer-aided modeling allows several possible docking modes of these ligands in the wide active site, and clear structure-activity relationships (SAR) have not been established so far.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

et al. 2009

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Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 microm and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times.

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Section: Designmentioning

confidence: 99%

Section: -Methoxy-7-nitroacridine (17)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

et al. 2009

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“…Tricyclic scaffolds such as acridines, [17] related compounds, such as phenothiazine-based derivatives, [18,19] and ring-opened 2-aminodiphenyl sulfide-based structures are known to interact with TR. [20] In general, clear structure-activity relationships (SAR) are difficult to determine for TR inhibitors. Computer-aided modeling proved to be problematic as well, since the large, solvent-exposed active site of the enzyme allows for multiple binding orientations of the ligands.…”

Section: Introductionmentioning

confidence: 99%

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities

et al. 2010

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Trypanothione reductase (TR) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. This system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against African sleeping sickness and Chagas' disease. Over the past two decades, a variety of nonpeptidic small-molecule ligands of the parasitic enzyme were discovered. A current goal is to decipher the binding mode of these known inhibitors in order to optimize their structures. We analyzed the binding mode of recently reported 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues using computer modeling methods. This led us to conclude that the analogues occupy a different region of the active site than the diaryl sulfide-based class of inhibitors. A combination of the two motifs significantly increased affinity for the enzyme compared to the respective parent compounds. The newly synthesized conjugates exhibit K(ic) values for TR as low as 0.51±0.1 μM and high selectivity for the parasitic enzyme over the related human glutathione reductase (hGR), as was predicted by our molecular modeling studies. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense, often in combination with low cytotoxicity against mammalian cells. Interestingly, even stronger activities were found against Plasmodium falciparum.

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“…[24] Noticeably, several of them feature a basic or quaternary nitrogen connected through a flexible alkyl chain to a hydrophobic core. One of the prototypes of this inhibitor class are diaryl sulfide-based compounds, first reported by Sergheraert et al [25] and further explored by Douglas et al [26] In order to explore the eligibility of SF 5 as a building block for TR inhibitors and to compare it with the corresponding CF 3 or CA C H T U N G T R E N N U N G (CH 3 ) 3 analogues, we designed and synthesized diarylamine derivatives 1-6, which are structurally related to the known class of diphenyl sulfide inhibitors (Scheme 1).…”

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Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines

et al. 2008

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2-Amino diphenylsulfides as new inhibitors of trypanothione reductase

Cited by 29 publications

References 19 publications

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities

Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines

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