Thiosemicarbazide, a fragment with promising indolamine-2,3-dioxygenase (IDO) inhibition properties

Serra, Silvia; Moineaux, Laurence; Vancraeynest, Christelle; Masereel, Bernard; Pochet, Lionel; Frédérick, Raphaël

doi:10.1016/j.ejmech.2014.05.044

Cited by 34 publications

(23 citation statements)

References 19 publications

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“…The benefits of halogen aromatic substitution have been recognized before in several previous reports of structure-activity relationship studies 19,30–35 . There are three potential explanations for the benefits of halogen substitution: Favorable pi stacking interactions between the halo-aromatics and aromatic amino acid side chains in the IDO1 active site; halogen bonding between the halogen atoms of the inhibitor and Lewis basic sites in the IDO1 active site 36 ; or beneficial hydrophobic interactions between the halogen and a complementary pocket in the active site.…”

Section: Resultsmentioning

confidence: 84%

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Malachowski

Winters

DuHadaway

et al. 2016

European Journal of Medicinal Chemistry

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Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1’s catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.

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Section: Resultsmentioning

confidence: 84%

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Malachowski

Winters

DuHadaway

et al. 2016

European Journal of Medicinal Chemistry

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“…2. The syntheses were conducted following the standard methodologies that were previously reported [6,[18][19][20][21][22].…”

Section: Synthesis Of Ligandsmentioning

confidence: 99%

Synthesis, antibacterial activity and DNA interactions of lanthanide(III) complexes of N(4)-substituted thiosemicarbazones

2018

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This paper reports the synthesis and detailed characterization of six novel lanthanide complexes of La(III), Eu(III) and Nd(III) with N(4)-substituted thiosemicarbazones derived from the 2-carboxybenzaldehyde. The IR, 1H-NMR and 13C-NMR spectroscopic studies confirmed the coordination of the thiocarbonyl (C=S), azomethine (C=N) and carboxylate (COO-) groups to the metal centers, and the carboxylate was coordinated in a bidentate manner. The elemental and thermal analyses suggest that lanthanide complexes were formed in 1:2 molar ratios (metal:ligand). The molar conductivity values confirmed the non-electrolytic nature of the complexes. The interaction of these complexes with calf thymus DNA (CT-DNA) was investigated by UV absorption and viscosity measurements. It was found that the Eu(III) and Nd(III) complexes could roll along the DNA strands through groove interactions. Furthermore, lanthanide complexes could promote the oxidative cleavage of plasmid pBR322 in a high-oxidative stress environment. Finally, the Schiff base ligands (L) and their complexes were evaluated for their antibacterial activities against gram-positive and gram-negative bacteria using a microdilution procedure. The results indicate that the lanthanide complexes exhibit more potent antibacterial activity than the free ligands.

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“…The starting material, N-(3-chlorophenyl)hydrazinecarbothioamide (2) was prepared in 85% yield from 1-chloro-3-isothiocyanatobenzene (1) and hydrazine hydrate in 2-propanol at room temperature as described [36,37]. In the present work, its 1 H-NMR in deuterated dimethyl sulfoxide differed from both reports, whereby two proton signals appeared at δ = 4.85 and 9.26 ppm, both are exchangeable with D 2 O and each is equivalent to two protons indicating the presence of two NH 2 groups.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and mass spectrometry of some arylidene-hydrazinyl-thiazolines and their 2-arylidene-N-(3-chlorophenyl)hydrazinecarbothioamide precursors

Ramadan

2019

SN Appl. Sci.

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N-(3-Chlorophenyl)hydrazinecarbothioamide (2) was prepared by reacting 1-chloro-3-isothiocyanatobenzene (1) with hydrazine hydrate in 2-propanol, whose 1 H-NMR spectrum showed its existence in a Zwitter ionic betain form. A number of 2-arylidene-N-(3-chlorophenyl)hydrazinecarbothioamides (3a-e) were synthesized by the condensation of 2 with aromatic aldehydes in absolute ethanol and in the presence of a catalytic amount of glacial acetic acid. They were reacted with 2-bromo-1-(4-bromophenyl)ethanone (4) in 2-propanol/DMF in the presence of anhydrous potassium carbonate to produce the respective 2-(arylidenehydrazono)-4-(4-bromophenyl)-3-(3-chlorophenyl)-2,3-dihydrothiazoles (5a-e) in excellent yields. The synthesized compounds were characterized by spectroscopic methods as well as mass spectrometry. The molecular modeling and atomic charges of heteroatoms in all compounds were performed using Chem3D Pro 12.0.2 software and provided an excellent tool to investigate the fragmentation pathways. The nitrogen rule was also found to be good predictors of molecular ions and their fragmentation patterns.

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Thiosemicarbazide, a fragment with promising indolamine-2,3-dioxygenase (IDO) inhibition properties

Cited by 34 publications

References 19 publications

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Synthesis, antibacterial activity and DNA interactions of lanthanide(III) complexes of N(4)-substituted thiosemicarbazones

Synthesis and mass spectrometry of some arylidene-hydrazinyl-thiazolines and their 2-arylidene-N-(3-chlorophenyl)hydrazinecarbothioamide precursors

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