Synthesis and GABA receptor potency of 3-thiomethyl-4-(hetero)aryl-5-amino-1-phenylpyrazoles

Meegalla, Sanath K.; Doller, Darı́o; Sha, Deyou; Soll, Rich; Wisnewski, Nancy; Silver, Gary M.; Dhanoa, Dale

doi:10.1016/j.bmcl.2004.07.033

Cited by 32 publications

(20 citation statements)

References 4 publications

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“…To obtain 10 , N -alkylation of the indole ring was carried out under the same conditions reported for the synthesis of 1 [7]. Refluxing 10 with 3-hydroxyphenylboronic acid in toluene:ethanol containing PdCl 2 (PPh 3 ) 2 and Na 2 CO 3 gave 11 in a higher yield than a known procedure [33]. The final product 2 was obtained by a reaction of 11 with excess hydroxylamine [34] that simultaneously converted methyl ester and phthalimide to hydroxamic acid and amine, respectively [35], [36].…”

Section: Resultsmentioning

confidence: 99%

Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

et al. 2007

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Optimization of a serotype-selective, small-molecule inhibitor of botulinum neurotoxin serotype A (BoNTA) endopeptidase is a formidable challenge because the enzyme-substrate interface is unusually large and the endopeptidase itself is a large, zinc-binding protein with a complex fold that is difficult to simulate computationally. We conducted multiple molecular dynamics simulations of the endopeptidase in complex with a previously described inhibitor (K i app of 7±2.4 µM) using the cationic dummy atom approach. Based on our computational results, we hypothesized that introducing a hydroxyl group to the inhibitor could improve its potency. Synthesis and testing of the hydroxyl-containing analog as a BoNTA endopeptidase inhibitor showed a twofold improvement in inhibitory potency (K i app of 3.8±0.8 µM) with a relatively small increase in molecular weight (16 Da). The results offer an improved template for further optimization of BoNTA endopeptidase inhibitors and demonstrate the effectiveness of the cationic dummy atom approach in the design and optimization of zinc protease inhibitors.

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Section: Resultsmentioning

confidence: 99%

Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

et al. 2007

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“…5-Amino-4-benzoyl-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazole III has been reported as a potent corticotrophin-releasing factor-1 (CRF-1) receptor antagonist [9]. 5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-(3-methoxyphenyl)-3-methylthiopyrazole IV has been described as a potent GABA inhibitor with selectivity towards insect versus mammalian receptors [10]. The simple N -phenyl amide of 5-amino -1,3-dimethylpyrazole-4-carboxylic acid V has been shown to exhibit antifungal activity [11] (Fig.…”

Section: Reviewmentioning

confidence: 99%

Approaches towards the synthesis of 5-aminopyrazoles

Aggarwal

Kumar²,

Kumar³

et al. 2011

Beilstein J. Org. Chem.

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SummaryThe biological and medicinal properties of 5-aminopyrazoles have prompted enormous research aimed at developing synthetic routes to these heterocyles. This review focuses on the biological properties associated with this system. Various synthetic methods developed up to 2010 for these compounds are described, particularly those that involve the reactions of β-ketonitriles, malononitrile, alkylidenemalononitriles and their derivatives with hydrazines, as well as some novel miscellaneous methods.

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“…Biological studies of the pyrazole nucleus have been shown to posses a variety of biological activities such as fungicidal [1], insecticidal [2], herbicidal [3], and plant growth regulatory activities [4]. Furthermore, several biological studies have also pointed out the value of alkyloxyacetate [5] and aryloxyacetate [6] as biologically active groups.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, crystal structure, and fungicidal activity of novel 1,5‐diaryl‐1H‐pyrazol‐3‐oxyacetate derivatives

Liu

Shi

et al. 2010

Journal of Heterocyclic Chem

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A series of ethyl 2-(1,5-diaryl-1H-pyrazol-3-yloxy)acetate derivatives (5a-5i) have been efficiently synthesized by the reaction of 1,5-diaryl-1H-pyrazol-3-ols (4a-4i) with ethyl 2-bromoacetate. The structures of the newly synthesized compounds were characterized by 1 H NMR spectra and elemental analysis, and the crystal structure of the compound ethyl 2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yloxy)acetate (5c) was determined by single crystal X-ray diffraction analysis. The compound 5c belongs to triclinic system with space group P(-1), a

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Synthesis and GABA receptor potency of 3-thiomethyl-4-(hetero)aryl-5-amino-1-phenylpyrazoles

Cited by 32 publications

References 4 publications

Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

Approaches towards the synthesis of 5-aminopyrazoles

Synthesis, crystal structure, and fungicidal activity of novel 1,5‐diaryl‐1H‐pyrazol‐3‐oxyacetate derivatives

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