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Open AccessArticle

Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation

1
Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile
2
Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago 8330074, Chile
3
Facultad de Ciencia, Universidad San Sebastián, Lota 2465, Providencia 7510157, Santiago, Chile
4
Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile
5
Departamento de Química-Física, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Jean Jacques Vanden Eynde
Molecules 2016, 21(8), 1070; https://doi.org/10.3390/molecules21081070
Received: 3 May 2016 / Revised: 6 August 2016 / Accepted: 8 August 2016 / Published: 16 August 2016
(This article belongs to the Section Medicinal Chemistry)
Based on a known pharmacophore model for 5-HT6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT6 receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay. View Full-Text
Keywords: arylsulfonylindole; 5-HT6 receptor antagonists; binding affinity; arylpiperazines arylsulfonylindole; 5-HT6 receptor antagonists; binding affinity; arylpiperazines
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MDPI and ACS Style

Vera, G.; Lagos, C.F.; Almendras, S.; Hebel, D.; Flores, F.; Valle-Corvalán, G.; Pessoa-Mahana, C.D.; Mella-Raipán, J.; Montecinos, R.; Recabarren-Gajardo, G. Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation. Molecules 2016, 21, 1070.

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