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

Abstract

Based on a known pharmacophore model for 5-HT 6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT 6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT 6 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 pK i = 7.87; 4g pK i = 7.73; 4j pK i = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC 50 = 32 nM) in calcium mobilisation functional assay.

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6receptor antagonists and beyond

“…22 The commonly recognized pharmacophore of the 5-HT 6 R antagonists consists of four key fragments: basic nitrogen atom (PI), hydrophobic core (H), aromatic ring(s) (Ar) and dual acceptor of hydrogen bonds (HBA). [23][24][25][26][27][28] In the pharmacophore model of the 5-HT 6 R antagonists, the sulfonyl fragment is usually considered as the strong hydrogen bond acceptor. [23][24][25]27,28 Based on docking study, it is postulated that it interacts with N6.55 and S5.…”

“…[23][24][25][26][27][28] In the pharmacophore model of the 5-HT 6 R antagonists, the sulfonyl fragment is usually considered as the strong hydrogen bond acceptor. [23][24][25]27,28 Based on docking study, it is postulated that it interacts with N6.55 and S5. 43 forming O-H/O and N-H/O bonds, 23,27,28 respectively.…”

1-[1-(4-Chlorobenzenesulfonyl)-1H-indole-3-yl]-3-[4-(pyridin-2-yl)piperazin-1-yl]propan-1-one

“…First, indole was formylated in C-3 employing the Vilsmeier-Haack synthesis, affording formylindole 1 in excellent yield [10]. Afterwards, N-sulfonylation in basic media gave N-(4-chlorobenzenesulfonyl)-3-formylindole 2 in good yield [8]. A nucleophilic attack on the formyl group with the commercially available Grignard reagent vinylmagnesium bromide led to secondary allylic alcohol 3, which was oxidized to the corresponding α,β-unsaturated ketone 4 employing MnO 2 /MgSO 4 [10].…”

“…In the context of our interest to produce highly active antagonists towards the 5-HT 6 receptor, 5 was tested in a standard radioligand competition binding assay, using membranes of HEK-293 cells expressing a recombinant human 5-HT 6 receptor, as previously described [8,12]. The product was assayed as a free base at eight concentrations, in triplicate, to obtain the dose-response curve, determine the IC 50 value and calculate the Ki through the Cheng-Prusoff equation [13].…”

“…A 5-HT 6 antagonist pharmacophore has been previously described in the literature [7]. In our efforts to prepare potent and highly selective antagonists targeting 5-HT 6 based on this reported pharmacophore [8,9], we performed the synthesis of the title compound 1-[1-(4-chlorobenzenesulfonyl)-1H-indole-3-yl]-3-[4-(pyridin-2-yl)piperazin-1-yl]propan-1-one and evaluated its affinity for the 5-HT 6 receptor in a standard binding assay.…”