Structure-activity relationships studies on weakly basic N-arylsulfonylindoles with an antagonistic profile in the 5-HT6 receptor

• Published in: Journal of molecular structure Vol. 1139; pp. 362 - 370
• Main Authors: Mella, Jaime, Villegas, Francisco, Morales-Verdejo, César, Lagos, Carlos F., Recabarren-Gajardo, Gonzalo
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.07.2017
• Subjects: 3D-QSAR; 5HT6 receptor; Antagonists; CoMSIA; Indole; Obesity; Serotonin; Obesity; Serotonin; Indole; 3D-QSAR; Antagonists; 5HT6 receptor; CoMSIA
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2017.03.067

We recently reported a series of 39 weakly basic N-arylsulfonylindoles as novel 5-HT6 antagonists. Eight of the compounds exhibited moderate to high binding affinities, with 2-(4-(2-Methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol 16 showing the highest binding affinity (pKi = 7.87). Given these encouraging results and as a continuation of our research, we performed an extensive step-by-step search for the best 3D-QSAR model that allows us to rationally propose novel molecules with improved 5-HT6 affinity based on our previously reported series. A comparative molecular similarity indices analysis (CoMSIA) model built on a docking-based alignment was developed, wherein steric, electrostatic, hydrophobic and hydrogen bond properties are correlated with biological activity. The model was validated internally and externally (q2 = 0.721; r2pred = 0.938), and identified the sulfonyl and hydroxyl groups and the piperazine ring among the main regions of the molecules that can be modified to create new 5-HT6 antagonists. We construct a CoMSIA model on potent N-arylsulfonylindoles 5-HT6 antagonists based in a docking alignment. [Display omitted] •We construct a docking based CoMSIA on potent indoles 5-HT6 antagonists.•The model was internally and externally validated (q2 = 0.721 and r2 pred = 0.938).•The electrostatic property is more important for activity than the other fields.•The elimination of the sulfonyl and the insertion of bulky groups are proposed.