Mella, JaimeJaimeMellaFrancisco VillegasCésar Morales-VerdejoCarlos F. LagosGonzalo Recabarren-Gajardo2025-12-072025-12-072017-03-2010.1016/j.molstruc.2017.03.0672-s2.0-85015797773https://cris-uv-2.scimago.es/handle/123456789/7238WOS:000400718500041We 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; r2 pred = 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.enacceso restringidoAnalytical ChemistryChemistry, PhysicalInorganic ChemistryOrganic ChemistrySpectroscopyarticle