N-(2,7-dimethyl-2-alkyl-2H-chromen-6-yl)sulfonamide derivatives as selective serotonin 5-HT6 receptor antagonists: Design, synthesis, and biological evaluation

•The N-(2,7-dimethyl-2-alkyl-2H-chromen-6-yl)sulfonamide scaffold was designed according to the previously reported HipHop pharmacophore model for the 5-HT6 receptor antagonists.•N-(2,7-dimethyl-2-alkyl-2H-chromen-6-yl)sulfonamide-based library was prepared in five steps from 1-(2-hydroxy-5-nitrophenyl)ethan-1-ones.•According to biological studies, compound 6m was identified as the most active compound, with IC50 = 87 nM.•The binding affinity of 95.3% of 6m (10 μM) demonstrated high selectivity of 6m towards the 5-HT6 receptor compared with other serotonin and dopamine receptors.•Structure-activity relationship studies revealed that the methyl group at the R2 position and 2-naphthalene at the R3 position are crucial for the high binding affinity, while methylation at the C7 position can improve the IC50 values of compounds.