Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists

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

“…32 Similar observations were made for sulfonyl derivatives with the ability to form strong intramolecular hydrogen bonds, stabilizing the geometry of two aromatic fragments. 4,9 To investigate the impact of the sulfonyl group on the conformational stability, selected N-arylsulfonyl indole/indazole derivatives, known 5-HT 6 R antagonists, were structurally studied. Bioisosteric replacement of the sulfonyl fragment was applied, including the methylene (tetrahedral conformation) and carbonyl (acceptor of the hydrogen bond) groups.…”

“…Attempts to replace this functional group with other fragments in most cases decreased the binding affinity to the receptor. 4,[8][9][10][11]30,31 Despite considering the HBA functionality of the sulfonyl group, its full impact on 5-HT 6 R ligand activity is still unclear.…”

Fingerprint-based consensus virtual screening towards structurally new 5-HT6R ligands

“…Though several reports have proven that the presence of a basic nitrogen atom enabling formation of the interaction of its protonated form and D3.32 is not indispensable for 5-HT 6 R anchoring [56][57][58][59][60] , the fraction of nonbasic compounds within known 5-HT 6 R ligands is low (~7% within the set of active compounds included in the training set). The majority of 5-HT 6 R ligands keep fitting the standard pharmacophore model, 61,62 which requires the possession of a positive ionizable group.…”

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

“…During this decade or so, there was a plenty of chemistry developed around different nuclei including the indole-based ones or even much simpler biphenyl sulfones and sulfonamides [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]34 ( Figure 2). Suven has reported several series of 1-sulfonylindoles bearing the amino group at 3 or 4 or 5 position of the central core [31][32][33] .…”