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

Abstract

The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C-H/O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.

Experimental and Theoretical Investigation of Hydrogen-Bonding Interactions in Cocrystals of Sulfaguanidine

“…Some work reported that the QTAIM analysis is not able to detect all expected weak noncovalent interactions, , which is also found in this work. As shown in Figure , SGD adopts conformation 1 in SGD·H 2 O, SGD-3NBA, SGD-PHE, SGD-PT, and SGD-TBA·2H 2 O, generating S(6) and S(5) rings.…”

Point-specific interactions of isovitexin with the neighboring amino acid residues of the hACE2 receptor as a targeted therapeutic agent in suppressing the SARS-CoV-2 influx mechanism

“…2A–C ; 3A ). The presence of such intramolecular interactions results in favorable protein–ligand orientation, leading to high binding affinity [ 42 ]. The high number of intramolecular interactions between the protein and ligand stabilizes the geometry of two interacting molecules [ 43 ].…”

“…It is believed to be a complex mechanism and is associated with symptoms such as ischemic stroke, pyramidal signs, hypo/anosmia, delirium, and impaired consciousness [ 6 ]. However, it should be noted that the neurological consequences of SARS-CoV-2 may be secondary to the manifestations of hypoxia and ARDS [ 7 ]. It has already been reported that hypoxia and ARDS can be the neurological disorders of COVID-19 progression [ 8 ].…”

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

“…Our data indicated that compounds containing unsubstituted phenylsulfonyl moiety are highly potent 5-HT6R ligands, whereas their benzyl analogs require substitution with a chlorine atom in the meta position. 35 To achieve inhibition of MAO-B activity, aryloxy fragments derived from rasagiline, safinamide and pargyline were linked to the 5-HT6R pharmacophore via different length alkylene linker. Although the molecular framework of the designed hybrids is different from that of classical MAO-B inhibitors (they are very long, with two basic centers and a flexible alkylene linker), the possibility of interaction with the catalytic domain of MAO-B was supported by in silico experiments.…”