Melatonin pharmacophoric motifs in the anancomeric spiranic oxindole-cycloalkane scaffold: Theoretical and 1H NMR conformational analysis

Abstract

N -[2′-oxospiro(cycloalkane-1,3′-indoline)methyl]acetamides ( 1a/b - 4a/b ), analogues conformationally restricted of neurohormone melatonin (MLT), were constructed through pharmacophoric ethylacetamido side chain incorporation into a chiral spiro-ring structure. A facile synthetic route was established to afford the epimeric spirocycloalkane pairs a / b starting from substituted spirocycloalkane nitriles through catalytic hydrogenation in acetic anhydride medium. The conformational profiles of the methylamido side chain were explored by computational methods. The main conformational features represent a balance between geometric restrictions imposed by the spiro-ring structure and the relative configuration of the corresponding stereocenters. The anancomeric structure of the spiranic oxindole-cycloalkane scaffold and the orientation of the amido side chain is discussed considering complete 750 MHz 1 H NMR data by applying an iterative full spin analysis (HiFSA), conformational analysis, and single crystal X-ray diffraction. The effect of the conformational restriction, ring size, and stereochemistry on melatoninergic agonist activity was analyzed in terms of pharmacophore-based virtual screening. • The anancomeric character of cycloalkane derivatives was analyzed through computational and experimental investigation. • The conformational NMR descriptions in solution were consistent with data derived from X-ray and molecular modeling. • The effect of conformational restriction, ring size, and stereochemistry on melatoninergic agonist activity was analyzed.