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

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 ¹H 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.