Classical Intermolecular Hydrogen Bonding Motifs of Heterocyclic rac-2-Amino-3-carbonitrile Derivatives: Linking Hirshfeld Surface Analysis, CT-DNA Binding Affinity, and Molecular Docking

Abstract

Four 2-amino-4-(aryl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (Series I) and three 2-amino-1-phenyl-7,7-dimethyl-5-oxo-4-(aryl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (Series II) derivatives were formed via multicomponent microwave reactions as racemic mixtures. The solid-state IR spectra revealed bands in the region between 3190 and 3414 cm–1 attributed to the amino functional group’s asymmetric, symmetric, and bending overtone vibration modes. Furthermore, the IR spectra of some of the compounds in each series were similar and this served as an indication of similar structural features in the solid state. This was confirmed via single-crystal X-ray diffraction. A detailed survey of the related 2-amino-3-carbonitrile derivatives in the Cambridge Structural Database revealed 12 classical intermolecular hydrogen-bonding motifs involving the amino functional group. The vast variation in the hydrogen bonding motifs was found to be caused by the type of group bonded to the 4H-pyran (in Series I) or dihydropyridine (in Series II) moiety. In this work, an unprecedented hydrogen bonding motif comprising a non-classical hydrogen bond acceptor was found in one instance. For both Series I and II, the N–H···N and N–H···O hydrogen bonds were investigated using noncovalent interaction (NCI) plots and molecular pairwise energy calculations. The contributions of reciprocal N···H and O···H contacts (attributed to N–H···N and N–H···O, respectively) toward the Hirshfeld surface range between 9.9 and 15.3% in Series I and between 10.8 and 15.0% in Series II. In addition, the compounds showed moderate to good binding affinity to calf thymus DNA (CT-DNA) with intrinsic binding constants (Kb) between 8.00 × 104 and 5.00 × 105 M–1 for Series I compounds and between 6.60 × 104 and 1.45 × 105 M–1 for Series II. A relationship was established between the reciprocal N···H to O···H contributions ratio from the Hirshfeld surface analysis and Kb. Molecular docking studies of each compound’s respective enantiomers into DNA were done using canonical–DNA dodecamer (B-DNA) as a model for CT-DNA. The compounds were found to interact with DNA via a minor groove-binding mode. The S-enantiomer for most of the compounds bound favorably compared to their respective R-enantiomers. The ratio of calculated ΔG for the DNA binding of the R-enantiomer to that of the S-enantiomer (ΔGR/ΔGS) follows the same positive trend as the experimental Kb value for each compound in Series I while a negative trend was observed for Series II. Finally, a relationship between the Hirshfeld surface analysis and calculated ΔG values was also established in this work.