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-1phenyl-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 (K b ) between 8.00 × 10 4 and 5.00 × 10 5 M −1 for Series I compounds and between 6.60 × 10 4 and 1.45 × 10 5 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 K b . 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 Renantiomer to that of the S-enantiomer (ΔG R /ΔG S ) follows the same positive trend as the experimental K b 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.

Synthesis and Therapeutic Potential of selected Schiff Bases: In vitro Antibacterial, Antioxidant, Antidiabetic, and Computational Studies

“…Molecular docking is a computational tool described to enhance compound-protein binding interactions, a mimic of drug-target interactions with applications in drug design and the pharmaceutical industry. [64][65][66][67] A preliminary step to molecular docking is energy minimization, and the minimization energies of all compounds considered in this study with other molecular parameters are presented in Table 6.…”

The link between relative stability constant of DNA- and BSA-chromenopyrimidine complexes and cytotoxicity towards human breast cancer cells (MCF-7)

“…The 2-uorophenyl moiety is almost orthogonal in relation to the 4Hpyran ring which is comparable to that of 1a. 49 To better understand the inuence of the various anilinyl moieties on the regional molecular conformation of the chromenopyrimidines, we focused on the geometric parameters between the anilinyl and pyrimidinyl moieties. The selected geometric parameters in 3a to 3c, 3e, 3h and 3j are depicted in Fig.…”

“…The 4H-pyran-based 2-amino-3-carbonitriles (1a and 1b) and the uorinated 2-formimidate-3-carbonitrile intermediate (2a), were prepared according to literature. 49,50 The microwaveassisted reactions of 2a with corresponding anilines in an acetic acid medium resulted in the formation of chromenopyrimidines (Scheme 1). The reactions were monitored via TLC and the desired products were precipitated from their mother liquor by the addition of water and were isolated in vacuo in moderate to high yields.…”

“…52 The changes in the electronic absorption spectral features serve as evidence of the biomolecule's electronic environment perturbation due to biomolecule-small molecule interactions. Importantly, this technique has been used and continues to be used to determine test compound's binding affinity towards DNA [53][54][55] and BSA. 53,[56][57][58] Small-molecules are known to interact with DNA in either a covalent or non-covalent manner.…”

Silver(I) pyridinyl complexes with benzothiazole, thiophene, and furan moieties: DNA/protein‐binding, antibacterial, antioxidant, and anticancer studies

“…[39][40][41][42] T A B L E 3 Mean ± standard deviation values of in vitro antioxidant activities of L 1 -L shift. [43,44] To estimate the binding affinity of L 1 -L 3 and 1-9…”