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In the present report, we describe the synthesis of the amide derivative, N-(2,4-dichlorophenyl)-1-naphthamide, 3, via a facile chemical route. The title compound was isolated in 86% yield. The structure of compound 3 was established using spectroscopic methods and X-ray crystallography. In the crystal structure of 3, supramolecular assembly is dominated by classical N–H⋯O hydrogen bonding and C–Cl … π halogen bonding interactions which were examined in detail using several theoretical methods and DFT calculations. The optimized geometric parameters of compound 3 were calculated using density functional theory (DFT/B3LYP and DFT/M06-2X) quantum chemical methods with the 6-311++G(d,p) basis set using the crystallographic coordinates. Additionally, fragments contributing to the HOMO and LUMO molecular orbitals were investigated at the same level of theory. The nature and various types of intermolecular interactions in the crystal structure were also realized by Hirshfeld surface analysis. The biological properties such as anti-Alzheimer's potential were also assessed which reveals strong acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory effects. Compound 3 was 16-fold more active inhibitor of acetylcholinesterase compared to neostigmine with an IC50 value of 1.044 ± 0.76 μM in addition to 21-fold strong inhibition against butyrylcholinesterase. The in vitro bioactivity results were further strengthened by the molecular docking analysis revealing the presence of several important interactions with the active site residues from cholinesterase (AChE & BChE) enzymes.

The present study examines the significance of various non-covalent interactions in the supramolecular assembly of (E)-1-(1-(4-nitrophenyl)ethylidene)-2-phenylhydrazine 1c and (E)-3‑bromo-N'-(1-phenylethylidene)benzohydrazide 2d. The synthesized compounds were fully characterized by spectroscopic methods and single crystal X-ray diffraction analysis. The topology of the supramolecular assemblies was controlled by various non-covalent interactions including classical hydrogen bonding, C H…π and Br…Br interactions which were examined in detail using several theoretical methods and DFT calculations. The optimized geometric parameters of compounds 1c and 2d were calculated using density functional theory (DFT/B3LYP) quantum chemical method with the 6–311++G(d,p) basis set using the crystallographic coordinates. Additionally, fragments contributing to the HOMO and LUMO molecular orbitals were investigated at the same level of theory. The nature and various types of intermolecular interactions in the crystal structures was also investigated by Hirshfeld surface analysis. The synthesized Schiff bases were also studied for their potential as drugs and physicochemical properties. Bioevaluation against four cancer cell lines (NCI-H460, NCI-H460/Bcl-2, MDA-MB-231 and MCF-7) showed that compound 1c was a more potent inducer of toxicity compared to 2d. The putative binding modes of the bioactive Schiff bases were investigated using molecular docking tools and the results revealed that both the inhibitors were stabilized in the active pocket of the enzyme via the formation of various interactions with the key amino acid residues.

Two new 3-aryl-5-(4-nitrobenzylidene)-2-thioxothiazolidin-4-one derivatives ( 1 & 2 ) were synthesized by the Knoevenagel condensation reaction of 3-(4-aryl)-2-thioxo-1,3-thiazolidin-4-ones with 4-nitrobenzaldehyde. Both products were isolated as orange crystalline solids in good yields and were fully characterized by analytical, spectroscopic and structural methods. The interesting supramolecular assemblies of the title compounds observed in the solid state were analyzed by Density Functional Theory (DFT) calculations (M06-2X/def2-TZVP), Molecular Electrostatic Potential (MEP) surfaces and characterized by means of the Bader's theory of “atoms-in-molecules” (AIM) and NCIplot. The computation of the energy features of the diverse noncovalent interactions including C H⋯π, π⋯π and lp⋯π-hole interactions revealed their conspicuous role in the stabilization of the three-dimensional supramolecular frameworks for both compounds in addition to the C H⋯O/S H-bonding interactions.

Tetrazoles are nitrogen rich heterocycles with a broad spectrum of medicinal properties and potential for use as drugs. A significant number of FDA approved drugs incorporate the tetrazole moiety indicating the versatile pharmaceutical potential associated with this heteroaromatic skeleton. Owing to the higher number of nitrogen atoms and σ-lone pairs, tetrazoles offer the opportunity to control structural topology through non-covalent interactions. In this perspective, the present research is focused on the investigation of various non-covalent interactions in a series of tetrazole derivatives (5a–c) incorporating a linear aliphatic chain (eight to fifteen carbon atoms) at N-2 and with a phenol moiety at the only carbon atom of the tetrazole ring. The detailed X-ray crystallographic investigations revealed the formation of various supramolecular architectures employing non-covalent interactions of a diverse nature. Further insights into these intermolecular interactions were obtained using Hirshfeld surface analysis and DFT calculations focusing on the H-bonds, C–H…π and π–π interactions in the structures. These contacts have been characterized by combining the quantum theory of “atoms-in-molecules” (QTAIM) with the non-covalent interaction index (NCIplot).

Halogenated and non-halogenated N-(4-phenyl-3-aroyl-2(3H)-ylidene) substituted acetamides were prepared by base-catalyzed cyclization of corresponding acetyl thioureas with phenacyl bromide. The synthesized compounds were structurally characterized by 1H NMR and 13C NMR spectroscopy and were screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme inhibition activities. Molecular docking studies, drug-like profiling and kinetic analysis were performed to further investigate the inhibition mechanism of the compounds. This study provided useful insights into the design and development of novel dual inhibitors, in addition to understanding the mechanism by which such drugs interact with targets and exert their biochemical action. All the compounds showed superior inhibition profile compared to the standards possessing sub-micromolar and micromolar IC50 values for AChE and BChE, respectively. Docking simulations revealed that the compound 6g showed strong binding inside the active site gorges of both AChE and BChE. An excellent agreement was obtained as the best docked poses showed important binding features mostly based on interactions due to aromatic moieties and oxygen atoms of the compound. Cation-pi/pi-pi interactions together with hydrogen bond forces were the key players responsible for ligand anchoring in the active sites. The striking results accomplished both in docking computations and experimental findings ascertained that the compound 6g can serve as a scaffold for both AChE and BChE inhibition.