When benzaldehyde, acetophenone, and thiourea are condensed in the presence of HCl, a compound, which is 4,5,8a-triphenylhexahydropyrimido[4,5-d]pyridine-2,7(1H,3H)-dithione (THPD) is derived (Barbero et al., A Br & oslash;nsted acid catalysed enantioselective Biginelli reaction. Green Chem. 2017;19:1529-1535. doi:). The structure of the compound synthesized was confirmed by using the single crystal X-ray diffraction technique, which showed that the asymmetric unit consisted of two crystallographically independent molecules with the core being a fused hexahydropyrimido[4,5-d]pyrimidine. The hydrogen bonding and aromatic ring interactions to support crystal packing were investigated by Hirshfeld surface analysis. The electronic structure and charge-transfer properties of the title compound were investigated using density functional theory (DFT) calculations to complement the experimental crystal structure. The results of single-crystal X-ray and optimized geometrical parameters are satisfactory and support each other. The frontier molecular orbital analysis reveals a moderate HOMO-LUMO energy gap, indicating balanced charge-transfer capability and chemical stability. Natural bond orbital investigations and molecular electrostatic potential studies underline strong intramolecular N-S-C conjugation and donor-acceptor nature, which is consistent with the solid-state packing nature, as reported. Molecular docking studies against human DNA topoisomerase II alpha revealed moderate binding affinity and favorable interactions within the protein-DNA binding region.

The reaction of 2-aminopyridine with mercaptoacetic acid was carried out in a benzene solution at a molar ratio of the initial components of 1:1. The thiylated reaction of p-bromoacetophenone with mercaptoacetic acid was carried out in a benzene solution, with a molar ratio of the initial components of 1:4. As a result, new compounds were obtained: 2-aminopyridin-1-ium-2,2 '-disulfanediyldiacetate (ASA) and 1,1-bis-(carboxymethylthio)-1-p-bromophenylethane (BSA). The structure of the newly synthesized compounds was confirmed by using single crystal XRD technique. The structure of ASA is a salt in which there exist two cations and one dianion in the asymmetric unit. The cations and dianions are interlinked by N-H & sdot;& sdot;& sdot;O and C-H & sdot;& sdot;& sdot;O bonding and further stabilization of the crystal packing is due to weak pi & sdot;& sdot;& sdot;pi and C-O & sdot;& sdot;& sdot;pi interactions. In second compound BSA, molecules are interlinked in the form of dimers through O-H & sdot;& sdot;& sdot;O bonding to complete two R22(8) loops and consecutive dimers are connected by C-H & sdot;& sdot;& sdot;Br bonding. Hirshfeld surface analysis is carried out for the exploration of the molecular interactions in terms of interatomic contacts. The theoretical investigation of two related organic compounds, ASA and BSA, using density functional theory (DFT) and related computational tools to evaluate their structural, electronic, and intermolecular interaction properties. Optimized geometries, frontier molecular orbitals (HOMO-LUMO), electrostatic potential (ESP) maps, and dipole moments were obtained using the B3LYP/6-311+G(d,p) level of theory. The analysis of electron localization function (ELF), reduced density gradient (RDG), and topological parameters (via QTAIM) provided insights into electron density distribution, hydrogen bonding, and interaction strengths within the molecules. Hirshfeld surface analysis was performed using Crystal Explorer to explore intermolecular interactions and visualize contact contributions in the crystal state. The findings suggest that ASA, with its higher dipole moment, lower energy gap, and stronger electrophilic nature, exhibits superior potential as a corrosion inhibitor compared to BSA.

Biologically active ketohydrazone derivative named as 2-(2-(4-fluorphenyl)hydrazono)-1,3-diphenylpropane-1,3-dione was synthesized based on the reaction of 1,3-diphenyl-1,3-propanedione with p-fluoroaniline. The crystal structure was determined via single crystal XRD which showed that the benzoyl groups of the structure are inclined at 84.8 (1)(degrees) relative to each other and the supramolecular assembly is stabilized by N-H & sdot;& sdot;& sdot;O, C-H & sdot;& sdot;& sdot;O, C-H & sdot;& sdot;& sdot;pi and pi & sdot;& sdot;& sdot;pi interactions. Hirshfeld surface analysis was performed for the further exploration of the intermolecular interactions in terms of interatomic contacts. The dispersion interactions make a substantial impact on the total interaction energy of fragments during crystal packing. The geometric properties of the compound are similar to the experimental findings. The bonding nature and electronic charge transport properties have been investigated using the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. The pi ->pi(& lowast;) and n ->pi(& lowast;) are observed as the most common orbital interactions in the present compound with notable stabilization energy. The molecular electrostatic potential (MESP) study, along with the density of states analysis, further reveals the reactive sites and electronic structure. Furthermore, ab-initio molecular dynamics simulations were considered to monitor the thermodynamic stability and conformation analysis at 300 K

The reaction of 1,1-bis-(carboxymethylthio)-1-phenylethane with piperidine was conducted in an acetone solution at a molar ratio of the initial components of 1:2. As a result, a new compound was obtained: piperidinium-1,1-bis-(carboxymethylthio)-1-phenylethane, characterized by FT-IR. The crystal structure of the synthesized compound is structurally elucidated via single crystal XRD technique, indicating that a H-atom is transferred from half of the piperidinium-1,1-bis-(carboxymethylthio)-1-phenylethane part to the piperidine ring and the structure is a salt in nature. N-H & ctdot;O and C-H & ctdot;O bondings contribute to the stability and enforcement of crystal packing; further assessment is supported via Hirshfeld surface analysis, considering interatomic contacts. We employed density functional theory (DFT)-based computations along with molecular dynamics (MD) simulations in a systematic manner, aiming for the investigation of the stabilizing interactions and electronic characteristics of the molecular ionic compound. The structural framework is notably stabilized by dual N-H & centerdot;& centerdot;& centerdot;O hydrogen bonding, originating from piperidine rings positioned on either side of the central fragment. Electronic structure analysis revealed intermolecular charge transfer characteristics through HOMO-LUMO orbital distributions, complemented by TD-DFT studies of excited state behavior. Furthermore, ab initio MD simulations at 300 K conclusively demonstrated the ionic compound's robust kinetic and dynamic stability.

Hexahydroquinoline is a favored scaffold in medicinal chemistry. However, the precise structural and electronic properties of its derivatives remain underexplored. Herein, we synthesized a novel hexahydroquinoline derivative, methyl 2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (I), characterized its structural and electronic properties and assessed its potential biological activity. Compound I was formed via the multicomponent reaction of 4-nitrobenzaldehyde, dimedone, methyl acetoacetate and ammonium acetate and its structure was unambiguously confirmed by X-ray crystallography and density functional theory (DFT) calculations. Hirshfeld surface, energy framework and quantum theory of atoms in molecules (QTAIM) analyses revealed dominant polarization effects in crystal packing, with intramolecular C-H & ctdot;O interactions (strength: -2.6 to -4.9 kJ/mol) playing a crucial role in stabilizing the structure. Crystal void analysis indicated the presence of complex or irregular void shapes, which may reduce the mechanical strength of the molecular crystal. Molecular docking predicted a strong binding affinity for cytochrome P450 2J2 (-8.0 kcal/mol), suggesting the potential of I as a molecular probe for steroidogenesis regulation. In silico investigation of the drug-likeness and pharmacokinetic properties of I demonstrated its excellent absorption, moderate lipophilicity and low risk of cytochrome P450 polymorphism. This study provides a comprehensive strategy from synthesis to computational validation for the development of hexahydroquinoline-based therapeutics.

We carried out a thiylating reaction of p-nitroacetophenone with thioglycolic acid. The reaction was carried out in a benzene solution, with a molar ratio of the initial components of 1:4. 1,1-bis-(carboxymethylthio)-1-p-nitrophenylethane (CTNE). Structural features are evaluated via Fourier transform infrared (FT-IR) spectroscopy, 1H NMR and single crystal X-ray diffraction (XRD) analysis. Structure is composed of an organosulfur molecule and a water molecule. Organosulfur molecule adopted non-planar conformation supported via dihedral angle of 71.3 (4)° among carboxylic acid groups. Supramolecular organization is primarily supported via O-H⋯O bonding. Further stability of the supramolecular organization is due to π⋯π interactions with inter-centroid separation range from 3.85 to 4.01 Å. Strong and weaker interactions are evaluated via Hirshfeld surface analysis which showed that H⋯O contact has highest contribution in stability of the supramolecular organization. DFT calculations at the B3PW91/6-311 + + g (2d,2p) level was employed to optimize the molecular geometry and assess the electronic properties of the synthesized compound. Highest Occupied Molecular Orbital (HOMO)– Lowest Unoccupied Molecular Orbital (LUMO) energy gap (∆E = 4.06 eV) of the synthesized compound indicates enhanced chemical reactivity and biological potential compared to precursor molecules. Furthermore, molecular docking studies demonstrated a promising binding affinity (-7.05 kcal/mol) toward VEGFR2, stabilized through hydrogen bonding and hydrophobic interactions, suggesting potential anticancer activity through angiogenesis inhibition.

We studied the three-component condensation of 2-chloraldehyde, acetophenone, and thiourea in conjunction with HCl, resulting in the formation of a new compound: 4,5-bis(2-chlorophenyl)-8a-phenylhexahydropyrimido [4,5-d]pyrimidine-2,7(1H,3H)-dithione (CPPD). The compound's structure was affirmed via X-ray diffraction study. The asymmetric unit contained two molecules that were independent relative to crystallography and an ethanol solvent. The difference between independent molecules was explored by dihedral angles between similar rings in both molecular. The difference between molecules was further explored by molecular overlay plot. The supramolecular assembly was supported via diverse intermolecular interactions which were studied through the use of Hirshfeld surface analysis. Electronic structure computations were carried out at the omega b97xd/tzvp level. Natural bonding orbital (NBO), and FMO study reveal reactivity and charge transfer mechanisms within the compound. Furthermore, the nature of bonding in the present molecule is characterized through quantum theory of atoms in molecules (QTAIM), ELF, and LOL studies. Ab-initio molecular dynamic (AIMD) revealed the kinetic and thermodynamic stability at 300 K. The DFT results have excellent correlation with experimental data. The molecular docking and molecular dynamics simulation further revealed the compound to get deep access in the active pocket of type 2 anti-diabetes GLUT4 protein. This was validated by the stable dynamics as demonstrated by the uniform behavior of the root mean square deviation (RMSD) plot. The root mean square fluctuation (RMSF) also showed stable interactions with amino acids in the presence of the compound. Further, simulation trajectories on the basis of binding free energies indicate the significant role of van der Waals force in the formation of the intermolecular docked complex. This concluded the compound might be a potent structure for the development of anti-diabetic compounds.

The tricyclic 1,4-benzodiazepines - seven-membered heterocyclic compounds were synthesized derived from the three-component reaction involving o-phenylenediamine, 5,5-dimethyl-1,3-cyclohexanedione and various aromatic aldehydes under the influence of HCl. The crystal structure of 11-(3-nitrophenyl)-3,3-dimethyl2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (NDDD) and 11-(2-chlorophenyl)-3,3-dimethyl2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (CDDD) corroborated through single crystal X-ray diffraction method. The Hirshfeld surface analysis indicates crystal packing along with role of intermolecular forces in stabilizing supramolecular assembly of NDDD and CDDD. 2D fingerprint analysis is carried out to envisage to the elemental interactions in the assumption of a single crystal containing molecular fragments. DFT investigations have been carried out to understand the reactivity of NDDD and CDDD at the m062x/def2tzvp method. The obtained geometric parameters from theoretical study are well consistent with experimentally reported XRD analysis. Bonding analysis and charge transfer were examined by performing quantum theory of atoms in molecules (QTAIM) and natural bonding orbital (NBO) analysis. The synthesized NDDD and CDDD exhibit excellent electronic and nonlinear optical properties. The NLO response is justified through computed hyperpolarizability values.

In order to study the structure-activity relationship of xanthene compound, hexahydro xanthene derivative was synthesized and characterized by single crystal X-rays diffraction. The molecular geometry was described in terms of dihedral angles between various rings present in structure. The stability of the supramolecular assembly was reinforced by multiple intermolecular interactions, which were inspected comprehensively via Hirshfeld surface analysis. DFT study revealed the excellent electronic properties and reactivity of synthesized compound. FMO is employed to uncover the orbitals energies and charge transfer within compound. The contribution of van der Waals forces is minor, while covalent nature of bonding is evidenced by the quantum theory of atoms in molecules (QTAIM) study. The electron transition from nonbonding orbitals (LP) to antibonding (LP*) are most prominent donor-acceptor interactions with significant stabilization energy. Ab-initio molecular dynamics reveals the kinetic and thermodynamic stability of present compound at room temperature. The excellent nonlinear optical properties and reactivity is revealed by its remarkable hyperpolarizability value.

The condensation reaction of p-dimethylaminobenzaldehyde with o-phenylenediamine under the gaze of CCl3COOH results in the synthesis of 2-(4-(dimethylamino)phenyl)- 1H-benzo[d]imidazole-3-ium chloride (DBIC) crystalline salt. The X-ray diffraction method confirms that DBIC is crystallized in monoclinic crystal system with space group P21/n and chemical formula 2(C15H16N3)+0 & sdot;2(Cl)-& sdot;H2O. XRD showed that DBIC is a salt with asymmetric unit composed of two cations, two anions and a water molecule. Difference between the orientation of two cations concerning each other is explored by molecular overlay plot. N-H & ctdot;O, N-H & ctdot;Cl, OH & ctdot;Cl, C-H & ctdot;Cl, C-H & ctdot;pi, pi & ctdot;pi intermolecular interactions stabilize the solid-state assembly which are explored via Hirshfeld surface analysis. The H & ctdot;H and H & ctdot;Cl are the most dominating elemental contacts within the crystal structure. DFT study reveals the superb electronic structures and reactivity of DBIC. The presence of noncovalent interactions between Cl-atom and H-atoms of cationic moiety can impart excellent NLO features in our complex. The molecular electrostatic potential and electron localizing function predicts the surface reactivity and bonding electrons in complex. The optical and nonlinear optical properties were anticipated through hyperpolarizability response.

The present study investigates non-covalent interactions of a hydrazine-imino-oxo hybrid Allyl 3‑oxo-2-(2-phenylhydrazone) butanoate (AOPB). The supramolecular assembly of AOPB is stabilized through various intermolecular contacts which are explored Hirshfeld surface analysis. The DFT computations conducted on AOPB provided evidence of its excellent stability, as manifested through the optimized molecular structure, the energy gap between the highest molecular orbital and lowest molecular orbital, as well as the interactions between molecules. The NBO analysis further validated the role of lone pair, bonding, and anti-bonding orbitals in mediating these interactions. DFT calculations inferred that AOPB possesses a high level of stability. These outcomes designate that AOPB is a potential candidate for further advancement as a potent inhibitor of Tyrosyl-DNA phosphodiesterase 1 DNA binding protein. In addition to that structural activity relationship studies are performed and based on that hit target Tyrosyl-DNA phosphodiesterase 1 DNA binding protein is taken for further molecular docking and molecular dynamics analysis.

The diazotization reaction of o-trifluoromethyl aniline from aromatic amines with 5,5-dimethylcyclohexane-1,3-dione was studied, as a result, 2-(2-(o-trifluoromethylphenyl)hydrazono)-5,5-dimethylcyclohexane-1 ,3-dione (THDCD) was synthesized and its structure was confirmed by X-ray diffraction analysis. The solid state assembly is stabilized by numerous intermolecular interactions which are deeply probed by Hirshfeld surface analysis. The enrichment ratio was computed for getting the contact with the highest propensity to form crystal packing interaction. The mechanical response of the crystal is predicted by voids analysis. Moreover, interaction energy calculations were performed at HF/3-21G electron density model to further inspect the supramolecular assembly of the crystal. DFT calculation was conducted using B3LYP level with 6–311++G(d, p) basic set with the help of Gaussian 09W and GaussView 6.0 packages. MEP surface, HOMO-LUMO orbitals, and NBO theory were analyzed via DFT approach. Theoretical method confirms the proposed geometry of THDCD by X-ray analysis.

The reaction of p-methylbenzaldehyde and 5,5-dimethyl-1,3-cyclohexanedione with the addition of HCl yielded 3,3,6,6-tetramethyl-9-(p-tolyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (TTHD). X-ray diffraction method was used for verification of the crystal structure. Supramolecular assembly was studied via various intermolecular interactions and explored via Hirshfeld surface analysis. The contact-making ability of the pairs of atoms is determined by enrichment ratios. The stability of the present compound is determined through interaction energies. Electronic structure calculations are conducted at the wb97xd/def2tzvp theoretical level. Charge transfer and reactivity are estimated through natural bonding orbital (NBO) charge analysis. Global reactivity parameters are calculated and compared with the reported molecule. Quantum theory of atoms in molecules (QTAIM) is exploited to unveil the bonding's nature and van der Waals interactions (vdW). Electron localizing function (ELF), and localized orbital locator (LOL) are also employed to investigate electronic properties. The optical and nonlinear optical (NLO) properties of the present compound are examined using the density functional theory (DFT) method.

It has been established that three-component condensation of benzaldehyde, acetone and urea catalyzed H2SO4 leads to the formation of spirobi[hexahidropyrimidine]-dione derivatives. The structure of the synthesized compound has been proved by X-ray method. The results of the quantum theory of atom-in-molecule and noncovalent interaction index analysis showed no intramolecular hydrogen bonds in the molecule studied. However, it contains four N-H bonds and two C--O groups. Based on the result of the DFT-NBO analysis, it was the lone pairs of oxygen on the C--O group which are forming strong orbital interactions with the antibonding orbital of the C-N single bond. The molecular docking was performed to investigate potential binding interactions of the compound with four target proteins including 5I4T (HIV-1), 5R7Z, 6M71 and 6VYB (SARS-Cov2). Additionally, in-silico drug-likeness and ADME studies suggested oral activity (violations <= 1) of scaffold and predicted to be actively effluxed by P-gp (PGP+).

The title compound, C30H34F2N6O2·2.5H2O, was obtained by condensation of 2-[2-(4-fluorophenyl)hydrazono]-5,5-dimethylcyclohexan-1,3-dione with ethylenediamine in ethanol and crystallized as a 1:2.5 hydrate in space group C2/c. The two independent molecules, with approximate crystallographic C2 symmetries, have different conformations and packing environments, are stabilized by intramolecular N—H...N hydrogen bonds and linked by O—H...O hydrogen bonds involving the water molecules. A Hirshfeld surface analysis showed that H...H contacts make by far the largest (48–50%) contribution to the crystal packing. From DFT calculations, the LUMO–HOMO energy gap of the molecule is 0.827 eV.

The multicomponent reaction of 4-nitrobenzaldehyde with acetophenone and urea in the presence of HCl was investigated, and, as a result, 4,5-bis(4-nitrophenyl)-8a-phenyl-decahydro-[1,3]diazino[4,5-d]pyrimidine-2,7-dione was synthesized. The structure of the synthesized compound was confirmed by the X-ray method. We performed Hirshfeld surfaces (HS) analysis and two-dimensional (2D) fingerprint plots for the studied compound to obtain surface reactivity and intermolecular interactions. The H∙∙∙H interactions were found to be higher, up to 32.2%, while the percentage C∙∙∙O contact was found to be the lowest among the reported interactions for single crystal packing. The energy framework analysis shows the strength of interaction energy within fragments of a single crystal at 3.08 A distances. The DFT study shows structural reactivity and a reduced HOMO-LUMO gap up to 4.0 eV. The NPA study reveals the reactivity and excellent charge transfer within the structure. The TD-DFT study reveals the absorbance in the UV region and excited state parameters during crucial transitions (transitions with maximum oscillator strength). The investigated compound shows excellent optical and nonlinear optical (NLO) properties, as indicated by its polarizability (αo) and hyperpolarizability (βo) values.

In the present paper, several computational binding analyses were performed on ethyl 3,3,5,5-tetracyano-2-hydroxy-2-methyl-4,6-diphenylcyclohexane-1-carboxylate which was newly synthesized by three-component condensation of benzaldehyde with ethyl acetoacetate and malononitrile in the presence of trichloroacetic acid, and the structure was finally proved by X-ray analysis. The visualization of molecular interaction was carried out through Hirshfeld surface analysis and ESP. The atomic charges, HOMO, LUMO, and electrostatic potential were also studied to explore the insight of the molecule deeper, and then, natural bonding orbitals (NBO) and non-linear optical properties (NLO) were calculated to reveal the interactions that happen to be between the filled and vacant orbitals. Afterwards, molecular docking studies predicted the compound binding mode fits in the minor groove of DNA and remained interacts via stable bonding as validated by molecular dynamics simulations. The binding energy estimation also affirmed domination van der Waals and electrostatic energies. Lastly, the compound was found as good drug-like molecule and had good pharmacokinetic profile with exception of toxic moieties.

It has been found that CF3COOH catalyzes the Knoevenagel condensation reaction of 5-bromo-2-hydroxybenzaldehyde and ethyl cyanoacetate. Consequently, the 6-bromo-2-oxo-2H-chromene-3-carbonitrile (BOCC) compound has been synthesized. The structure was proved by single crystal X-rays diffraction analysis. The asymmetric unit contained two identical molecules A and B which are different with respect to crystallography. The crystal packing is mainly stabilized by C–H⋯N and C–H⋯O bonding which is further stabilized by C–N⋯π and off-set π⋯π stacking interactions. Hirshfeld surface analysis is employed for the further exploration of the intermolecular interactions. Enrichment ratio is computed for the interatomic contacts to find the tendency of the contacts to form the crystal packing interactions. The void analysis is performed to predict the mechanical behaviour. Furthermore, the computational study is performed for finding the interaction energy between molecular pair by using B3LYP/6-31G(d,p) electron density model. The study inferred the role of various types of interaction energies in stabilizing the molecular pair.

The title compound was obtained by the condensation of ethylenediamine and (5E,5E,6Z,6Z)-6,6-[ethane-1,2-diylbis(azanylylidene)]bis{5-[2-(4-fluorophenyl)hydrazono)-3,3-dimethylcyclohexanone} in ethanol and crystallized as a 1:2.5 hydrate containing two different conformers stabilized by intramolecular N—H⋯N and linked by O—H⋯O (involving the water molecules) hydrogen bonds.