Structural and theoretical exploration of a multi-methoxy chalcone: Synthesis, quantum theory, electrostatics, molecular packing, DFT analysis, and in-silico anti-cancer evaluation.

This study explores the pharmacological potential of chalcones through a multidisciplinary approach, including synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations. The synthesized compound, analyzed via single crystal X-ray diffraction, crystallized in the triclinic system (space group P-1) with C-H⋯O interactions stabilizing its structure. Hirshfeld surface analysis confirms these interactions, with H-H contacts dominating (45.1 %). Molecular electrostatics analysis reveals charge distribution, and a 3.10 eV HOMO-LUMO energy gap indicates bioactivity. Molecular docking identifies the compound (3a) showed a maximum Gscore of HTNF-α (-9.81 kcal/mol); Tubulin (-7.96 kcal/mol); COX2 (-7.88 kcal/mol), EGFR (-6.72 kcal/mol), and VEGFR1(-2.50 kcal/mol). Where compound (3c) showed maximum binding at the putative binding site with dock scores for VEGFR2 (-9.24 kcal/mol). This research not only advances molecular science but also holds promise for diverse applications, including drug design. The significance of this study lies in its comprehensive exploration of the pharmacological potential of chalcones using a multidisciplinary approach. Through the integration of synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations, we have extensively explored the structural and biochemical characteristics of these compounds. This investigation has revealed valuable insights that have the potential to lead to significant advancements in the fields of molecular science and drug design. Moreover, the molecular docking studies shed light on the compound's interaction with various biological targets. The significant binding affinities observed for these targets underscore the potential therapeutic relevance of the synthesized compound in diverse disease conditions.

Synthesis, crystal structure, Hirshfeld surface analysis, energy frameworks and computational studies of Schiff base derivative.

The compound (E)-ethyl 3-(2-(2,4-dinitrophenyl)hydrazono)butanoate (3) was synthesised and crystallized using ethanol as a solvent. The compound was characterized by 1H NMR, and single crystal X-ray diffraction. The compound crystallizes in the monoclinic crystal system with the space group P21/c. The intermolecular interactions and the interaction energies responsible for the stabilization of the molecules were determined by Hirshfeld surface analysis and energy framework calculations. The structure of the compound was optimized by Density Functional Theory calculations and HOMO-LUMO energy gap was calculated. The non-covalent interactions were revealed by reduced density gradient analysis. The Mulliken atomic charges and natural atomic charges were calculated by density functional theory calculations. The reactive sites present in the molecule are shown by molecular electrostatic potential map. The inter and intra molecular charge transfer were investigated by NBO analysis.

Synthesis, structural characterization, and DFT studies of anti-cancer drug N-(2-Aminophenyl)-2-(4-bromophenoxy)acetamide.

Drug design is an integrated and developing system that portends an era of a novel and safe tailored drugs. It involves studying the effects of biologically active synthetic, semi-synthetic, and natural compounds based on molecular interactions in terms of molecular structure with activated functional groups or its unique physicochemical properties involved. The title compound, N-(2-aminophenyl)-2-(4-bromophenoxy) acetamide (c), was synthesized in a good yield and characterized by different spectroscopic techniques (1H, 13CNMR, and LC-MS) and finally, the structure was confirmed by X-ray diffraction (XRD) studies. The XRD data confirms that the cryatal structure is orthorhombic with space group of Pca2 1 . The intermolecular interactions (N-H … O and N-H … Cg) inside the molecule stabilizes the crystal structure. The existence of this intermolecular interactions are computed by the Hirshfeld surfaces (HS) and two-dimensional (2D) fingerprints plot analysis. In addition to this, Energy frame work analysis is performed to quantify the interaction energies between the molecular pairs in a crystal by incorporating new version of CrystalExplorer17 using the energy model of HF/3-21G. Also to calculate the HOMO and LUMO energies, DFT calculations were carried out.

Synthesis, mol-ecular structure and Hirshfeld surface analysis of (4-meth-oxy-phen-yl)[2-(methyl-sulfan-yl)thio-phen-3-yl]methanone.

The title compound, C13H12O2S2, crystallizes in the triclinic space group P . The mol-ecular structure is substanti-ally twisted, with a dihedral angle of 43.70 (2)° between the 2-(methyl-sulfan-yl)thio-phene and 4-meth-oxy-phenyl rings. In the crystal, mol-ecules are linked through C-H⋯O inter-actions and form a bifurcated layer stacking along the b-axis direction and enclosing R 2 2(10) ring motifs. The phenyl rings are involved in π-π inter-actions with a centroid-centroid separation of 3.760 (2) Å. The Hirshfeld surfaces were studied and the contributions of the various inter-molecular inter-actions were qu-anti-fied.

Crystal structure of (E)-N-phenyl-N'-[1-(thio-phen-2-yl)ethyl-idene]formo-hydrazide.

In the title compound, C13H12N2OS, the planes of the thio-phene and phenyl rings are nearly perpendicular to each other, making a dihedral angle of 86.42 (12)°. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming a helical chain along the b-axis direction.

(4-Fluoro-phen-yl)(2-hy-droxy-5-methyl-phen-yl)methanone.

In the title compound, C14H11FO2, the dihedral angles beteen the central C3O ketone residue and the fluoro- and hy-droxy-substituted benzene rings are 50.44 (9) and 12.63 (10)°, respectively. The planes of the benzene rings subtend a dihedral angle of 58.88 (9)° and an intra-molecular O-H⋯O hydrogen bond closes an S(6) ring. No directional inter-actions beyond van der Waals packing contacts were identified in the crystal structure.

(4-Fluoro-phen-yl)(4-hy-droxy-3-methyl-phen-yl)methanone.

In the title compound, C14H11FO2, the two benzene rings are not coplanar, with a dihedral angle of 57.45 (12)° between their planes. In the crystal, mol-ecules are linked by an O-H⋯O hydrogen bond, forming a 21 helical chain along the b axis.

(4-Hy-droxy-3-methyl-phen-yl)(phen-yl)methanone.

In the title compound, C14H12O2, the benzene rings make a dihedral angle of 58.84 (12)°. In the crystal, mol-ecules are linked into chains along the b-axis direction by O-H⋯O hydrogen bonds. These chains are further linked by C-H⋯O hydrogen bonds, forming layers parallel to the bc plane.

(R)-2-Cyano-N-(1-phenyl-eth-yl)acetamide.

In the title compound, C11H12N2O, the dihedral angle between the acetamide group and the benzene ring is 68.7 (1)°. In the crystal, N-H⋯O and weak C-H⋯O hydrogen bonds link the mol-ecules into chains along the a-axis direction.

5-Bromo-2-chloro-pyrimidin-4-amine.

In the title compound, C4H3BrClN3, the pyrimidine ring is essentially planar (r.m.s. deviation from the plane = 0.087 Å). In the crystal, pairs of N-H⋯N hydrogen bonds connect the mol-ecules into inversion dimers; these are connected by further N-H⋯N hydrogen bonds into a two-dimensional framework parallel to the bc plane.

Ethyl 2-(quinolin-8-yl-oxy)acetate monohydrate.

In the title compound, C13H13NO3·H2O, the dihedral angle between the ethyl ester group [C-C-O-C(=O); maximum deviation = 0.003 (2) Å] and the quinoline ring system is 7.94 (12)°. The water solvent mol-ecule is linked to the title mol-ecule via O-H⋯O and O-H⋯N hydrogen bonds. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming chains propagating along [100].

(4-Hy-droxy-3,5-di-methyl-phen-yl)(phen-yl)methanone.

In the mol-ecule of the title compound, C15H14O2, the dihedral angle between the benzene and phenyl rings is 61.27 (8)°. In the crystal, O-H⋯O and weak C-H⋯O hydrogen bonds link the mol-ecules into chains extending along the c-axis direction.

N-(2-{[5-Bromo-2-(piperidin-1-yl)pyrimidin-4-yl]sulfan-yl}-4-meth-oxy-phen-yl)-4-methyl-benzene-sulfonamide.

In the title compound, C(23)H(25)BrN(4)O(3)S(2), the benzene rings bridged by the sulfonamide group are tilted relative to each other by 69.7 (1)° and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 70.4 (1)°. The mol-ecular conformation is stabilized by a weak intra-molecular π-π stacking inter-action between the pyrimidine and the 4-methyl benzene rings [centroid-centroid distance = 3.633 (2) Å]. The piperidine ring adopts a chair conformation. In the crystal, mol-ecules are linked into inversion dimers by pairs of N-H⋯O hydrogen bonds.

(E)-N'-[1-(Thio-phen-2-yl)ethyl-idene]isonicotinohydrazide.

In the title compound, C(12)H(11)N(3)OS, the dihedral angle between the pyridine and thio-phene rings is 46.70 (9)° and the C-N-N-C torsion angle is 178.61 (15)°. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R(2) (2)(8) loops.

N-(2-{[5-Bromo-2-(piperidin-1-yl)pyrimidin-4-yl]sulfan-yl}-4-meth-oxy-phen-yl)-2,4,6-trimethyl-benzene-sulfonamide.

In the title compound, C(25)H(29)BrN(4)O(3)S(2), the benzene rings bridged by the sulfonamide group are tilted relative to each other by 63.9 (1)° and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 64.9 (1)°. The mol-ecular conformation is stabilized by a weak intra-molecular π-π stacking inter-action between the pyrimidine and the 2,4,6-trimethyl-benzene rings [centroid-centroid distance = 3.766 (2) Å]. The piperidine ring adopts a chair conformation. In the crystal, mol-ecules are linked into inversion dimers by pairs of N-H⋯O hydrogen bonds and these dimers are further linked by C-H⋯O hydrogen bonds into chains propagating along [010].

N-(2-{[5-Bromo-2-(morpholin-4-yl)pyrimidin-4-yl]sulfan-yl}-4-meth-oxy-phen-yl)-4-chloro-benzene-sulfonamide.

In the title compound, C(21)H(20)BrClN(4)O(4)S(2), the benzene rings bridged by the sulfonamide group are tilted relative to each other by a dihedral angle of 70.2 (1)° and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 69.5 (1)°. The mol-ecular conformation is stabilized by a weak intra-molecular π-π stacking inter-action between the pyrimidine and the 4-chloro-benzene rings [centroid-centroid distance = 3.978 (2) Å]. The morpholine ring adopts a chair conformation. In the crystal, mol-ecules are linked into inversion dimers by pairs of C-H⋯N hydrogen bonds and these dimers are further connected by N-H⋯O hydrogen bonds, forming a tape along the a axis.

N-(2-{[5-Bromo-2-(morpholin-4-yl)pyrimidin-4-yl]sulfan-yl}-4-meth-oxy-phen-yl)-4-methyl-benzene-sulfonamide.

In the title compound, C(22)H(23)BrN(4)O(4)S(2), the benzene rings bridged by the sulfonamide group are tilted relative to each other by 68.9 (1)° and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 69.7 (1)°. The mol-ecular conformation is stabilized by a weak intra-molecular π-π stacking inter-action between the pyrimidine and the 4-methylbenzene rings [centroid-centroid distance = 3.934 (2) Å]. The morpholine ring adopts a chair conformation and is disordered over two positions with an occupancy ratio of 0.853 (6):0.147 (6). In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds into chains extending along the a axis and further, through C-H⋯N and C-H⋯O inter-actions, into a three-dimensional supramolecular structure.

N-[2-(5-Bromo-2-morpholin-4-ylpyrim-idin-4-ylsulfan-yl)-4-meth-oxy-phen-yl]-2,4,6-trimethyl-benzene-sulfonamide.

In the title compound, C(24)H(27)BrN(4)O(4)S(2), the mol-ecule is twisted at the sulfonyl S atom with a C-S(O(2))-N(H)-C torsion angle of 62.6 (3)°. The benzene rings bridged by the sulfonamide group are tilted to each other by a dihedral angle of 60.6 (1)°. The dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 62.7 (1)°. The morpholine ring adopts a chair conformation. The mol-ecular conformation is stabilized by a weak intra-molecular π-π stacking inter-action between the pyrimidine and the 2,4,6-trimethyl-benzene rings [centroid-centroid distance = 3.793 (2) Å]. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds into a chain along the b axis.

1H-Indole-3-carbaldehyde.

In the title compound, C(9)H(7)NO, the benzene ring forms a dihedral angle of 3.98 (12)° with the pyrrole ring. In the crystal, N-H⋯O hydrogen bonds links the mol-ecules into chains which run parallel to [02-1].

N-(2-{[5-Bromo-2-(piperidin-1-yl)pyrimidin-4-yl]sulfan-yl}-4-meth-oxy-phen-yl)benzene-sulfonamide.

The title compound, C(22)H(23)BrN(4)O(3)S(2), crystallizes with two mol-ecules, A and B, in the asymmetric unit. In one of these, the meth-oxy group is disordered over two sets of sites in a 0.565 (9):0.435 (9) ratio. The benzene rings bridged by the sulfonamide group are tilted relative to each other by 37.4 (1) and 56.1 (1)° in mol-ecules A and B, respectively, while the dihedral angles between the sulfur-bridged pyrimidine and benzene rings are 72.4 (1) and 70.2 (1)° for A and B, respectively. The piperidine ring adopts a chair conformation in both mol-ecules. In the crystal, inversion dimers linked by pairs of N-H⋯N hydrogen bonds occur for both A and B; the dimers are linked into [010] chains by C-H⋯O hydrogen bonds. The crystal structure also features inversion-generated aromatic π-π stacking inter-actions between the pyrimidine rings for both mol-ecules [centroid-centroid distances = 3.412 (2) (mol-ecule A) and 3.396 (2) Š(mol-ecule B)].