5-Acetyl-4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile has been successfully prepared by the condensation between the acetylacetone and 2-cyano-3-(4'-methoxyphenyl)thio acrylamide and used to search for a potential drug that could be used to treat COVID-19. The structure was characterized and confirmed by X-ray diffraction analysis, and the crystal packing stability was also performed by the Hirshfeld surface analysis. The chemical reactivity and other properties of the title compound were determined using the density functional theory (DFT) computation and the NBO analysis. Also, the molecular electrostatic potential (MEP) surface was investigated. The CN group was the most nucleophilic site in the entire molecule based on the results. The title compound’s in-silico molecular docking revealed a strong binding potential. Eventually, molecular dynamic (MD) simulation studies are conducted to examine the stability of the molecule inside the receptor cavity. The findings of the in-silico analysis manifested affirmative evidence for the title molecule with good binding, as a potent inhibitor for the main protease of SARS-Cov-2. Hence, it holds the striking potential to serve as a prospective lead compound for designing efficacious drugs against COVID-19.

Ethyl-5,8-dimethyl-6-phenyl-(1H-pyrrol-1-yl)-6,7-dihydrothieno[2,3-c]isoquinoline-2-carboxylate has been synthesized and single-crystal X-ray diffraction at 170 K and DFT calculations were performed to characterize the reactivity and its electronic structure. The asymmetric unit of the title molecule, C₂₆H₂₄N₂O₂S, contains two independent molecules differing primarily in the rotational orientations of the pyrrolyl substituent. The two independent molecules are connected by a C—H···O hydrogen bond and in the crystal, two asymmetric units are linked by inversion-related C—H···N hydrogen bonds. The Hirshfeld surface (HS) analysis reveals intermolecular interactions and surface reactivity in a single crystal. The highest fraction of intermolecular contact of 64% can be seen for H⋅⋅⋅H while the lowest contribution of 3.9% was observed for O⋅⋅⋅H contact in crystal packing. The interaction energies between chemical pairs in the crystal structure are investigated by energy framework analysis which indicates repulsion outweighs the coulomb energy and dispersion energy. The performed density functional theory (DFT) investigation has provided us an electronic picture the of structure and fabulous reactivity. The frontier molecular orbital (FMO) analysis reveals a narrow HOMO-LUMO gap (3.81 eV) and global reactivity descriptors also agree with molecular reactivity and remarkable electronic properties. The density of state (DOS) study shows a pictorial representation the of density of states while MESP shows reactive sites (electron-rich) of the compound for electrophilic attack.

The present study elaborates on the synthesis, crystal structure, and computational studies of two new ionic liquids. In the crystal structure, [C₅H₁₂N][C₂₁H₁₄ClN₂O₂S] (4a), the anions form chains along the a-axis direction through C—H···π(ring) interactions. These are connected into layers that run approximately parallel to the ac plane by a variety of hydrogen bonds. In the compound structure, [C₅H₁₂N][C₁₈H₁₅N₂O₂S] (4b), the two ions are primarily associated by an N—H···N hydrogen bond. In the crystal structure, layers parallel to the bc plane are formed by pairs of C—H···O and N—H···S hydrogen bonds and by C—H···π(ring) interactions. A theoretical study reveals that 4a has lower energy than 4b and is more stable. The NBO and DOS studies further confine the liquids’ structural reactivity and electronic properties. The quantum theory of atoms in a molecule (QTAIM) analysis reveals the important non-covalent interactions among the fragments and charge transfer. The global reactivity descriptors indicate their molecular reactivity relationship with the presence of functional groups. The remarkable polarizability (α_o) and hyperpolarizability (β_o) values indicate their optical and nonlinear optical (NLO) properties. Furthermore, the analysis performed by CrystalExplorer shows the intermolecular interactions and reactive sites between cations and anions in ionic liquids. The 2D fingerprint plots and Hirshfeld surfaces indicate the major interactions of crystals with neighboring elements in crystal packing. For both compounds, the H···H interactions are significantly higher than the other element interactions.

The reaction of ethyl 5-cyano-2-methyl-4-(thiophen-2-yl)-6-thioxo-1,6-dihydropyridine-3-carboxylate (1) with 2-chloroacetamide or its N-aryl derivatives gave ethyl 6-((2-amino-2-oxoethyl)thio)-5-cyano-2-methyl-4-(thiophen-2-yl) nicotinate (2a) or its N-aryl derivatives 2b–f, respectively. Cyclization of 2a–f into their isomers 3a–f was carried out by heating in absolute ethanol in the presence of a catalytic amount of sodium ethoxide. The o-aminoamide 3a was reacted with some aryl aldehydes in refluxing ethanol containing a few drops of conc. HCl to afford the corresponding tetrahydropyrimidinones 4a–d. The cyclocondensation reaction of 3a with some cycloalkanones such as cyclopentanone and cyclohexanone gave the corresponding spiro compounds 5a,b. The crystal structures of compounds 2a and 2d were determined by single-crystal X–ray diffraction techniques. All new compounds were evaluated for their insecticidal activity toward nymphs and adults of Aphis gossypi.

Isoquinoline and its derivatives, which constitute an important category of heterocyclic compounds and are found in a variety of naturally occurring alkaloids, serve a variety of biological purposes such as a potent agonist for human melatonin receptors 1. This research was conducted in an attempt to develop new dihydroisoquinoline molecules (III and IV). Single-crystal X-ray crystallography study validated their structures. The Hirshfeld surface analysis identifies intermolecular interactions by using a 2-D fingerprint map to recognize each type's relative contribution H⋅⋅⋅H connections are discovered to be dominating. The interaction energies between chemical pairs in crystal structures were found using an energy framework analysis. The DFT investigation demonstrates the electronic stability and reactivity of the compounds using the HOMO-LUMO and global reactivity descriptors, indicating that IV has higher chemical reactivity than III. The derived polarizability (αo) and hyperpolarizability (βo) values were used to calculate the optical and nonlinear optical characteristics of III and IV. The IV's significant βo value (488.94 au) indicates that it has good optical and NLO qualities. Molecular docking simulation using human melatonin receptors 1 was used to better understand the binding interaction mechanism of the title compounds. In addition, ADMET evaluations were performed to establish the therapeutic potential of III and IV.

In the present work, we describe the synthesis of new tetrahydroisoquinoline derivatives and the crystal structures of two of them. Density functional theory (DFT) investigations at the B3LYP/6-31+G(d,p) level provided their structural reactivity and nonlinear optical properties. The low HOMO-LUMO gaps (E_H-L) suggest a soft nature and higher reactivity, while calculated global reactivity descriptors provide assessments of their reactivity and electronic stability. The calculated natural bonding molecular orbital (NBO) charges show excellent charge separation (charge transfer) and identify the donor and acceptor parts of the molecules. Density of states (DOS) analyses show the newly generated energy states and reduced band gaps, which impart higher conductive properties. For surface reactivity, 3D MESP surfaces are plotted and show electron-rich sites near the nitrogen atoms of the tetrahydroisoquinoline rings. Nonlinear optical (NLO) properties of the crystals are predicted from calculated polarizability (α_o) and hyperpolarizability (β_o) values. For IVb, the α_o and β_o values are 415.53 and 1003.44 au. The remarkable value (1003.44 au) of the hyperpolarizability (β_o) shows IVb has excellent NLO properties. Structural activity relationship analysis suggests that nitric oxide synthases are better targets for both compounds, and they were further subjected to molecular docking simulations to understand the binding efficiency. In addition, ADMET analyses were carried out to understand the potential activity of the molecules as drug candidates.

In the era of modern synthetic methodology and advanced bio-evaluation techniques and considering the notorious history of hepatocellular carcinoma (HCC), hopeful expectations regarding novel bioactive chemotypes have grown dramatically. Among the widely versatile motifs in drug discovery studies are isoquinoline and thieno[2,3-b]pyridine. Herein, the molecular merging of both motifs evoked thieno[2,3-c]isoquinoline as a novel antiproliferative chemotype being hardly studied against HCC. Accordingly, compound series 4, 5, 7 and 8 were synthesized and bioevaluated against the HepG2 cell line. The role of C7-Ac/C8-OH substituents, C8-C9 unsaturation, 1H-pyrrol-1-yl ring closure at C1-NH₂ and C6-Ph p-halo-substitution were biologically studied and successfully furnished the lead 5b while showing safe profile against Vero cells. Further, flow cytometric and Annexin V-FITC/PI apoptotic bio-investigations of 5b unveiled remarkable cell cycle arrest at the G2/M phase besides a 60-fold increase in apoptosis. The use of a DFT conformational study followed by Molecular docking and molecular mechanics/generalized born surface area scoring evoked potential tubulin-targeting activity of 5b at colchicine-binding site, which was confirmed by experimental evidence (Tub Inhib IC₅₀ = 71 µM vs. 14 µM for colchicine). Accordingly, preserving C7-acetyl and optimizing halogen position while preserving [6S,7R]-stereochemistry is crucial for optimum binding to colchicine binding site of tubulin.

Both 2-(N-arylcarbamoyl)methylsulfanyl-3-cyano-5-ethoxycarbonyl-6-methyl-4-(2′-thienyl)pyridines 2a-e and their isomers, 3-amino-2-(N-arylcarbamoyl)-5-ethoxy-carbonyl-6-methyl-4-(2′-thienyl)thieno[2,3-b]pyridines 3a-e were synthesized by reaction of ethyl 3-cyano-1,2-dihydro-6-methyl-4-(2′-thienyl)-2-thioxopyridine-5-carboxylate (1) with the respective N-aryl-2-chloroacetamides in the presence of different basic catalysts. Compounds 3a-e were used as precursors for synthesizing of pyridothienopyrimidinones 4a-e, pyridothienotriazinones 5a-e and tetrahydropyridothienopyrimidinones 6a-c via treatment with triethyl orthoformate, nitrous acid, and/or 4-chlorobenzaldehyde respectively. The photophysical properties of aminothienylthienopyridines 3a-e and tetrahydropyridothieno-pyrimidine-4(3H)-ones 6a-c were studied and the fluorescence data revealed that all selected compounds possess AIE behaviors in solution and in solid state. Most of the prepared compounds were evaluated in vitro for their antibacterial and antifungal activities, and considerable results were obtained. Moreover, the cytotoxic activity of thienopyridines 3a-d against MCF-7 and HepG2 cell lines was evaluated and they showed moderate to very strong activity.

Two new homologous series of non-symmetric liquid crystal dimers N-(4-(n-(4- (benzothiazol-2-yl)phenoxy)alkyloxy)benzylidene)-4-bromoanilines and N-(4-(n-(4- (benzothiazol-2-yl)phenoxy)alkyloxy)benzylidene)-4-methoxyanilines in which the methylene spacer of CnH2n with even parity of n ranging from 4 to 12 and the substituents of bromo and methoxy attached to respective aniline fragments have successfully been synthesized and characterized. The salient feature of these series can be attributed to the conversion of non-mesogenic units of benzothiazole and aromatic imine units to mesogens through the formation of dimers. All the title compounds exhibit enantiotropic nematic phases. The smectogenic properties also prevail among the series containing Br entity wherein the spacers are C8H16, C10H20 and C12H24. In general, the isotropization temperatures for both series were seen to descend with the increase in the spacer length. Comparison among the compounds possessing Br and OCH3 substituents shows that the anisotropic properties are governed partially by the presence of substituent residing in the aniline unit.

Tetrahydroisoquinolines (THIQs) are a significant class within the broad range of natural compounds known as isoquinoline alkaloids. Natural and manmade drugs based on THIQ have a variety of biological effects that protect against different infectious pathogens and neurological diseases. In this study, two new THIQ derivatives were synthesized and characterized using by X-ray crystallographic analysis. The performed Hirshfeld analysis shows the intermolecular interactions and reactive sites of compounds. The 2D fingerprints reveal dominants H···C interactions up to 8.8% in 3a while 43% H···H elemental interactions are observed in compound 3b. In studied compound 3a, the repulsion energies (k_-rep) dominate the other energies where the highest amount of 63.8 kJ/mol is obtained whereas 3b has a significant contribution from E_-dis to the total energy of the molecule from the energy framework study. Moreover, the density functional theory study reveals better thermodynamic and electronic stabilities. These compounds have reduced HOMO-LUMO gaps (E_H-L) ranging from 3.66 to 3.60 eV, indicating their remarkable conductive and electronic properties. The significant reduction in E_H-L also guarantees our synthesized compounds’ soft nature and reactivity. Our studied compound’s NBO charges and MEPs analysis show electron-rich sites and donor–acceptor mechanism. Our synthesized compounds have remarkable polarizability (α_o) and hyperpolarizability (β_o) values (446.23 − 1312.73 au), which indicates their optical and nonlinear optical properties. The density of states spectra further illustrates their notable structural-electronic properties and reduced band gaps. Based on structural activity relationship studies, we found that these tetrahydro-isoquinolines derivatives are potent against microsomal prostaglandin E synthase 1(MPGES1), the docking analysis shows that studied compounds have a good binding affinity with MPGES1, and further ADME/T analysis was carried out for both compounds. In addtion to this molecular dynamics, studies were performed to understand the binding stability of both compounds in protien complex system during 100 ns simulation.