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.

Ethyl-2-((8-cyano-3,5,9a-trimethyl-1-(4-oxo-4,5-dihydrothiazol-2-yl)-4-phenyl-3a,4,9,9a-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-7-yl)thio)acetate (5) was synthesized, and its structure was characterized by IR, MS, and NMR (¹H and ¹³C) and verified by a single-crystal X-ray structure determination. Compound 5 adopts a “pincer” conformation. In the crystal, the hydrogen bonds of −H···O, C–H···O, and O–H···S form thick layers of molecules that are parallel to (101). The layers are linked by C–H···π(ring) interactions. The Hirshfeld surface analysis shows that intermolecular hydrogen bonding plays a more important role than both intramolecular hydrogen bonding and π···π stacking in the crystal. The intramolecular noncovalent interactions in 5 were studied by QTAIM, NCI, and DFT-NBO calculations. Based on structural activity relationship studies, leucine-rich repeat kinase 2 (LRRK2) was found to bind 5 and was further subjected to molecular docking studies, molecular dynamics, and ADMET analysis to probe potential drug candidacy.

The present work undertakes the study of newly synthesized 1,1′-(3,5-dhydroxy-3-methyl-2′-nitro-1,2,3,4-tetrahydro-[1,1′-biphenyl]-2,6-diyl)bis(ethan-1-one) whose structure has been confirmed by X-ray diffraction analysis. The title molecule, C₁₇H₁₉NO₆, is considered to be a superimposition of the two enol forms of an acetylacetone derivative. Its conformation is partly determined by intramolecular C—H···O hydrogen bonds and a C—H···π(ring) interaction. In the crystal, O—H···O and C—H···O hydrogen bonds form corrugated layers parallel to the ab plane. To confirm the results from the crystallographic study, both the Hirshfeld surface and energy framework were further calculated to investigate the interactions between the title compound and its neighboring molecules in the crystal. Due to the tautomerism of a molecule playing an important role in its biological activity, the intrinsic electronic properties of the title molecule and its tautomer were investigated by a DFT-B3LYP study. Both the Natural Bond Orbital (NBO) analysis and Quantum Theory of Atoms in Molecules (QTAIM) study were used to compare the intramolecular hydrogen bonding in the title compound with those in its tautomer. In addition, molecular docking simulations were carried out with CYP3A4, and an ADMET analysis was also performed to explore the compound's possible biological properties.