Synthesis, Crystal Structure, Hirshfeld Surface Analysis, and Computational Approach of a New Pyrazolo[3,4-g]isoquinoline Derivative as Potent against Leucine-Rich Repeat Kinase 2 (LRRK2).

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.

New tetrahydroisoquinoline-4-carbonitrile derivatives as potent agents against cyclin-dependent kinases, crystal structures, and computational studies.

The synthesis of two new hexahydroisoquinoline-4-carbonitrile derivatives (3a and 3b) is reported along with spectroscopic data and their crystal structures. In compound 3a, the intramolecular O-H···O hydrogen bond constraints the acetyl and hydroxyl groups to be syn. In the crystal, inversion dimers are generated by C-H···O hydrogen bonds and are connected into layers parallel to (10-1) by additional C-H···O hydrogen bonds. The layers are stacked with Cl···S contacts 0.17 Å less than the sum of the respective van der Waals radii. The conformation of the compound 3b is partially determined by the intramolecular O-H···O hydrogen bond. A puckering analysis of the tetrahydroisoquinoline unit was performed. In the crystal, O-H···O and C-H···O hydrogen bonds together with C-H···π(ring) interactions form layers parallel to (01-1) which pack with normal van der Waals interactions. To understand the binding efficiency and stability of the title molecules, molecular docking, and 100 ns dynamic simulation analyses were performed with CDK5A1. To rationalize their structure-activity relationship(s), a DFT study at the B3LYP/6-311++G** theoretical level was also done. The 3D Hirshfled surfaces were also taken to investigate the crystal packings of both compounds. In addition, their ADMET properties were explored.Communicated by Ramaswamy H. Sarma.

Pyridine Derivatives as Insecticides─Part 4: Synthesis, Crystal Structure, and Insecticidal Activity of Some New Thienylpyridines, Thienylthieno[2,3-b]pyridines, and Related Heterocyclic Derivatives.

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.

Thieno[2,3-c]isoquinolines: A novel chemotype of antiproliferative agents inducing cellular apoptosis while targeting the G2/M phase and Tubulin.

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.

Exploration of Dihydrothieno[2,3-c] Isoquinolines As Luminescent Materials and Corrosion Inhibitors.

The reaction of the starting compound, 7-acetyl-4-cyano-1,6-dimethyl-8-phenyl-7,8-dihydroisoquinoline-3(2H)-thione, with some N-aryl-2-chloroacetamides or chloroacetonitrile, in the presence of sodium acetate trihydrate, gave the corresponding substituted 3-methylsulfanyl-7-acetyl-4-cyano-1,6-dimethyl-8-phenyl-7,8-dihydroisoquinolines. Upon heating of the latter compounds with sodium methoxide in methanol, they underwent intramolecular Thorpe-Zeigler cyclization, affording the target isomers 1-amino-2-(substituted)-5,8-dimethyl-6-phenyl-6,7-dihydrothieno[2,3-c]isoquinolines (DHTIQs). The chemical structures of all produced substances were characterized by elemental and spectral analyses. The photophysical characteristics of the produced DHTIIQs (He1-Ph-Cl, He2-Ph-CH3, He3-Ph, and He4-CN) have been investigated as luminous compounds. Potentiodynamic, surface morphology, and theoretical calculations were used to study the behavior of the synthesized DHTIQs as corrosion inhibitors on mild steel in a 1.0 M sulfuric acid solution.

Pyridine Derivatives as Insecticides. Part 3. Synthesis, Crystal Structure, and Toxicological Evaluation of Some New Partially Hydrogenated Isoquinolines against Aphis gossypii (Glover, 1887).

Three new series of isoquinolines, that is, 7-acetyl-3-acetonylsulfanyl-8-aryl-1,6-dimethyl-6-hydroxy-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles (3a-c); 3-acetonylsulfanyl-8-aryl-1,6-dimethyl-7,8-dihydroisoquinoline-4-carbonitriles (4a-c); and 7-acetyl-8-aryl-1,6-dimethyl-3-ethylsulfanyl-7,8-dihydroisoquinoline-4-carbo-nitriles (6a,b) were carefully synthesized. Also, pyrazoloisoquinoline 7 was used as a precursor for synthesis of 7-ethylsulfanyl-4-phenyl-1-thiocarbamoyl-3,5,9a-trimethyl-3a,4,9,9a-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-8-carbonitrile (8); 7-benzyl-sulfanyl-4-phenyl-1-thiocarbamoyl-3,5,9a-trimethyl-3a,4,9,9a-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-8-carbonitrile (9); and 7-ethylsulfanyl-1-(4-oxo-4,5-dihydrothiazol-2-yl)-4-phenyl-3,5,9a-trimethyl-3a,4,9,9a-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-8-carbonitrile (10). Moreover, the crystal structures of two representative compounds were determined. Eleven new compounds 3a, 4a, 3b, 4b, 3c, 4c, 6a, 6b, 8, 9, and 10 were screneed for their toxicological activity against nymphs and adults of Aphis gossypii by using acetamprid, as a reference. After 24 h of treatment, the bioefficacy results indicate that all tested isoquinolines exhibit toxicological activity that varied from very high to low against nymphs and adults of Aphis gossypii, some compounds showing activity near to that of acetampirid and only one compound which possesses higher activity against nymphs and adults of Aphis gossypii than that of acetampirid itself.

Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-4-cyano-6-hy-droxy-8-(4-meth-oxyphen-yl)-1,6-dimethyl-5,6,7,8-tetra-hydro-isoquinolin-3-yl-]sulfan-yl}acetic acid ethyl ester.

In the title mol-ecule, C25H28N2O5S, (alternative name ethyl 2-{[7-acetyl-4-cyano-6-hy-droxy-8-(4-meth-oxy-phen-yl)-1,6-dimethyl-5,6,7,8-tetra-hydro-isoquinolin-3-yl]sulfanyl}-acetate) the 4-meth-oxy-phenyl group is disposed on one side of the bicyclic core and the oxygen atoms of the hydroxyl and acetyl groups are disposed on the other side. In the crystal, a layered structure parallel to the ac plane is generated by O-H⋯O and C-H⋯O hydrogen bonds plus C-H⋯π(ring) inter-actions.

Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-8-(4-chloro-phen-yl)-4-cyano-6-hy-droxy-1,6-dimethyl-5,6,7,8-tetra-hydro-isoquinolin-3-yl]sulfan-yl}-N-(4-chloro-phen-yl)acetamide.

In the title mol-ecule, C28H25Cl2N3O3S, the heterocyclic portion of the tetra-hydro-iso-quinoline unit is planar while the cyclo-hexene ring adopts a twist-boat conformation. The two 4-chloro-phenyl groups extend away from one side of this unit while the hydroxyl and acetyl groups extend away from the opposite side and form an intra-molecular O-H⋯O hydrogen bond. The crystal packing consists of layers parallel to the bc plane. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from H⋯H (37.3%), Cl⋯H/H⋯Cl (17.6%), O⋯H/H⋯O (11.1%), C⋯H/H⋯C (10.9%) and N⋯H/H⋯N (9.7%) inter-actions.

Synthesis, Characterization, and Crystal Structure of Some New Tetrahydroisoquinolines and Related Tetrahydrothieno[2,3-c]isoquinolines.

The starting compounds 7-acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-5,6,7,8-tetrahydroisoquinoline(2H)-3-thiones 3a,b were synthesized and reacted with some N-aryl-2-chloroacetamides 4a-e in the presence of sodium acetate to produce 7-acetyl-8-aryl-3-(N-arylcarbamoylmethylsulfanyl)-4-cyano-1,6-dimethyl-6-hydroxy-5,6,7,8-tetrahydroisoquinolines 5a-g. Upon heating in ethanol containing sodium ethoxide, they underwent intramolecular Thorpe-Zeigler cyclization, affording the corresponding 7-acetyl-1-amino-6-aryl-2-(N-arylcarbamoyl)-5,8-dimethyl-8-hydroxy-6,7,8,9-tetrahydrothieno[2,3-c]isoquinolines 6a-g. Compounds 6c,g,f were converted into the corresponding 1-(1-pyrrolyl) derivatives 7a-c by heating with 2,5-dimethoxytetrahydrofuran in glacial acetic acid. Structures of all synthesized compounds were characterized by elemental and spectral analyses. Also, the crystal structure of compounds 5a was determined by X-ray diffraction analysis.

Synthesis and Characterization of Novel Functionally Substituted Planar Pyrimidothienoisoquinolines and Nonplanar (3aR, 4S, 9aS)-pyrazolo[3,4-g]isoquinolines.

7-Acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-5,6,7,8-tetrahydroisoquinolin-3(2H)-thiones 2a,b are prepared and dehydrated to give 7-acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-7,8-dihydrodroisoquinolin-3(2H)-thiones 6a,b via a novel method by heating with acetyl chloride in acetic acid. The reaction of both compounds 2a,b and 6a,b with N-aryl-2-chloroacetamides 7a-c under two different conditions gave the same corresponding products, 7-acetyl-8-aryl-3-(N-aryl)carbamoylmethylsulfanyl-4-cyano-1,6-dimethyl-7,8-dihydroisoquinolines 8a-e, in high yields. On treatment of compounds 8a,b,e in methanol with a slightly excess molar amount of sodium methoxide, they underwent intramolecular Thorpe-Ziegler cyclization followed by spontaneous aromatization, providing the planar 7-acetyl-1-amino-6-aryl-2-(N-aryl)carbamoyl-5,8-dimethyl-8,9-dihydrothieno[2,3-c] isoquinolines 9a,b,e in good yield. Cyclocondensation reactions of 6a,b with phenyl hydrazine, thiosemicarbazide, or hydrazine hydrate led to the formation of nonplanar (3aR, 4S, 9aS)-pyrazolo[3,4-g]isoquinolines 11a, 11b, and 13, respectively. The reaction of compound 13 with 2-chloromethylquinazolin-4(3H)-one in the presence of anhydrous sodium acetate gave the expected thienopyrazoloisoquinolone 14. Heating the latter compound (14) with triethyl orthoformate in glacial acetic acid afforded the fused heptacyclic compound 15. All of the synthesized compounds were characterized based on their full spectral analyses such as IR, 1H nuclear magnetic resonance (NMR), and mass spectrometry (MS). Moreover, the crystal structure of compound 6a was elucidated by X-ray diffraction analysis.