RESUMEN
Ethyl 5-cyano-1,6-dihydro-2-methyl-4-(2'-thienyl)-6-thioxonicotinate (A) was synthesized and reacted with ethyl chloroacetate in the presence of sodium acetate or sodium carbonate to give ethyl 5-cyano-6-((2-ethoxy-2-oxoethyl)thio)-2-methyl-4-(2'-thienyl)nicotinate (1a) or its isomeric thieno[2,3-b]pyridine 2a. 3-Aminothieno[2,3-b]pyridine-2-carboxamide 2b was also synthesized by the reaction of A with 2-chloroacetamide. The reaction of 1a with hydrazine hydrate in boiling ethanol gave acethydrazide 3. Heating ester 1a with hydrazine hydrate under neat conditions afforded 3-amino-1H-pyrazolo[3,4-b]pyridine 10. Compounds 2b, 3, and 10 were used as precursors for synthesizing other new thieno[2,3-b]pyridines and pyrazolo[3,4-b]pyridines containing mainly the ethyl nicotinate scaffold. Structures of all new compounds were confirmed by elemental and spectral analyses. Most of the obtained compounds were evaluated for their insecticidal activity toward the nymphs and adults of Aphis gossypii (Glover,1887). Some compounds such as 4, 9b, and 9c showed promising results. The effect of some sublethal concentrations, less than LC50, of compounds 4, 9b, and 9c on the examined Aphis was subjected to a further study. The results demonstrated that exposure of A. gossypii nymphs to sublethal concentrations of compounds 4, 9b, and 9c had noticeable effects on their biological parameters, i.e., nymphal instar duration, generation time, and adult longevity. The highest concentration C1 of all three compounds increased the nymphal instar duration and generation time and decreased adult longevity and vice versa.
Asunto(s)
Áfidos , Insecticidas , Piridinas , Insecticidas/química , Insecticidas/farmacología , Insecticidas/síntesis química , Animales , Piridinas/química , Áfidos/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologíaRESUMEN
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.
RESUMEN
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.
Asunto(s)
Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Cristalografía por Rayos X , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/metabolismo , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacología , Conformación Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Modelos Moleculares , Nitrilos/química , Simulación de Dinámica Molecular , Estructura Molecular , Relación Estructura-Actividad , HumanosRESUMEN
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.
Asunto(s)
Insecticidas , Insecticidas/farmacología , Piridinas/química , Ciclización , EtanolRESUMEN
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.