RESUMEN
Here, An efficient approach to obtaining previously unknown furo[2',3':2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1-a]isoquinolines.
Asunto(s)
Isoquinolinas , Lactonas , Espironolactona , Ácido Acético , MetalesRESUMEN
An easy synthesis of novel highly functionalized 5,6-dihydroindolo[2,1-a]isoquinolines was developed via a pseudo four-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal α,ß-ynones, and malononitrile. The selective formation of this biologically relevant heterocyclic core was achieved using a one-pot approach under microwave irradiation. The formation of the same skeleton through the reaction of 5,6-dihydropyrrolo[2,1-a]isoquinolines with malonic acid dinitrile supports the proposed mechanism, involving the intermediate product of the three-component reaction. Furthermore, the disproval of an alternative reaction pathway, which involved the dimerization of malononitrile followed by three-component transformation, was demonstrated. Introducing the malononitrile dimer as a CH acid resulted in the formation of a different pyrido[3',4':4,5]pyrrolo[2,1-a]isoquinoline core. Additionally, the synthesized 5,6-dihydroindolo[2,1-a]isoquinolines were examined for their photophysical properties, revealing their attractive luminescent characteristics.
RESUMEN
Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.
RESUMEN
Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of drugs for the treatment of Alzheimer's disease and related dementias, herein we investigated diverse newly and previously synthesized ß-enamino esters (and ketones) derivatives of 1,4,7,8-tetrahydroazocines (and some azonines) fused with benzene, 1H-indole, 4H-chromen-4-one and pyrimidin-4(3H)-one. Twenty derivatives of diversely annelated eight-to-nine-membered azaheterocyclic ring, prepared through domino reaction of the respective tetrahydropyridine and azepine with activated alkynes, were assayed for the inhibitory activity against AChE and butyrylcholinesterase (BChE). As a major outcome, compound 7c, an alkylamino derivative of tetrahydropyrimido[4,5-d]azocine, was found to be a highly potent BChE-selective inhibitor, which showed a noncompetitive/mixed-type inhibition mechanism against human BChE with single digit nanomolar inhibition constant (Ki = 7.8 ± 0.2 nM). The four-order magnitude BChE-selectivity of 7c clearly reflects the effect of lipophilicity upon binding to the BChE binding cavity. The ChEs' inhibition data, interpreted by chemoinformatic tools and an in-depth in-silico study (molecular docking combined with molecular dynamics calculations), not only highlighted key structural factors enhancing inhibition potency and selectivity toward BChE, but also shed light on subtle differences distinguishing the binding sites of equine BChE from the recombinant human BChE. Compound 7c inhibited P-glycoprotein with IC50 of 0.27 µM, which may support its ability to permeate blood-brain barrier, and proved to be no cytotoxic in human liver cancer cell line (HepG2) at the BChE bioactive concentrations. Overall, the biological profile allows us to envision 7c as a promising template to improve design and development of BChE-selective ligands of pharmaceutical interest, including inhibitors and fluorogenic probes.
Asunto(s)
Acetilcolinesterasa , Butirilcolinesterasa , Animales , Humanos , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Ésteres/farmacología , Indoles , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R3 = CH2OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (Ki = 4.9 µM), equipotent with the corresponding 6-phenyl derivative 3n (R3 = Ph, Ki = 4.5 µM), but 90-fold more water-soluble.
Asunto(s)
Inhibidores de la Colinesterasa , Inhibidores de la Monoaminooxidasa , Acetilcolinesterasa/metabolismo , Alcoholes , Alcadienos , Alquinos , Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Humanos , Isoquinolinas , Simulación del Acoplamiento Molecular , Estructura Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/química , Relación Estructura-Actividad , AguaRESUMEN
Synthesis of novel C3-substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines via a three-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal alkynes and CH-acids under microwave irradiation in dry acetonitrile is described. The method developed enables the obtainment of highly functionalized compounds with pharmacophore groups, which are potentially biologically active.
Asunto(s)
Isoquinolinas/química , Pirroles/química , Alquinos/química , Reacción de Cicloadición , Isoquinolinas/síntesis química , Espectroscopía de Resonancia Magnética , Microondas , Conformación Molecular , Pirroles/síntesis químicaRESUMEN
Various 4'-R-substituted phenyl azacyclic allenes were synthesized in good yields, and their thermal transformations were studied. For the first time, the obtained rearrangement products-new N-bridged cyclopenta[a]indenes, and the corresponding parent allenes were evaluated as potential inhibitors of acetyl- and butyrylcholinesterase. Among the tested compounds, the allene derivative 2g proved to competitively inhibit human AChE with inhibition constant value (Ki) in the low micromolar range.
Asunto(s)
Butirilcolinesterasa , Inhibidores de la Colinesterasa , Acetilcolinesterasa/metabolismo , Alcadienos , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Indenos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Inhibidores de la Colinesterasa/farmacología , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Nitrógeno , Relación Estructura-ActividadRESUMEN
A convenient protocol for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines with various electron-withdrawing substituents at C-2 atom is described. This approach is based on the two-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines with α,ß-unsaturated ketones, nitroalkenes and acrylonitrile. Depending on the selected substrates, the reaction was performed in TFE under reflux or under microwave irradiation. Only for the two examples, a transition metal catalyst was used.
Asunto(s)
CetonasRESUMEN
Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure-activity relationships (SARs) pointed out that CO2Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC50 = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Alcadienos/farmacología , Antibióticos Antineoplásicos/farmacología , Compuestos Aza/farmacología , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Alcadienos/química , Compuestos Aza/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclización , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismoRESUMEN
1-(p-Methoxyphenyl)tetrazolyl-substituted 6,7-dimethoxy(6,7-methylenedioxy)-1,2,3,4-tetrahydroisoquinolines formed tetrazolyl-substituted azocines in high yields by using activated alkynes. Unsubstituted at 6,7,8-aromatic fragment 1-tetrazolylisoquinoline interacted in several pathways forming tetrazolyl-substituted azocines, 1-tetrazolyl-1-R-vinylisoquinolines and 3-azaspiro[5.5]undeca-1,7,9-triene.
Asunto(s)
Alquinos/química , Tetrahidroisoquinolinas/síntesis química , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Análisis Espectral , Tetrahidroisoquinolinas/químicaRESUMEN
The title compound, C19H19NO5, (I), is the product of a domino reaction between cotarnine chloride and acetyl-acetylene catalysed by copper(I) iodide. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two terminal five-membered rings (pyrrole and 1,3-dioxole) and two central six-membered rings (di-hydro-pyridine and benzene). The five-membered 1,3-dioxole ring has an envelope conformation and the central six-membered di-hydro-pyridine ring adopts a twist-boat conformation. The acyl substituent is almost coplanar with the pyrrole ring, whereas the meth-oxy substituent is twisted by 27.93â (16)° relative to the benzene ring. The 2-oxopropan-1-yl substituent is roughly perpendicular to the pyrrole ring. In the crystal, mol-ecules are stacked along the a-axis direction; the stacks are linked by weak C-Hâ¯O hydrogen bonds into puckered layers lying parallel to (001).
RESUMEN
The title compound, C25H27NO4 (I), the product of the unusual thermolysis of aza-cyclic allene methyl 10,11-dimeth-oxy-3,8-dimethyl-6-phenyl-3-aza-benzo[d]cyclo-deca-4,6,7-triene-5-carboxyl-ate, represents a bicyclic heterosystem and crystallizes in the monoclinic space group P21/c with three crystallographically independent mol-ecules in the unit cell. These independent mol-ecules adopt very similar geometries and differ only in the conformations of the two meth-oxy substituents on the benzene ring. In two of the three independent mol-ecules, both meth-oxy groups are almost coplanar with the benzene ring [the C-C-O-Me torsion angles are 10.8â (2), 12.3â (2), 9.1â (2) and 13.6â (3)°], whereas in the third mol-ecule, one of the meth-oxy groups is practically coplanar to and the other meth-oxy group is roughly perpendicular to the benzene ring, the C-C-O-Me torsion angles being 14.1â (2) and 76.5â (2)°. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two five-membered rings (cyclo-pentenes) and two six-membered rings (piperidine and benzene). The five-membered rings have the usual envelope conformation, with the methyl-subsituted C atom as the flap in each molecule, and the six-membered piperidine ring has a chair conformation. The methyl substituent at the N atom occupies the sterically favourable equatorial position. The carboxyl-ate group lies almost within the basal plane of the parent cyclo-pentene ring [making dihedral angle of 11.68â (8), 18.94â (9) and 15.16â (9)° in the three independent mol-ecules], while the phenyl substituent is twisted by 48.26â (6), 42.04â (6) and 41.28â (6)° (for the three independent mol-ecules) relative to this plane. In the crystal, mol-ecules of (I) form stacks along the b-axis direction. The mol-ecules are arranged at van der Waals distances.