RESUMEN
A broad biological screening of the natural alkaloid N-methylisosalsoline (2) extracted from Hammada scoparia leaves against a panel of human and parasitic proteases revealed an interesting activity profile of 2 towards human 20S proteasome. This outcome suggests that the 1,2,3,4-tetrahydroisoquinoline skeleton may be exploited as a template for the development of novel anticancer agents. In this article, we report the synthesis and chemical characterization of a new series of isosalsoline-type alkaloids (10-11) with variations at N2 and C3 positions with respect to the natural Compound 2, obtained by a synthetic strategy that involves the Bischler-Napieralski cyclization. The substrate for the condensation to the tetrahydroisoquinoline system, i.e., a functionalized ß-arylethyl amine, was obtained through an original double reduction of nitroalkene. The synthetic strategy can be directed to the construction of highly substituted and functionalized 1,2,3,4-tetrahydroisoquinolines.
Asunto(s)
Tetrahidroisoquinolinas/síntesis química , Animales , Bovinos , Proliferación Celular/efectos de los fármacos , Humanos , Parásitos/efectos de los fármacos , Parásitos/enzimología , Péptido Hidrolasas/metabolismo , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacologíaRESUMEN
A straightforward and efficient method for the synthesis of novel highly substituted and diversely functionalized indazolone derivatives has been developed. The transformation consists of a cyclocondensation of selected 1,3,3'-tricarbonyls with monosubstituted hydrazines. The starting ß-triketones were prepared by an efficient chemo- and regioselective method under MW irradiation, exploiting the oxazolone chemistry. The reaction is easily accomplished under mild conditions and appears versatile, providing a synthetic diversification method with potential for drug-like compounds preparation.
Asunto(s)
Indazoles/química , Indazoles/síntesis química , Técnicas de Química Sintética , Hidrazinas/químicaRESUMEN
A novel approach for the synthesis of unprecedented C3-mono-functionalized indolin-2-ones is reported, starting from 2-oxindole and chalcones. The reactions proceed regioselectively under mild conditions, without di- and tri-alkylated side products. The new compounds have been evaluated in vitro for their antiproliferative effects against the protozoan Leishmania infantum. Interestingly, they appear able to kill L. infantum promastigotes and amastigotes, without significant cytotoxic effects.
Asunto(s)
Antiprotozoarios/química , Antiprotozoarios/farmacología , Indoles/química , Leishmania infantum/efectos de los fármacos , Animales , Antiprotozoarios/síntesis química , Línea Celular/efectos de los fármacos , Chalcona , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Ratones , Oxindoles , Relación Estructura-Actividad , Pruebas de ToxicidadRESUMEN
A straightforward transformation of indole-3,4-diones is reported. The reaction feasibility is evidenced by kinetic studies on a model substrate, revealing a double phase process with a first faster pseudo-first-order step (i.e., deprotonation of the dione and self-nucleophilic attack of the anion) and a subsequent slower dehydration of the intermediate. The overall process is faster at pH higher than the pK value of the investigated substrate. The biological relevance of new compounds has been assessed in vitro against herpes simplex virus type-1 (HSV-1), showing a more promising biological profile with respect to their precursors.
Asunto(s)
Aldehídos/farmacología , Antivirales/farmacología , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Indoles/farmacología , Aldehídos/síntesis química , Aldehídos/farmacocinética , Antivirales/síntesis química , Antivirales/farmacocinética , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Indoles/síntesis química , Indoles/farmacocinéticaRESUMEN
A new method for the preparation of highly functionalized ß-enamino diones has been developed. The protocol involves an initial self-catalyzed Mannich-type reaction of enolizable cyclic 1,3-dicarbonyls to nitrones, followed by a spontaneous intramolecular reorganization of the resulting nonisolated hydroxylamine to enamino derivatives. These compounds retain the features of unnatural α-amino acids. The ease of preparation makes them attractive intermediates for the synthesis of peptidomimetics, polyheterocycles, and other multifunctional compounds. All experimental results have been efficiently rationalized by in silico studies at the M06-2X level of theory, and a valid mechanistic pathway has been proposed.
Asunto(s)
Aminoácidos/química , Dioxanos/química , Óxidos de Nitrógeno/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Enolizable 6-membered cyclic 1,3-dicarbonyls undergo an efficient and diastereoselective domino condensation/addition/heterocyclization reaction with arylaldehydes and phenacyl chloride, producing highly substituted dihydrofuran-fused derivatives. Ring size of the cyclic 1,3-dicarbonyls and the presence of at least one keto group are crucial to the reaction's success. The new compounds were evaluated in vitro for antiviral activity against herpes simplex virus type-1 (HSV-1). Interestingly, some of them appeared able to interfere with HSV-1 replication, without detection of cytotoxic effects.
Asunto(s)
Antivirales/síntesis química , Furanos/síntesis química , Animales , Antivirales/química , Antivirales/farmacología , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Furanos/química , Furanos/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/crecimiento & desarrollo , Estructura Molecular , Estereoisomerismo , Células Vero , Ensayo de Placa Viral , Replicación Viral/efectos de los fármacosRESUMEN
The crystal structure of N-(3,9-dimethyl-4-phenyl-2,5-dioxo-3,4-dihydro-2H,5H-pyrano[3,2-c]chromen-3-yl)-N-methylbenzamide methanol monosolvate, C(28)H(23)NO(5)·CH(3)OH, has been determined at room temperature by X-ray diffraction. Structural parameters are discussed with reference to ab initio calculations.
RESUMEN
The title compound, C27H21NO4S, is a 2-benzothieno[2,3-b]pyrrole derivative with several substituents, present in the crystal as a racemate. The tetracyclic fused-ring system shows a 'U-shaped' molecular architecture, since the two rings flanking the central pyrrolidine ring both point in the same direction.
RESUMEN
Conformational analyses and a structural comparison of the four spiro compounds 3-bromo-1,9-diphenyl-4-p-tolyl-7-oxa-1,2,8-triazaspiro[4.4]nona-2,8-dien-6-one, (I), C(24)H(18)BrN(3)O(2), 3-bromo-4-(4-methoxyphenyl)-1,9-diphenyl-7-oxa-1,2,8-triazaspiro[4.4]nona-2,8-dien-6-one, (II), C(24)H(18)BrN(3)O(3), 3-bromo-4-(4-chlorophenyl)-1,7,9-triphenyl-1,2,7,8-tetraazaspiro[4.4]nona-2,8-dien-6-one, (III), C(29)H(20)BrClN(4)O, and 3-bromo-1,7,9-triphenyl-4-p-tolyl-1,2,7,8-tetraazaspiro[4.4]nona-2,8-dien-6-one, (IV), C(30)H(22.89)Br(1.11)N(4)O, are presented. The molecular structures are rather similar, which is as expected since the compounds are all products of concerted 1,3-dipolar attack on (Z)-4-arylidene oxazolone and pyrazolone derivatives. The observed conformations tend to favour extended pi conjugation of the benzene rings and other pi systems, as shown by a comparison of selected geometric parameters of the four structures.
RESUMEN
The title compound, C18H15BrN2O5, a promising N-protected alpha-amino acid, was synthesized directly from an unusual bromo dipole and a 4-(arylmethylene)oxazolone. The crystal packing of the title compound is a racemic mixture. Peculiar graph-set motifs driven by the most important hydrogen bonds are described.
RESUMEN
The one-pot reaction of enolisable 1,3-dicarbonyls and N-methyl-1,3-oxazolium-5-olate derivatives provided enol lactones directly in good yield and with excellent regio- and diastereocontrol.