RESUMEN
A new class of heterocyclic N,O-aminal and hemiaminal scaffolds was successfully obtained by means of a three-component reaction (3-CR) of 1,2-diaza-1,3-dienes (DDs), α-aminoacetals and iso(thio)cyanates. These stable imine surrogates are generated from key-substituted (thio)hydantoin intermediates through selective FeCl3-catalyzed intramolecular N-annulation.
RESUMEN
A chemoselective one-pot synthesis of pharmaceutically prospective indole-pyrrole hybrids by the formal [3 + 2] cycloaddition of 3-cyanoacetyl indoles (CAIs) with 1,2-diaza-1,3-dienes (DDs) has been developed. The new indole-pyrrole hybrids were phenotypically screened for efficacy against Leishmania infantum promastigotes. The most active compounds 3c, 3d, and 3j showed IC50 < 20 µM and moderate cytotoxicity, lower than miltefosine. Compound 3d was the most active with IC50 = 9.6 µM and a selectivity index of 5. Consequently, 3d could be a new lead compound for the generation of a new class of antileishmanial hybrids.
RESUMEN
A practical and environmentally benign protocol for the assembly of poly substituted-thiazolo[3,2-a]indoles from 3-alkylated indoline-2-thiones and 2-halo-ketones has been developed. This metal-free approach consists in a complete chemo/regioselective formal [3 + 2] annulation that occurs in air, at 60 °C, and in water as the sole reaction medium. The opportunity to vary the substitution pattern up to six different positions, odorless manipulation of sulfurylated compounds, very easy product isolation, and mild reaction conditions are the main synthetic features of this method. The scaled-up experiment and the successive transformations of the products further demonstrate the utility of this chemistry.
RESUMEN
A metal-free strategy, alternative to the known complex cycloaddition reactions, towards 2-carboxylated thieno [2,3-b] indole derivatives has been successfully developed. The novel approach involves as starting materials easy accessible 1,2-diaza-1,3-dienes and indoline 2-thione and requires mild reaction conditions. Furthermore, the easy work-up required makes this method amenable for a one-pot approach as demonstrated in the preparation of thienodolin, a natural product isolated from Streptomyces albogriseolus that exhibits valuable biological properties.
Asunto(s)
Alcaloides , Antineoplásicos , Ácidos Carboxílicos , Reacción de Cicloadición , Indoles , TiofenosRESUMEN
An unprecedented synthesis of polysubstituted indole-fused pyridazines (azacarbolines) from α-indolylhydrazones under oxidative conditions using a combination of iodylbenzene (PhIO2) and trifluoroacetic acid (TFA) has been developed. This transformation is conducted without the need for transition metals, harsh conditions, or an inert atmosphere.
Asunto(s)
Estrés Oxidativo , Ciclización , Oxidación-Reducción , Ácido TrifluoroacéticoRESUMEN
Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1H-pyrazol-5(4H)-ones and 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, starting from 1,2-diaza-1,3-dienes (DDs) and propargyl alcohol. The reaction proceeds through a sequence Michael-type nucleophilic attack/cyclization/[2,3]-Wittig rearrangement. In the same way, the reaction between the aforementioned DDs and allyl alcohol furnished 4-allyl-4-hydroxy-3-alkyl-1-aryl-1H-pyrazol-5(4H)-ones. A DFT study was also carried out, in order to have decisive clarifications about the mechanism.
RESUMEN
We report the evaluation of a small library of azole-bisindoles for their antileishmanial potential, in terms of efficacy on Leishmania infantum promastigotes and intracellular amastigotes. Nine compounds showed good activity on L. infantum MHOM/TN/80/IPT1 promastigotes with IC50 values ranging from 4 to 10 µM. These active compounds were also tested on human (THP-1, HEPG2, HaCaT, and human primary fibroblasts) and canine (DH82) cell lines. URB1483 was selected as the best compound, with no quantifiable cytotoxicity in mammalian cells, to test the efficacy on intracellular amastigotes. URB1483 significantly reduced the infection index of both human and canine macrophages with an effect comparable to the clinically used drug pentamidine. URB1483 emerges as a new anti-infective agent with remarkable antileishmanial activity and no cytotoxic effects on human and canine cells.
RESUMEN
Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1H-pyridazino[3,4-b]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazines to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles.
Asunto(s)
Indoles/química , Oxígeno/química , Piridazinas/química , Piridinas/química , Cromatografía , Espectroscopía de Resonancia Magnética , Oxidantes/química , Oxidación-Reducción , Solventes/química , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura , Ácido Trifluoroacético/químicaRESUMEN
Zn(II)-catalyzed divergent synthesis of functionalized polycyclic indolines through formal [3 + 2] and [4 + 2] cycloadditions of indoles with 1,2-diaza-1,3-dienes (DDs) is reported. The nature and type of substituents of substrates are found to act as a chemical switch to trigger two distinct reaction pathways and to obtain two different types of products upon the influence of the same catalyst. The mechanism of both [4 + 2] and [3 + 2] cycloadditions was investigated and fully rationalized by density functional theory (DFT) calculations.
RESUMEN
Heterocycles constitute the largest and most diverse family of organic compounds that have received extensive interest owing to their popularity in many natural products, pharmaceuticals, and materials [...].
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Compuestos Heterocíclicos/síntesis química , Productos Biológicos/química , Compuestos Heterocíclicos/químicaRESUMEN
Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.
RESUMEN
A small library of sugar-based (i.e., glucose, mannose and lactose) monoesters containing hydrophobic aliphatic or aromatic tails were synthesized and tested. The antimicrobial activity of the compounds against a target panel of Gram-positive, Gram-negative and fungi was assessed. Based on this preliminary screening, the antibiofilm activity of the most promising molecules was evaluated at different development times of selected food-borne pathogens (E. coli, L. monocytogenes, S. aureus, S. enteritidis). The antibiofilm activity during biofilm formation resulted in the following: mannose C10 > lactose biphenylacetate > glucose C10 > lactose C10. Among them, mannose C10 and lactose biphenylacetate showed an inhibition for E. coli 97% and 92%, respectively. At MICs values, no toxicity was observed on Caco-2 cell line for all the examined compounds. Overall, based on these results, all the sugar-based monoesters showed an interesting profile as safe antimicrobial agents. In particular, mannose C10 and lactose biphenylacetate are the most promising as possible biocompatible and safe preservatives for pharmaceutical and food applications.
RESUMEN
A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS2 in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained ensures post-modifications in view of N-bridgeheaded heterobicyclic structures.
Asunto(s)
Imidazoles/síntesis química , Tionas/síntesis química , Técnicas de Química Sintética , Reacción de Cicloadición , Imidazoles/química , Estructura Molecular , Tionas/químicaRESUMEN
Substituted hydroxy-benzofurans are easily accessible by treatment of resorcinols and 1,2-diaza-1,3-dienes (DDs) under acidic conditions. The reaction happens through an uncommon Michael reaction between aromatic derivatives as aromatic C(sp2)-H nucleophiles and DDs as acceptors. Also, the behavior of different phenols and 2-naphthol was investigated.
RESUMEN
An umpolung α-(hetero)arylation strategy that involves the Michael-type reaction between electron-rich (hetero)aromatic substrates and azoalkenes is developed. The reaction proceeds under very mild conditions at room temperature and in the presence of inexpensive, nontoxic ZnCl2 catalyst to provide access to otherwise inaccessible hydrazone structures. Subsequent hydrolysis of these latter to ketones as well as other valuable synthetic transformations to a variety of heterocyclic scaffolds demonstrate the usefulness of this protocol.
RESUMEN
The antimicrobial activity of the marine bisindole alkaloid 2,2-bis(6-bromo-3-indolyl) ethylamine (1) and related synthetic analogues (compounds 2â»8) against target microorganisms was investigated by Minimum Inhibitory Concentration (MIC) determination. Compound 1 showed the greatest antimicrobial activity with the lowest MIC (8 mg/L) against Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae, while the derivatives exhibited higher MICs values (from 16 to 128 mg/L). Compounds 1, 3, 4, and 8, the most active ones, were then tested against E. coli, S. aureus, K. pneumoniae, and Candida albicans during biofilms formation as well as on 24 h developed biofilms. The natural alkaloid 1 inhibited the biofilm formation of all the tested microorganisms up to 82.2% and disaggregated biofilms of E. coli, S. aureus, K. pneumoniae, and C. albicans after 30 min of contact, as assessed by viable plate count and crystal violet (CV) staining (optical density at 570 nm). Synthetic derivatives 3, 4, and 8 displayed anti-biofilm activity toward individual bacterial populations. This study highlights the potential of marine bisindole alkaloid 1 as anti-biofilm agent and shows, through a preliminary structure activity relationship (SAR), the importance of halogens and ethylamine side chain for the antimicrobial and antibiofilm activities of this bisindole series.
RESUMEN
Herein we report a domino protocol able to reach regioselectively thiazolylidene systems by combining the reactive peculiarities of both ß-amidothioamides (ATAs) and 1,2-diaza-1,3-dienes (DDs). Depending on the reaction conditions and/or the nature of the residue at C4 of the heterodiene system, ATAs can act as hetero-mononucleophiles or hetero-dinucleophiles in the diversified thiazolylidene ring assembly.
RESUMEN
A Pd(II)-catalyzed intramolecular oxidative C-H/C-H cross-coupling has been developed for the direct construction of valuable polycyclic heteroarene scaffolds. From a retrosynthetic point of view, the strategic formation of a C-C bond via C(sp2)-H/C(sp2)-H dehydrogenative coupling across C3,N-linked biheterocyclic precursors may be useful in de novo syntheses of indole-derived natural products and pharmaceuticals. The reaction exhibited good functional group/heterocycle tolerance, and a proposed mechanism involving an azoylpalladium complex is also supported.
RESUMEN
The base (NaH)-promoted Michael addition of N-arylhydrazones (AHs) with 1,2-diaza-1,3-dienes (DDs) produces unprecedented ß-azohydrazone adducts. Strategically, the use of AHs as acyl anion equivalents (d(1) synthon) and DDs as α-electrophiles (a(2) synthon) of carbonyl compounds open the way to two important classes of pyrazole compounds.
Asunto(s)
Alcadienos/química , Compuestos Aza/química , Hidrazonas/química , Pirazoles/síntesis química , Estructura Molecular , Pirazoles/químicaRESUMEN
A simple reaction of some oxindole derivatives with 1,2-diaza-1,3-dienes to produce 2-oxo-spiro[indole-3,4'-pyridines] in good yields is described here. This transformation represents a practical two steps approach to new and biologically interesting 2-oxo-spiro[indole-3,4'-pyridine] scaffolds using a double Michael addition/cyclization sequence.