RESUMO
The reaction between ninhydrin-malononitrile adduct [2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)malononitrile] and ethyl 2-(alkylamino)-4-aryl-4-oxo-but-2-enoates (prepared from ethyl 2,4-dioxo-4-arylbutanoate and alkylamines) in the presence of Et3N in MeCN at room temperature afforded 3-alkylamino-2-aryloyl-1',3',4-trioxo-1',3'-dihydrospiro[cyclopentane-1,2'-inden]-2-ene-5,5-dicarbonitriles in 78-95% yields. Five derivatives of these NH-acidic compounds are used to intercept the reactive zwitterionic intermediates generated from dimethyl acetylenedicarboxylate and Ph3P to produce dimethyl 4,4-dicyano-6-aryloyl-1-alkyl-1',3'-dioxo-1',2,3',4-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,2'-indene]-2,3-dicarboxylates. Radical scavenging activity of four derivatives was investigated by radical trapping of diphenylpicrylhydrazine and ferric reduction power experiments. The antibacterial activities of six derivatives were studied by disk diffusion test on Gram-positive and Gram-negative bacteria.
Assuntos
Antibacterianos , Indenos , Antibacterianos/farmacologia , Pirróis , Bactérias Gram-Negativas , Bactérias Gram-PositivasRESUMO
Design and synthesis of three novel series of aryl enaminones (3a-f and 5a-c) and pyrazole (4a-c) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO2 hydrase assay. Enaminone sulphonamide derivatives (3a-c) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC50 = 4.918 and 12.27 µM, respectively) and hypoxic (IC50 = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC50 = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC50 = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.
Assuntos
Antineoplásicos , Anidrases Carbônicas , Humanos , Anidrases Carbônicas/metabolismo , Anidrase Carbônica IX , Sulfaguanidina , Relação Estrutura-Atividade , Ácidos Carboxílicos/farmacologia , Sulfonamidas/química , Antineoplásicos/química , Inibidores da Anidrase Carbônica/química , Pirazóis/farmacologia , Pirazóis/química , Estrutura MolecularRESUMO
The study aimed to investigate the in vitro inhibitory activities of spiro N-propargylic ß-enaminones, SPEs 1-31, against BCa cells, to perform in silico molecular docking studies to understand the nature of the interaction between the compounds and the ERα, PR, EGFR, and Her2, and to determine the ADMET and drug-likeness properties. Cytotoxic activity was investigated via MTT assay. DNA fragmentation was evaluated via ELISA assay. Cell cycle distributions were investigated by flow cytometry. Expression levels of Bcl-2, Bax, p21 and Cyclin D1 were measured by qRT-PCR and western blot analysis. Molecular docking was done using Autodock/vina software. ADMET analysis was calculated using the ADMETlab 2.0 tool. SPEs 1, 22, and 28 showed selective cytotoxic activity against all BCa cells with SI values >2. SPEs induced apoptosis and caused significant changes in Bcl-2 and Bax levels. The cell cycle was arrested at the S phase and levels of p21 and Cyclin D1 were induced in all BCa cells. Molecular docking analysis revealed that SPE1, SPE22, and SPE28 showed high binding affinities with ERα, PR, EGFR, and Her2. ADMET analysis revealed that SPEs are drug-like compounds as they obey the five rules of Lipinsky and are not toxic. Therefore, these potential anticancer compounds should be further validated by in vivo studies for their appropriate function in human health with a safety profile, and a comprehensive drug interaction study should be performed.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Receptor alfa de Estrogênio , Ciclina D1/metabolismo , Proteína X Associada a bcl-2/metabolismo , Antineoplásicos/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose , Proliferação de Células , Relação Estrutura-AtividadeRESUMO
A controllable synthesis of trisubstituted imidazoles and pyrroles has been developed through rhodium(II)-catalyzed regioselective annulation of N-sulfonyl-1,2,3-trizaoles with ß-enaminones. The imidazole ring was formed through a 1,1-insertion of the N-H bond to α-imino rhodium carbene, followed by a subsequent intramolecular 1,4-conjugate addition. This occurred when the α-carbon atom of the amino group was bearing a methyl group. Additionally, the pyrrole ring was constructed by utilizing a phenyl substituent and undergoing intramolecular nucleophilic addition. The mild conditions, good tolerance towards functional groups, gram-scale synthesis capability, and ability to undergo valuable transformations of the products qualify this unique protocol as an efficient tool for the synthesis of N-heterocycles.
Assuntos
Pirróis , Ródio , Pirróis/química , Triazóis/química , Catálise , Ródio/químicaRESUMO
As a new approach, pyrrolo[1,2-a]pyrazines were synthesized through the cyclization of 2-formylpyrrole-based enaminones in the presence of ammonium acetate. The enaminones were prepared with a straightforward method, reacting the corresponding alkyl 2-(2-formyl-1H-pyrrol-1-yl)acetates, 2-(2-formyl-1H-pyrrol-1-yl)acetonitrile, and 2-(2-formyl-1H-pyrrol-1-yl)acetophenones with DMFDMA. Analogous enaminones elaborated from alkyl (E)-3-(1H-pyrrol-2-yl)acrylates were treated with a Lewis acid to afford indolizines. The antifungal activity of the series of substituted pyrroles, pyrrole-based enaminones, pyrrolo[1,2-a]pyrazines, and indolizines was evaluated on six Candida spp., including two multidrug-resistant ones. Compared to the reference drugs, most test compounds produced a more robust antifungal effect. Docking analysis suggests that the inhibition of yeast growth was probably mediated by the interaction of the compounds with the catalytic site of HMGR of the Candida species.
Assuntos
Antifúngicos , Indolizinas , Antifúngicos/farmacologia , Pirróis/farmacologia , Indolizinas/farmacologia , Pirazinas/farmacologia , Testes de Sensibilidade Microbiana , CandidaRESUMO
ß-Keto amides were used as convenient precursors to both 2-alkyl-4-quinolones and 2-alkyl-4-quinolone-3-carboxamides. The utility of this approach is demonstrated with the synthesis of fourteen novel and four known quinolone derivatives, including natural products of microbial origin such as HHQ and its C5-congener. Two compounds with high activity against S. aureus have been identified among the newly obtained quinolones, with MICs ≤ 3.12 and ≤ 6.25 µg/mL, respectively.
RESUMO
An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosphonites to cyclic 1-benzyloxycarbonyl enaminones. Interestingly, the hydride reduction of the resulting 2-phospho-4-oxopiperidine proceeds with high diastereofacial preference using NaBH4. In the last step, the cleavage of N-Cbz group under hydrogenolysis followed by the hydrolysis of the phosphonate or phosphinate functionalities, led to the target cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic acids, respectively.
Assuntos
Organofosfonatos , Ácidos Pipecólicos , HidróliseRESUMO
Trifluoromethylated N-benzamide enaminones have been identified as potential anticonvulsants for the treatment of drug-resistant epilepsy. T-type Ca2+ channels are an important target for anti-seizure medications. Our laboratory has developed several fluorinated N-benzamide enaminone analogs that were evaluated by their ability to target T-type Ca2+ channels. Using whole cell voltage-clamp recordings, we identified two meta-trifluoromethyl N-benzamide enaminones with a significant inhibitory effect on T-type Ca2+ channels. These compounds had no effect on voltage-activated Na+ channels. We also evaluated the effect of the fluorinated N-benzamide enaminone analogs on the T-type Ca2+ channel subunits Cav3.2 and Cav3.3. The meta-trifluoromethyl N-benzamide enaminone lead analogs altered the steady-state inactivation of Cav3.2 T-type Ca2+ channels, which resulted in a significant increase in the inactivation recovery time of the channels. There was no effect of fluorinated N-benzamide enaminone analogs on the gating mechanism of T-type Ca2+ channels, as proven by the lack of effect on the activation and inactivation time constant of Ca2+ currents. On the contrary, the meta-trifluoromethyl N-benzamide enaminone lead analogs altered the gating mechanism of Cav3.3 T-type Ca2+ channels, as proven by the reduction in the activation and inactivation time constant of the channels. There was no effect on the inactivation kinetics of Cav3.3 T-type Ca2+ channels. The present results demonstrate that meta-substituted trifluoromethyl N-benzamide enaminone analogs target T-type Ca2+ channels by different mechanisms depending on the channel subunit. Meta-trifluoromethyl N-benzamide enaminone analogs can potentially lead to the design of more specific blockers of T-type Ca2+ channels for the treatment of epileptic seizures.
Assuntos
Anticonvulsivantes , Canais de Cálcio Tipo T , Anticonvulsivantes/farmacologia , Benzamidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Cinética , Técnicas de Patch-ClampRESUMO
Novel tetracyclic pyrazolo[1,5-a]pyrimidine derivatives; namely benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2-amines 6a-e and benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2(6H)-ones 15a-d, were designed and synthesized as topoisomerase IIα inhibitors with potential anticancer activity. The structure and their mechanistic pathway were discussed and confirmed based on spectral data and DFT calculations. Compounds 6a, 6c, 15b, 15c and 15d exhibited potent Topo II inhibitory activity at one-digit IC50 values (2.35 - 7.18 µM). Among the tested compounds, aminopyrazolopyrimidine derivatives 6a (IC50 = 3.44 µM) and 6c (IC50 = 2.35 µM) were comparable/ equipotent to Doxorubicin (IC50 = 2.71 µM) against Topo II. The most active compounds in Topo II assay were further investigated in vitro for their cytotoxic potential. The oxo-pyrazolopyrimidine derivative 15c; was the most potent possessing one-digit IC50 values (HCT116 IC50 = 2.32 ± 0.13 µM, MCF7 IC50 = 1.137 ± 0.06 µM). Compound 15c was two times more potent than Doxorubicin against MCF7 breast cancer cells. 15c exhibited a safety profile much better than that of Doxorubicin against non-cancerous cells. Compound 15c was also found to be a good apoptotic inducer. Moreover, docking result revealed well-fitting and proper orientation of 15c into Topo II-DNA complex.
Assuntos
Antineoplásicos , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Recently, different mechanisms for inhibition of carbonic anhydrases (CAs) have been reported, such as the classical zinc-binding (exerted by sulfonamides and carboxylic acids) as well as occluding the entrance of the CA active site (exerted by coumarins). In this manuscript, we studied the effect of combining the pharmacopheric parts responsible for these two mechanisms on CA inhibitory potency and selectivity through the design and synthesis of novel coumarins tethered with the zinc-binding sulfonamide (5a-f, 11a-b and 13a-b) or carboxylic acid (7a-f) groups. In addition, another set of coumarin derivatives (9a-b) with no zinc-binding group (ZBG) was designed to act as non-classical CA inhibitors. The synthesized coumarins were examined for their inhibitory activities towards four hCA isoforms I, II, IX and XII. Coumarin sulfonamides (5a-f, 11a-b and 13a-b) effectively inhibited both tumor-associated hCA IX (KIs: 8.9-133.5 nM) and hCA XII (KIs: 3.4-42.9 nM) isoforms, whereas coumarin carboxylic acids (7a-f) weakly affected hCA IX (KIs: 0.49-11.2 µM) and hCA XII (KIs: 0.51-10.1 µM) isoforms. The coumarin based inhibitors featuring zinc-binding sulfonamide or carboxylic acid group achieved low to moderate hCA IX/XII selectivity. Interestingly, the ZBG-free coumarin derivatives (9a-b) emerged not only as effective hCA IX (KIs = 93.3 and 63.8 nM, respectively) and hCA XII (KIs = 85.7 and 72.1 nM, respectively) inhibitors, but also as a highly hCA IX/XII selective inhibitors over the off-target hCA I/II isoforms (SIs > 1000). Coumarin 9a was further evaluated for its anti-proliferative effect on MCF-7 and PANC-1 cancer cell lines, as well as its effect on the cell cycle and apoptosis towards MCF-7 cell line.
Assuntos
Anidrases Carbônicas , Neoplasias , Antígenos de Neoplasias/metabolismo , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Ácidos Carboxílicos/farmacologia , Cumarínicos/química , Humanos , Estrutura Molecular , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfanilamida , Sulfonamidas/química , ZincoRESUMO
A new and suitable multicomponent one-pot reaction was developed for the synthesis of 2-amino-3-cyanopyridine derivatives. BACKGROUND: This synthesis was demonstrated by the efficient and easy access to a variety of substituted 2-aminopyridines using enaminones as key precursors under solvent-free conditions. METHODS: A range of spectroscopic techniques was used to determine and confirm the chemical structures (FTIR, 1H NMR, 13C NMR). The antimicrobial potency of synthesized compounds (2a-d) was tested using disk diffusion assays, and the Minimum Inhibitory Concentration (MIC) for the active compounds was determined against a panel of microorganisms, including Gram-positive and Gram-negative bacteria and yeasts. Moreover, a docking analysis was conducted by Molecular Operating Environment (MOE) software to provide supplementary information about the potential, as well as an ADME-T prediction to describe the pharmacokinetic properties of the best compound and its toxicity. RESULTS: The results of the antimicrobial activity indicated that compound 2c showed the highest activity against Gram-positive bacteria, particularly S. aureus and B. subtilis whose MIC values were 0.039 ± 0.000 µg·mL-1. The results of the theoretical study of compound 2c were in line with the experimental data and exhibited excellent antibacterial potential. CONCLUSIONS: On the basis of the obtained results, compound 2c can be used as an antibacterial agent model with high antibacterial potency.
Assuntos
Antibacterianos , Anti-Infecciosos , Aminopiridinas/farmacologia , Antibacterianos/química , Anti-Infecciosos/farmacologia , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Staphylococcus aureus , Relação Estrutura-AtividadeRESUMO
A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1H-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower temperature and microwave power, although requiring much longer time. A possible mechanism for the cyclization is presented, and further functionalization of the newly created pyrrole ring in the dihydropyrrolizine core is described.
RESUMO
Concise construction of furan and thiophene units has played an important role in the synthesis of potentially bioactive compounds and functional materials. Herein, an efficient Lewis acid ZnCl2 catalyzed [4+1] annulation of alkylthio-substituted enaminones is reported, that is, α-oxo ketene N,S-acetals with sulfur ylides to afford 2-acyl-3-aminofuran derivatives. In a similar fashion, [4+1] annulation of the corresponding enaminothiones, that is, α-thioxo ketene N,S-acetals, with sulfur ylides efficiently proceeded to give multisubstituted 3-aminothiophenes. This method features wide substrate scopes as well as broad functional group tolerance, offering a concise route to highly functionalized furans and thiophenes.
RESUMO
Unprecedented phosphine-catalyzed [4+1] cycloadditions of allenyl imides have been discovered using various N-based substrates including methyl ketimines, enamines, and a primary amine. These transformations provide a one-pot access to cyclopentenoyl enamines and imines, or (chiral) γ-lactams through two geminal C-C bond or two C-N bond formations, respectively. Several P-based key intermediates including a 1,4-(bis)electrophilic α,ß-unsaturated ketenyl phosphonium species have been detected by 31 Pâ NMR and HRMS analyses, which shed light on the postulated catalytic cycle. The synthetic utility of this new chemistry has been demonstrated through a gram-scaling up of the catalytic reaction as well as regioselective hydrogenation and double condensation to form cyclopentanoyl enamines and fused pyrazole building blocks, respectively.
RESUMO
The reactions of thioamides with ortho-nitro-substituted iodonium ylides proceeded under mild conditions to give enaminones or thiazoles, depending on the iodonium ylide used. This protocol allowed the use of protic solvents, including aqueous solutions, and therefore coupling reactions with complex molecules such as peptides or steroids were possible. A mild and efficient method for the synthesis of various iodonium ylides was established. DFT calculations suggested that the halogen bonding between a thioamide and iodonium ylide was important in this chemoselective coupling reaction. The potential use of enaminones conjugated with pharmaceuticals as prodrugs was also demonstrated.
RESUMO
SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs: 0.21-7.1â¯nM), with 6- to 21-fold enhanced activity than SLC-0111 (KIâ¯=â¯45â¯nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 - >35714), hCA II (SI: 2 - 1689) and hCA IV (SI: 11 - >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.
Assuntos
Compostos de Anilina/farmacologia , Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Ensaios Enzimáticos , Humanos , Cinética , Estrutura Molecular , Compostos de Fenilureia/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Amide substituted (Z)-ß-enaminones were synthesized by green chemistry and stereo-specific synthetic pathway as novel phosphoinositide 3-kinase (PI3K) inhibitors and breast cancer drugs. PI3K inhibition was measured by competitive ELISA. A panel of cancer cell lines including MCF-7 (breast cancer), G-361 (skin cancer), and HCT 116 (colon cancer) were used to assess the anticancer potentials. In the PI3K assay, 2c and 2f were indolent for the proposed inhibitory action, which was recognized from the obtained IC50 (>1.0 µM). Excellent activity potential of 2a, 2b, and 2d was recognized from the IC50 range (<0.05 µM) whereas an intermediate action potential was observed for compounds 2e and 2i (IC50 0.1 and 0.25, respectively). The docking results exclusively proposed that the hydrophobic interactions in the PI3K binding pocket were overwhelmed by the binding affinity of the most potent ligands (2a, 2b, and 2d: inhibitory constant Ki = 18.16, 84.87, and 56.14 nM). MTT assay results revealed the antiproliferative activity domination of selected compounds (2a, 2b, and 2d) toward MCF-7. The relative activities of 2a, 2b, and 2d of 84.56, 80.87, and 90.12%, respectively, were comparable to that of the standard, doxorubicin (82.16%). SAR studies demonstrated amide substituted (Z)-ß-enaminones as precise PI3K inhibitors to treat breast cancer.
Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An efficient RhII -catalyzed synthesis of functionalized α-vinyl aldehydes with high E/Z stereoselectivity was developed. The reaction mediates the cyclopropanation of enaminones with vinyl carbenoids that are generated from cyclopropenes inâ situ to give the aminocyclopropane intermediates. Selective C-C bond cleavage of the cyclopropane intermediates leads to formation of α-vinyl aldehyde derivatives with high E/Z selectivity. This method proceeds at room temperature under very mild reaction conditions and works with a broad substrate scope.
RESUMO
The synthesis of 4-acyl-NH-1,2,3-triazoles has been accomplished with high efficiency through the cycloaddition reactions between N,N-dimethylenaminones and tosyl azide. This method is featured with extraordinary sustainability by employing water as the sole medium, free of any catalyst or additive, authentically mild conditions (40 °C stirring) as well as practical scalability.
RESUMO
Ethylenediamine-derived ß-enamino amides are used as equivalents of amide enolate synthons in C-acylation reactions with N-protected amino acids. Domino fragmentation of the obtained intermediates leads to functionalised ß-keto amides, bearing a protected amino group in their side chain.