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1.
Eur J Med Chem ; 185: 111780, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655429

RESUMO

Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC50 = 0.10-22.96 µM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1-258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13-44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of COX-2. The study of SAR revealed favorable cytotoxic outcomes of the aliphatic side chain and 4-thiazolidinone moiety at C6 of the pyrrolizine nucleus, while anti-inflammatory activities was improved with the (hetero)aromatic substituents. The IC50 values which inhibit COX-2 were higher than those needed to inhibit the growth of cancer cell lines. Mechanistic studies also revealed inhibition of multiple kinases by compounds 12, 19 and 22. Moreover, compounds 12, 14, 16 and 22 induced cell cycle arrest and apoptosis in MCF-7 cells. Docking studies revealed nice fitting of the new compounds into COX-1/2. Additionally, compounds 12, 19 and 22 also exhibited higher affinity for CDK2 than CAN508. To sum up, the above-mentioned data highlight these compounds as promising anti-inflammatory and anticancer agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Drogas , Edema/tratamento farmacológico , Pirrolidinas/farmacologia , Tiazolidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HT29 , Humanos , Células MCF-7 , Masculino , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tiazolidinas/química
2.
Eur J Med Chem ; 188: 111986, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31884407

RESUMO

Breast cancer is the second leading cause of deaths in women globally. Present communication deals with design and synthesis of a few diarylnaphthyls as possible anti-breast cancer agents. Among the thirty three representatives with significant antiproliferative activity compounds 23 and 50 were quite efficacious against human breast cancer cells. Compound 50 induced apoptosis in both MCF-7 and MDA-MB-231 cells and exerted S phase and G2/M phase arrest respectively via distinct mechanistic pathways. It showed moderate microtubule destabilization. Further, it exhibited DNA topoisomerase-II inhibition effect in MCF-7 cells. It was well tolerable and found safe up to 300 mg/kg dose in Swiss albino mice. The dual action antiproliferative effect of compound 50 is quite interesting and warrants for future development.


Assuntos
Antineoplásicos/farmacologia , Naftalenos/farmacologia , Pirrolidinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Naftalenos/síntese química , Naftalenos/toxicidade , Pirrolidinas/síntese química , Pirrolidinas/toxicidade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/toxicidade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/toxicidade
3.
Eur J Med Chem ; 182: 111654, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494474

RESUMO

A series of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives were designed and synthesized. Their protective activities against N-methyl-d-aspartic acid (NMDA)-induced cytotoxicity were investigated in vitro. All of the compounds exhibited neuroprotective activities, especially 12k, which showed higher potency than reference compound 1 (ifenprodil). Further investigation showed that 12k could attenuate Ca2+ influx and suppress the NR2B upregulation induced by NMDA. The docking results indicated that 12k could fit well into binding site of 1 in the NR2B-NMDA receptor. Additionally, 12k exhibited excellent metabolic stability. Furthermore, the results of behavioral tests showed that compound 12k could significantly improve learning and memory in vivo. These results suggested that 12k is a promising neuroprotective drug candidate and that the NR2B-NMDA receptor is a potential target of 12k.


Assuntos
Comportamento Animal/efeitos dos fármacos , Desenho de Drogas , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pirrolidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , N-Metilaspartato/antagonistas & inibidores , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Molecules ; 24(17)2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31450696

RESUMO

A library of novel 2-(het)arylpyrrolidine-1-carboxamides were obtained via a modular approach based on the intramolecular cyclization/Mannich-type reaction of N-(4,4-diethoxybutyl)ureas. Their anti-cancer activities both in vitro and in vivo were tested. The in vitro activity of some compounds towards M-Hela tumor cell lines was twice that of the reference drug tamoxifen, whereas cytotoxicity towards normal Chang liver cell did not exceed the tamoxifen toxicity. In vivo studies showed that the number of surviving animals on day 60 of observation was up to 83% and increased life span (ILS) was up to 447%. Additionally, some pyrrolidine-1-carboxamides possessing a benzofuroxan moiety obtained were found to effectively suppress bacterial biofilm growth. Thus, these compounds are promising candidates for further development both as anti-cancer and anti-bacterial agents.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Anti-Infecciosos/química , Antineoplásicos/química , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Pirrolidinas/química , Relação Estrutura-Atividade
5.
Chem Pharm Bull (Tokyo) ; 67(6): 599-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155566

RESUMO

The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543.


Assuntos
Antineoplásicos/síntese química , Pirrolidinas/química , Sulfonas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
6.
Amino Acids ; 51(7): 991-998, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079215

RESUMO

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-D-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of ß-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation. DMDP N-acetic and propionic acids are potent α-galactosidase inhibitors in contrast to potent ß-galactosidase inhibition by DMDP.


Assuntos
Acetatos/síntese química , Aminoácidos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/isolamento & purificação , Propionatos/síntese química , Pirrolidinas/síntese química , Stevia/química , Aminoácidos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Glicina/química , Glicosídeos/metabolismo , Hidroxiprolina/química , Imino Açúcares/química , Piperidinas/síntese química , alfa-Galactosidase/antagonistas & inibidores , beta-Alanina/química , beta-Galactosidase/antagonistas & inibidores
7.
Drug Test Anal ; 11(8): 1144-1161, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31033229

RESUMO

A number of substances based on the 1,2-diarylethylamine template have been investigated for various potential clinical applications whereas others have been encountered as research chemicals sold for non-medical use. Some of these substances have transpired to function as NMDA receptor antagonists that elicit dissociative effects in people who use these substances recreationally. 1-[1-(2-Fluorophenyl)-2-phenylethyl]pyrrolidine (fluorolintane, 2-F-DPPy) has recently appeared as a research chemical, which users report has dissociative effects. One common difficulty encountered by stakeholders confronting the appearance of new psychoactive substances is the presence of positional isomers. In the case of fluorolintane, the presence of the fluorine substituent on either the phenyl and benzyl moieties of the 1,2-diarylethylamine structure results in a total number of six possible racemic isomers, namely 2-F-, 3-F-, and 4-F-DPPy (phenyl ring substituents) and 2"-F-, 3"-F-, and 4"-F-DPPy (benzyl ring substituents). The present study reports the chemical syntheses and comprehensive analytical characterizations of the two sets of three positional isomers. These studies included various low- and high-resolution mass spectrometry platforms, gas- and liquid chromatography (GC and LC), nuclear magnetic resonance (NMR) spectroscopy and GC-condensed phase and attenuated total reflection infrared spectroscopy analyses. The differentiation between each set of three isomers was possible under a variety of experimental conditions including GC chemical ionization triple quadrupole tandem mass spectrometric analysis of the [M + H - HF]+ species. The latter MS method was particularly helpful as it revealed distinct formations of product ions for each of the six investigated substances.


Assuntos
Psicotrópicos/química , Pirrolidinas/química , Técnicas de Química Sintética , Cromatografia Gasosa-Espectrometria de Massas , Halogenação , Isomerismo , Espectroscopia de Ressonância Magnética , Psicotrópicos/síntese química , Pirrolidinas/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Espectrometria de Massas em Tandem
8.
Chemphyschem ; 20(11): 1475-1487, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30950574

RESUMO

Specific spin labeling allows the site-selective investigation of biomolecules by EPR and DNP enhanced NMR spectroscopy. A novel spin labeling strategy for commercially available Fmoc-amino acids is developed. In this approach, the PROXYL spin label is covalently attached to the hydroxyl side chain of three amino acids hydroxyproline (Hyp), serine (Ser) and tyrosine (Tyr) by a simple three-step synthesis route. The obtained PROXYL containing building-blocks are N-terminally protected by the Fmoc-protection group, which makes them applicable for the use in solid-phase peptide synthesis (SPPS). This approach allows the insertion of the spin label at any desired position during SPPS, which makes it more versatile than the widely used post synthetic spin labeling strategies. For the final building-blocks, the radical activity is proven by EPR. DNP enhanced solid-state NMR experiments employing these building-blocks in a TCE solution show enhancement factors of up to 26 for 1 H and 13 C (1 H→13 C cross-polarization). To proof the viability of the presented building-blocks for insertion of the spin label during SPPS the penta-peptide Acetyl-Gly-Ser(PROXYL)-Gly-Gly-Gly was synthesized employing the spin labeled Ser building-block. This peptide could successfully be isolated and the spin label activity proved by EPR and DNP NMR measurements, showing enhancement factors of 12.1±0.1 for 1 H and 13.9±0.5 for 13 C (direct polarization).


Assuntos
Aminoácidos/síntese química , Fluorenos/síntese química , Oligopeptídeos/síntese química , Pirrolidinas/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Marcadores de Spin/síntese química , Espectroscopia de Ressonância de Spin Eletrônica , Hidroxiprolina/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Serina/síntese química , Tirosina/síntese química
9.
Pharmacol Rep ; 71(2): 357-360, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30844686

RESUMO

BACKGROUND: A variety of spirooxindoles have demonstrated cytotoxic activity toward several cancer cell lines. This study investigates the cytotoxicity of five novel spirooxindole-pyrrolidines by using the Vero and HeLa cell lines. METHODS: Vero and HeLa cells were treated with the synthesized spirooxindoles, and the cytotoxicity was evaluated by using the AlamarBlue Cell Viability Reagent and live/dead assay. RESULTS: A series of poly-substituted pyrrolidines differing in nature and in substituent positions were obtained, with yields of 42-63%. Of the synthesized cycloadducts, 3-picolinoyl-4-(2,4-dichlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (4) was the most cytotoxic (IC50 < 20 µg/ml for both cell lines). Besides, 3-picolinoyl-4-(2-chlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (1) was three times more toxic to the HeLa cancer cell line (IC50 = 70 µg/ml) than it was to the Vero healthy cell line. The cytotoxicity of compounds 1 and 4 was confirmed with a live/dead assay. The cytotoxicity of a molecule was found to depend on the substitution nature on the benzene ring at the C-4 atom. CONCLUSION: 3-Picolinoyl-4-(2-chlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (1) can be used as a source for the synthesis of novel therapeutic agents against cancer.


Assuntos
Antineoplásicos/farmacologia , Oxindois/farmacologia , Pirrolidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células HeLa , Humanos , Concentração Inibidora 50 , Oxindois/síntese química , Oxindois/química , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade , Células Vero
10.
Org Lett ; 21(8): 2493-2497, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30816719

RESUMO

Successive nucleophilic and electrophilic allylation mediated by the bis-Boc-carbonate derived from 2-methylene-1,3-propane diol enables formation of enantiomerically enriched 2,4-disubstituted pyrrolidines. An initial enantioselective iridium-catalyzed transfer hydrogenative carbonyl C-allylation is followed by Tsuji-Trost N-allylation using 2-nitrobenzenesulfonamide. Subsequent Mitsunobu cyclization provides the N-protected 2,4-disubstituted pyrrolidines.


Assuntos
Compostos Alílicos/química , Pirrolidinas/síntese química , Catálise , Complexos de Coordenação/química , Reação de Cicloadição , Irídio/química , Nitrocompostos/química , Estereoisomerismo , Sulfonamidas/química
11.
Bioorg Med Chem Lett ; 29(6): 815-820, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30704812

RESUMO

The voltage-gated sodium channel, Nav1.1, is predominantly expressed in parvalbumin-positive fast spiking interneurons and has been genetically linked to Dravet syndrome. Starting from a high throughput screening hit isoxazole derivative 5, modifications of 5 via combinations of IonWorks and Q-patch assays successfully identified the nicotinamide derivative 4. Its increasing decay time constant (tau) of Nav1.1 currents at 0.03 µM along with significant selectivity against Nav1.2, Nav1.5, and Nav1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Nav1.1 activator that can be used to analyze pathophysiological functions of the Nav1.1 channel towards treating various central nervous system diseases.


Assuntos
Descoberta de Drogas , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Pirrolidinas/farmacologia , Agonistas do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Células CHO , Cricetulus , Camundongos , Estrutura Molecular , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Niacinamida/síntese química , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade , Agonistas do Canal de Sódio Disparado por Voltagem/síntese química , Agonistas do Canal de Sódio Disparado por Voltagem/química
12.
ACS Comb Sci ; 21(1): 1-5, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30485058

RESUMO

We present the solid-phase synthesis of 1,2-dihydroquinazoline-2-carboxylate derivatives with a quaternary carbon in position 2 and their subsequent cyclization in solution into compounds with unique 3D architectures and pharmacological relevance-spiroquinazolines, namely, 1' H-spiro[pyrrolidine-3,2'-quinazolin]-2-ones and 1' H-spiro[piperidine-3,2'-quinazolin]-2-ones. Acyclic precursors were prepared from commercially available building blocks: protected amino acids (2,4-diaminobutyric acid and ornithine), 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The crucial step of the synthesis was a base-mediated tandem reaction including C-arylation followed by cyclization into indazole oxides, and the formation of a 5-membered heterocycle was accomplished by ring expansion into quinazolines. These derivatives were cyclized into spiro compounds in solution after cleavage from the resin.


Assuntos
Piperidinas/síntese química , Pirrolidinas/síntese química , Quinazolinas/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Compostos de Espiro/síntese química , Acetofenonas/química , Aminobutiratos/química , Ciclização , Nitrobenzenos/química , Ornitina/química
13.
Bioorg Chem ; 82: 423-430, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30508794

RESUMO

Anticancer therapeutics with profiles of high potency, low toxicity, and low resistance is of considerable interest. A new series of functionalized spirooxindole linked with 3-acylindole scaffold is reported, starting from chalcones derived from 3-acetyl indole with isatin, and l-4-thiazolidinecarboxylic acid. The reactions proceeded regioselectivity, stereoselectivity, without side products in high yield (71-89%). The new spirooxindole hybrids have been evaluated in vitro for their antiproliferative effects against colon cancer (HCT-116), hepatocellular carcinoma (HepG2) and prostate cancer (PC-3). The selectivity of their activity was evaluated. Some of the synthesized compounds showed considerable anticancer activities. Compound 4k proved to retain a high cytotoxic activity and selectivity against colon cancer cells HCT-116 (IC50 = 7 ±â€¯0.27 µM, SI: 3.7), and HepG2 (IC50 = 5.5 ±â€¯0.2 µM, SI: 4.7) in comparison to (IC50 = 12.6 ±â€¯0.5, SI: 0.4 and 5.5 ±â€¯0.3 µM, SI: 0.9, respectively). Compound 4k was less active (IC50 = 6 ±â€¯0.3 µM, SI: 4.3) than cisplatin (IC50 = 5 ±â€¯0.56 µM, SI: 1.0) but showed greater selectivity towards prostate cancer cells PC-3 in comparison to cisplatin. The details of the binding mode of the active compounds were clarified by molecular docking. Ligand Efficiency (LE) and Ligand Lipophilic Efficiency (LLE) were evaluated and revealed that compound 4k had acceptable value.


Assuntos
Antineoplásicos/farmacologia , Oxindois/farmacologia , Pirrolidinas/farmacologia , Compostos de Espiro/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxindois/síntese química , Oxindois/química , Oxindois/toxicidade , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/toxicidade , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/toxicidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Células Vero
14.
Bioorg Chem ; 83: 226-234, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30380451

RESUMO

In this work, we describe the regioselective synthesis of some new dispiro[indene-2,3'-pyrrolidine-2',3″-indoline]-1,2″(3H)-dione 4-29 attributable to the previously described methods. All the new chemical entities were assessed in-vitro as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes; while no significant inhibitory activity for the tested compounds were assigned on AChE, compounds 4, 27, 29, 28 and 15 were the most active against BChE enzyme with IC50 = 13.7 µM, 21.8 µM, 22.1 µM, 22.9 µM and 24.9 µM respectively compared to Donepezil (IC50 = 0.72 µM). Compound 4 was found to have a mixed type mode of inhibition, the bioactivity of the new chemical entities (N = 26, n = 5, R2 = 0.893, R2 cvOO = 0.831, R2 cvMO = 0.838, F = 33.32, s2 = 0.003) was elucidated via a statistically significant QSAR model utilizing CODESSA-Pro software that validated the observed results.


Assuntos
Inibidores da Colinesterase/química , Oxindois/química , Pirrolidinas/química , Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/síntese química , Estrutura Molecular , Oxindois/síntese química , Pirrolidinas/síntese química , Relação Quantitativa Estrutura-Atividade
15.
Chem Biodivers ; 16(1): e1800490, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30382617

RESUMO

The approach to the novel 1-[(2-aminoethyl)sulfonyl]-2-arylpyrrolidines via unique intramolecular cyclization/aza-Michael reactions of N-(4,4-diethoxybutyl)ethenesulfonamide have been developed, which benefits from high yields of target compounds, mild reaction conditions, usage of inexpensive and low-toxic reagents, and allows for wide variability in both amine and aryl moieties. Biotesting with whole-cell luminescent bacterial biosensors responding to DNA damage showed that all tested compounds are not genotoxic. Tested compounds differently affect the formation of biofilms by Vibrio aquamarinus DSM 26054. Some of the tested compounds were found to suppress the bacterial biofilms growth and thus are promising candidates for further studies.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Vibrio/efeitos dos fármacos , Antibacterianos/química , Biomassa , Dano ao DNA , Pirrolidinas/química , Solubilidade , Análise Espectral/métodos , Vibrio/genética , Vibrio/crescimento & desenvolvimento , Vibrio/metabolismo , Água/química
16.
Bioorg Chem ; 82: 100-108, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30278281

RESUMO

Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on a N1-(isoquinolin-5-yl)-N2-phenylpyrrolidine-1,2-dicarboxamide platform that evolved from a 5-aminoisoquinoline urea lead. Advancing the SAR of this series led to the eventual identification of 3b, comprising a p-Br substituted phenyl. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 3b displayed potent antagonism activated by capsaicin (IC50 = 0.084 µM) and protons (IC50 = 0.313 µM). In the preliminary analgesic and body temperature tests, 3b exhibited good efficacy in capsaicin-induced and heat-induced pain models and without hyperthermia side-effect. On the basis of its superior profiles, 3b could be considered as the lead candidate for the further development of antinociceptive drugs.


Assuntos
Analgésicos/farmacologia , Isoquinolinas/farmacologia , Pirrolidinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Masculino , Camundongos , Estrutura Molecular , Dor/tratamento farmacológico , Pirrolidinas/administração & dosagem , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Relação Estrutura-Atividade
17.
Carbohydr Res ; 472: 103-114, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30544044

RESUMO

A critical step in the synthesis of the hydroxypyrrolidines, 1,4-dideoxy-1,4-imino-l-lyxitol and 1,4-dideoxy-1,4-imino-d-lyxitol, from the corresponding d-sugars is the synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses. Instead of applying homogeneous catalysis process with conventional inorganic acid catalysts like HCl and HClO4, it was found that heterogeneous catalysis using zeolites could be used for the one-pot synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses directly from d-sugars, MeOH and acetone at mild condition. The best catalyst was H-beta zeolite containing a Si/Al molar ratio of 150, where a yield of >83% was obtained. The overall yields of the five-step procedure to 1,4-dideoxy-1,4-imino-l-lyxitol and 1,4-dideoxy-1,4-imino-d-lyxitol were 57% and 50%, respectively. This synthetic procedure has several advantages such as competitive overall yield, reduced number of steps, and mild reaction conditions. Furthermore, the zeolite catalyst can be easily recovered from the reaction mixture and reused with no loss of activity.


Assuntos
Pirrolidinas/síntese química , Zeolitas/química , Catálise , Química Verde , Estrutura Molecular , Pirrolidinas/química
18.
J Anal Toxicol ; 43(1): e1-e6, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30060126

RESUMO

We report the analysis of the synthetic cathinones α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinopentiophenone (α-PVP), both pyrovalerone derivatives, in blood, urine, gastric contents, main tissues and hair of a deceased person. Qualitative and quantitative analyses were performed by LC-MS-MS. All the biological samples were collected during autopsy and extracted/purified onto a solid phase extraction cartridge before instrumental analysis. The method was validated for blood and urine and proved to be highly sensitive and specific for both the synthetic cathinones (limit of detection: 0.2 ng/mL and limit of quantification: 0.5 ng/mL). Analyses provided negative results for α-PVP in all biological samples except for the 2-cm proximal hair segment, confirming that the young man had consumed in the last 2 months this compound; instead hair analysis proved that the man was a heavy α-PHP user. α-PHP was identified and quantified in biological fluids and tissues. Interestingly, bile and urine concentrations (1.2 and 5.6 ng/mL, respectively) were fairly lower than blood collected into the thoracic cavity (15.3 ng/mL). The highest concentrations were measured for lung (71.1 ng/mL) and spleen (83.8 ng/mL). Concentrations of 3.5, 7.9, 4.7 and 23.6 ng/mL were measured in liver, kidney, brain and heart, respectively. Even if it is not possible to evaluate the presence of this drug in biological samples as a cause of death, to our knowledge, this is the first case of α-PHP finding in postmortem samples, and its potential toxic effects should be elucidated in the future.


Assuntos
Líquidos Corporais/química , Pirrolidinas/análise , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Adulto , Autopsia , Bile/química , Causas de Morte , Cromatografia Líquida de Alta Pressão , Toxicologia Forense/métodos , Suco Gástrico/química , Cabelo/química , Humanos , Masculino , Pirrolidinas/sangue , Pirrolidinas/síntese química , Pirrolidinas/urina , Extração em Fase Sólida , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Espectrometria de Massas em Tandem , Distribuição Tecidual
19.
ChemMedChem ; 13(23): 2488-2503, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30485691

RESUMO

In this study, pyrrolidine-3-acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ-aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine-3-acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution experiments to identify single oximes responsible for the observed activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine-3-acetic acid motif were found, of which the most potent oxime, possessing a 2',4'-dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi =7.87±0.01).


Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/química , Inibidores da Captação de GABA/farmacologia , Oximas/química , Oximas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Animais , Inibidores da Captação de GABA/síntese química , Camundongos , Oximas/síntese química , Ligação Proteica , Pirrolidinas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
20.
Molecules ; 23(10)2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30274224

RESUMO

In order to provide a more detailed view on the structure⁻antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1a⁻d)/dichlorides (1e⁻h) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1i⁻l)/dichlorides (1m⁻p; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube's stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1a⁻p was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M. tuberculosis H37Ra ATCC 25177, M. kansasii CNCTC My 235/80 (identical with ATCC 12478), the M. kansasii 6509/96 clinical isolate, M. kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M. smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set 1a⁻p were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 µM to 8 µM, which were lower compared to those of used standards, especially if concerning ability to fight M. tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1a⁻p represented a very promising molecular framework for development of 'non-traditional' but effective antimycobacterial agents.


Assuntos
Antituberculosos/síntese química , Azepinas/síntese química , Mycobacterium/efeitos dos fármacos , Oxalatos/química , Fenilcarbamatos/síntese química , Pirrolidinas/síntese química , Antituberculosos/farmacologia , Azepinas/farmacologia , Ciprofloxacino/química , Ciprofloxacino/uso terapêutico , Simulação por Computador , Desenho de Drogas , Etambutol/química , Etambutol/uso terapêutico , Isoniazida/química , Isoniazida/uso terapêutico , Testes de Sensibilidade Microbiana , Mycobacterium avium/efeitos dos fármacos , Mycobacterium kansasii/efeitos dos fármacos , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Ofloxacino/química , Ofloxacino/uso terapêutico , Oxalatos/farmacologia , Fenilcarbamatos/farmacologia , Pirrolidinas/farmacologia , Solubilidade , Relação Estrutura-Atividade
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