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1.
Arch Pharm (Weinheim) ; 352(5): e1800373, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025433

RESUMO

N'-Cyanoisonicotinamidine and N'-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5-HT1A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1 , D2 , α1 , and α2 ). Compound 8e (Ki = 21.4 nM) was the most affine for the 5-HT2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds 4a and 4c, instead, showed an interesting mixed 5-HT1A /5-HT2C activity with Ki values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5-HT2C (4a, 4c, 8b, and 8e) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that compounds 4a, 8b, and 8e exerted antidepressant-like effects and 4a and 8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be 4a, which displayed antipsychotic-, antidepressant- and anxiolytic-like properties. No side effects, like catalepsy, motor-impairment or ethanol-potentiating effects, were observed after the injection of the tested compounds.


Assuntos
Amidinas/metabolismo , Antipsicóticos/farmacologia , Simulação de Acoplamento Molecular , Receptor 5-HT2C de Serotonina/metabolismo , Amidinas/síntese química , Amidinas/química , Amidinas/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
2.
Org Biomol Chem ; 17(12): 3118-3128, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30730519

RESUMO

An efficient four-step, six-transformation protocol was developed to afford bioactive N-alkyl- or N-arylamide (E)-arylamidines featuring strategic amidine C3 modifications which were inaccessible or low yielding by previous methods. This synthetic approach, exemplified with 24 amidines and requiring only a single purification, highlights a multicomponent Ugi-Mumm rearrangement to afford highly diversified quinazolinones which undergo regiospecific rearrangement to afford new amidines. The method extensively broadens the structural scope of this new class of trisubstituted amidines and demonstrates the tolerance of regional C3 amidine steric bulk, visualized with X-ray crystallographic analysis.


Assuntos
Amidinas/síntese química , Quinazolinonas/química , Amidinas/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
3.
J Labelled Comp Radiopharm ; 61(14): 1095-1105, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30375667

RESUMO

GluN2B-containing NMDA receptors (NMDARs) play fundamental roles in learning and memory, although they are also associated with various brain disorders. In this study, we synthesized and evaluated three 11 C-labeled N-benzyl amidine derivatives 2-[11 C]methoxybenzyl) cinnamamidine ([11 C]CBA), N-(2-[11 C]methoxybenzyl)-2-naphthamidine ([11 C]NBA), and N-(2-[11 C]methoxybenzyl)quinoline-3-carboxamidine ([11 C]QBA) as PET radioligands for these receptors. The 11 C-benzyl amidines were synthesized via conventional methylation of corresponding des-methyl precursors with [11 C]CH3 I. In vitro binding characteristics were examined in brain sagittal sections using various GluN2B modulators and off-target ligands. Further, in vivo brain distribution studies were performed in normal mice. The 11 C-labeled benzyl amidines showed high-specific binding to the GluN2B subunit at in vitro. In particular, the quinoline derivative [11 C]QBA had the best binding properties in terms of high-brain localization to GluN2B-rich regions and specificity to the GluN2B subunit. Conversely, these 11 C-radioligands showed the brain distributions were inconsistent with GluN2B expression in biodistribution experiments. The majority of the radiolabeled compounds were identified as metabolized forms of which amido derivatives seemed to be the major species. Although these 11 C-ligands had high-specific binding to the GluN2B subunit, significant improvement in metabolic stability is necessary for successful positron emission tomography (PET) imaging of the GluN2B subunit of NMDARs.


Assuntos
Amidinas/síntese química , Amidinas/metabolismo , Radioisótopos de Carbono , Tomografia por Emissão de Pósitrons/métodos , Receptores de N-Metil-D-Aspartato/metabolismo , Amidinas/química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Técnicas de Química Sintética , Marcação por Isótopo , Ligantes , Camundongos , Radioquímica
4.
Eur J Med Chem ; 150: 771-782, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29604581

RESUMO

A series of novel diamidines with N-substituents on an amidine N-atom were synthesized and evaluated for their cytotoxicity and in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacterial strains. Based on structure-activity relationship, N-substituents with a branched chain and a shorter carbon chain on the amidine N-atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria; compounds 5c and 5i were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug-resistant Gram-positive bacteria and exhibited broad-spectrum antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2-16 µg/mL. Slightly more potent antibacterial activity against Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterobacter cloacae, and Proteus mirabilis was observed for 5i in comparison with 5c. Compound 5i also showed remarkable antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2-4 µg/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an ED50values of 2.62 mg/kg.


Assuntos
Amidinas/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Indóis/farmacologia , Amidinas/síntese química , Amidinas/química , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 28(8): 1292-1297, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29567345

RESUMO

Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC50 value of 0.3 µM.


Assuntos
Amidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Quinona Redutases/antagonistas & inibidores , Amidinas/síntese química , Amidinas/química , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Furanos/síntese química , Furanos/química , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Oxazóis/farmacologia , Oximas/síntese química , Oximas/química , Oximas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
6.
Eur J Med Chem ; 143: 1616-1634, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29133046

RESUMO

A series of novel amidino 2-substituted benzimidazoles linked to 1,4-disubstituted 1,2,3-triazoles were synthesized by implementation of microwave and ultrasound irradiation in click reaction and subsequent condensation of thus obtained 4-(1,2,3-triazol-1-yl)benzaldehyde with o-phenylenediamines. In vitro antiproliferative screening of compounds performed on human cancer cell lines revealed that p-chlorophenyl-substituted 1,2,3-triazolyl N-isopropylamidine 10c and benzyl-substituted 1,2,3-triazolyl imidazoline 11f benzimidazoles had selective and potent cytostatic activities in the low nM range against non-small cell lung cancer cell line A549, which could be attributed to induction of apoptosis and primary necrosis. Additional Western blot analyses showed different mechanisms of cytostatic activity between compounds 10c and 11f that could be associated with the nature of aromatic substituent at 1-(1,2,3-triazolyl) and amidino moiety at C-5 position of benzimidazole ring. Specifically, compound 11f abrogated the activity of several protein kinases including TGM2, CDK9, SK1 and p38 MAPK, whereas compound 10c did not have profound effect on the activities of CDK9 and TGM2, but instead showed moderate downregulation of SK1 activity concomitant with a significant reduction in p38 MAPK. Further in silico structural analysis demonstrated that compound 11f bound slightly better to the ATP binding site of p38 MAPK compared to 10c, which correlated well with observed stronger decrement in the expression level of phospho-p38 MAPK elicited by 11f in comparison with 10c.


Assuntos
Amidinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desenho de Drogas , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Amidinas/síntese química , Amidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Quinases , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
7.
Chemistry ; 23(65): 16574-16585, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-28940589

RESUMO

Inhibition of the heat shock protein 90 (Hsp90) C-terminus represents a promising therapeutic strategy for the treatment of cancer. Novobiocin, a coumarin antibiotic, was the first Hsp90 C-terminal inhibitor identified, however, it manifested poor anti-proliferative activity (SKBr3, IC50 ≈700 µm). Subsequent structure-activity relationship (SAR) studies on novobiocin led to development of several analogues that exhibited improved anti-proliferative activity against several cancer cell lines. Recent studies demonstrate that the biphenyl core could be used in lieu of the coumarin ring system, which resulted in more efficacious analogues. In continuation of previous efforts, the work described herein has identified the phenyl cyclohexyl core as a novel scaffold for Hsp90 C-terminal inhibition. Structure-activity relationship (SAR) studies on this scaffold led to the development of compounds that manifest mid-nanomolar activity against SKBr3 and MCF-7 breast cancer cell lines through Hsp90 inhibition.


Assuntos
Amidinas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Amidinas/síntese química , Amidinas/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Células MCF-7 , Novobiocina/química , Novobiocina/toxicidade , Domínios Proteicos , Relação Estrutura-Atividade
8.
An Acad Bras Cienc ; 89(2): 1051-1059, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28640352

RESUMO

A series of arylamidines 3a-j was designed, synthesized and investigated for antimicrobial activity. Structures of the compounds were confirmed by IR, 1H-NMR and 13C-NMR and a 2D spectroscopic study was performed. A preliminary screening of the antimicrobial tests clearly showed that three out of ten arylamidines, viz, 3f, 3g and 3i, were effective against all the gram-negative bacteria: Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella enteric; and against the yeast, candida albicans. Further, the Minimum Inhibitory Concentrations (MIC) against the bacteria and yeast were determined. All compounds 3a-d, 3f, 3g, 3i and 3j were also investigated for their low cytotoxic effects on tested cell lines. Compounds 3d and 3f were the most effective derivatives against HL-60 and HEp-2 cells, respectively, with IC50 value (2µg/mL), and low normal cells toxicity.


Assuntos
Amidinas/síntese química , Amidinas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Candida albicans/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Teste de Materiais , Testes de Sensibilidade Microbiana , Reprodutibilidade dos Testes , Espectrofotometria Infravermelho , Sais de Tetrazólio , Tiazóis , Testes de Toxicidade
9.
Drug Des Devel Ther ; 11: 1095-1105, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28435221

RESUMO

Arylimidamides (AIAs), previously termed as reversed amidines, present a broad spectrum of activity against intracellular microorganisms. In the present study, three novel AIAs were evaluated in a mouse model of Trypanosoma cruzi infection, which is the causative agent of Chagas disease. The bis-AIAs DB1957, DB1959 and DB1890 were chosen based on a previous screening of their scaffolds that revealed a very promising trypanocidal effect at nanomolar range against both the bloodstream trypomastigotes (BTs) and the intracellular forms of the parasite. This study focused on both mesylate salts DB1957 and DB1959 besides the hydrochloride salt DB1890. Our current data validate the high activity of these bis-AIA scaffolds that exhibited EC50 (drug concentration that reduces 50% of the number of the treated parasites) values ranging from 14 to 78 nM and 190 to 1,090 nM against bloodstream and intracellular forms, respectively, also presenting reasonable selectivity indexes and no mutagenicity profile predicted by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET). Acute toxicity studies using murine models revealed that these AIAs presented only mild toxic effects such as reversible abdominal contractions and ruffled fur. Efficacy assays performed with Swiss mice infected with the Y strain revealed that the administration of DB1957 for 5 consecutive days, with the first dose given at parasitemia onset, reduced the number of BTs at the peak, ranging between 21 and 31% of decrease. DB1957 was able to provide 100% of animal survival, while untreated animals showed 70% of mortality rates. DB1959 and DB1890B did not reduce circulating parasitism but yielded >80% of survival rates.


Assuntos
Amidinas/farmacologia , Doença de Chagas/tratamento farmacológico , Modelos Animais de Doenças , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Amidinas/síntese química , Amidinas/química , Animais , Doença de Chagas/parasitologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Fenótipo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química
10.
J Org Chem ; 82(5): 2515-2522, 2017 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-28150496

RESUMO

A Pd-catalyzed and ligand-free carbonylation/cycloaddition/decarboxylation cascade synthesis of sulfonyl amidines from sulfonyl azides and substituted amides at low CO pressure is reported. The reaction proceeds via an initial Pd-catalyzed carbonylative generation of sulfonyl isocyanates from sulfonyl azides, followed by a [2 + 2] cycloaddition with amides and subsequent decarboxylation, which liberates the desired sulfonyl amidines, generating N2 and CO2 as the only reaction byproducts. Using this simple protocol, a diverse range of sulfonyl amidines was obtained in moderate to excellent yields. In addition, the reaction can also be directed through a more conventional amidocarbonylation pathway by employing N-monosubstituted amide nucleophiles to afford acyl sulfonyl ureas in good yields.


Assuntos
Amidas/química , Amidinas/síntese química , Azidas/química , Monóxido de Carbono/química , Sulfonas/química , Ureia/síntese química , Reação de Cicloadição , Análise Espectral/métodos , Ureia/química
11.
Bioorg Med Chem Lett ; 26(24): 5907-5910, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27843114

RESUMO

A series of novel benzimidazole diamidines were prepared from the corresponding dicyano analogues either by applying Pinner methodology (5a-c, 10 and 13a) or by making amidoximes intermediates that were reduced to the corresponding amidines (15a-c). The new amidines were evaluated in vitro against the protozoan parasite Trypanosoma brucei rhodesiense (T. b. r.). The thiophene analogue 5b and the N-methyl compound 15a showed superior antitrypanosomal activity compared to that of the parent I.


Assuntos
Amidinas/farmacologia , Benzimidazóis/farmacologia , DNA/efeitos dos fármacos , Indóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Amidinas/síntese química , Amidinas/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Sítios de Ligação/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Estrutura Molecular , Mioblastos/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Ratos , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química
12.
Org Lett ; 18(18): 4714-7, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27607538

RESUMO

Trimethylsilyl-transient protection successfully allowed the use of lithium hexamethyldisilazane to prepare benzimidazole (BI) and 4-azabenzimidazole (azaBI) amidines from nitriles in 58-88% yields. This strategy offers a much better choice to prepare BI/azaBI amidines than the lengthy, low-yielding Pinner reaction. Synthesis of aza/benzimidazole rings from aromatic diamines and aldehydes was affected in dimethyl sulfoxide in 10-15 min, while known procedures require long time and purification. These methods are important for the BI/azaBI-based drug industry and for developing specific DNA binders for expanded therapeutic applications.


Assuntos
Amidinas/síntese química , Compostos Aza/química , Benzimidazóis/química , Imidazóis/síntese química , Compostos de Lítio/química , Nitrilos/química , Silanos/química , Amidinas/química , Compostos Aza/síntese química , Benzimidazóis/síntese química , Dimetil Sulfóxido/química , Imidazóis/química , Estrutura Molecular , Nitrilos/síntese química
13.
Bioorg Med Chem ; 24(16): 3371-7, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27298003

RESUMO

Aiming at the development of potent inhibitors of ß-glucosidases, a small library of galactonoamidines and one arabinoamidine derived in analogy were studied as inhibitors of sweet almond ß-glucosidase. The five-membered glycon in arabinoamidine was shown to interact with the proton donor in the active site of the retaining enzyme, but not with the nucleophile. By contrast, the corresponding galactonoamidine with a six-membered glycon and identical aglycon interacts with both hydrolysis-promoting amino acids in the active site and inhibits the enzymatic hydrolysis of ß-glucosides in the low nanomolar concentration range. While both inhibitors are competitive, their inhibition ability is more than 37,000-fold different.


Assuntos
Amidinas/síntese química , Amidinas/farmacologia , Inibidores Enzimáticos/farmacologia , beta-Glucosidase/antagonistas & inibidores , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Domínio Catalítico , Hidrólise , Cinética , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , beta-Glucosidase/metabolismo
14.
ChemMedChem ; 11(13): 1428-35, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27245480

RESUMO

Myotonic dystrophy is the most common form of adult-onset muscular dystrophy, originating in a CTG repeat expansion in the DMPK gene. The expanded CUG transcript sequesters MBNL1, a key regulator of alternative splicing, leading to the misregulation of numerous pre-mRNAs. We report an RNA-targeted agent as a possible lead compound for the treatment of myotonic dystrophy type 1 (DM1) that reveals both the promise and challenges for this type of small-molecule approach. The agent is a potent inhibitor of the MBNL1-rCUG complex with an inhibition constant (Ki ) of 25±8 nm, and is also relatively nontoxic to HeLa cells, able to dissolve nuclear foci, and correct the insulin receptor splicing defect in DM1 model cells. Moreover, treatment with this compound improves two separate disease phenotypes in a Drosophila model of DM1: adult external eye degeneration and larval crawling defect. However, the compound has a relatively low maximum tolerated dose in mice, and its cell uptake may be limited, providing insight into directions for future development.


Assuntos
Amidinas/uso terapêutico , Distrofia Miotônica/tratamento farmacológico , Proteínas de Ligação a RNA/antagonistas & inibidores , Triazinas/uso terapêutico , Expansão das Repetições de Trinucleotídeos , Amidinas/síntese química , Amidinas/farmacologia , Animais , Animais Geneticamente Modificados , Carbocianinas/química , Química Click , Reação de Cicloadição , Drosophila , Corantes Fluorescentes/química , Células HeLa , Humanos , Ligantes , Camundongos , RNA/antagonistas & inibidores , Processamento de RNA/efeitos dos fármacos , Receptor de Insulina/genética , Triazinas/síntese química , Triazinas/farmacologia
15.
Drug Des Devel Ther ; 10: 1133-46, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27042005

RESUMO

This research work deals with the design and synthesis of a series of substituted phenylfuranylnicotinamidines 4a-i. Facile preparation of the target compounds was achieved by Suzuki coupling-based synthesis of the nitrile precursors 3a-i, followed by their conversion to the corresponding nicotinamidines 4a-i utilizing LiN(TMS)2. The antimicrobial activities of the newly synthesized nicotinamidine derivatives were evaluated against the Gram-negative bacterial strains Escherichia coli and Pseudomonas aeruginosa as well as the Gram-positive bacterial strains Staphylococcus aureus and Bacillus megaterium. The minimum inhibitory concentration values of nicotinamidines against all tested microorganisms were in the range of 10-20 µM. In specific, compounds 4a and 4b showed excellent minimum inhibitory concentration values of 10 µM against Staphylococcus aureus bacterial strain and were similar to ampicillin as an antibacterial reference. On the other hand, selected nicotinamidine derivatives were biologically screened for their cytotoxic activities against a panel of 60 cell lines representing nine types of human cancer at a single high dose at National Cancer Institute, Bethesda, MD, USA. Nicotinamidines showing promising activities were further assessed in a five-dose screening assay to determine their compound concentration causing 50% growth inhibition of tested cell (GI50), compound concentration causing 100% growth inhibition of tested cell (TGI), and compound concentration causing 50% lethality of tested cell (LC50) values. Structure-activity relationship studies demonstrated that the activity of members of this series can be modulated from cytostatic to cytotoxic based on the substitution pattern/nature on the terminal phenyl ring. The most active compound was found to be 4e displaying a submicromolar GI50 value of 0.83 µM, with TGI and LC50 values of 2.51 and 100 µM, respectively. Finally, the possible underlying mechanism of action of this series of compounds was investigated by determining their nuclease-like DNA degradation ability in addition to their antioxidant power and all monocations proved to be effective in all assays.


Assuntos
Amidinas/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Piridinas/farmacologia , Amidinas/síntese química , Amidinas/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
16.
Org Lett ; 18(8): 1864-7, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27020621

RESUMO

A cesium carbonate promoted three-component reaction of N-H containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an amine to preformed α-iminoketones, followed by an air- or oxygen-mediated oxidation to form α-oxo-acetamidines. The scope of the reaction is enticingly broad, and this novel methodology is applied toward the synthesis of various polycyclic heterocycles.


Assuntos
Amidinas/síntese química , Aminas/química , Carbonatos/química , Césio/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Indóis/química , Nitrogênio/química , Amidinas/química , Catálise , Estrutura Molecular , Oxirredução
17.
Eur J Med Chem ; 111: 33-45, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-26854376

RESUMO

NRH:quinone oxidoreductase 2 enzyme (NQO2) is a potential therapeutic target in cancer and neurodegenerative diseases, with roles in either chemoprevention or chemotherapy. Here we report the design, synthesis and evaluation of non-symmetrical furan-amidines and their analogues as novel selective NQO2 inhibitors with reduced adverse off-target effects, such as binding to DNA. A pathway for the synthesis of the non-symmetrical furan-amidines was established from the corresponding 1,4-diketones. The synthesized non-symmetrical furan-amidines and their analogues showed potent NQO2 inhibition activity with nano-molar IC50 values. The most active compounds were non-symmetrical furan-amidines with meta- and para-nitro substitution on the aromatic ring, with IC50 values of 15 nM. In contrast to the symmetric furan-amidines, which showed potent intercalation in the minor grooves of DNA, the synthesized non-symmetrical furan-amidines showed no affinity towards DNA, as demonstrated by DNA melting temperature experiments. In addition, Plasmodium parasites, which possess their own quinone oxidoreductase PfNDH2, were inhibited by the non-symmetrical furan-amidines, the most active possessing a para-fluoro substituent (IC50 9.6 nM). The high NQO2 inhibition activity and nanomolar antimalarial effect of some of these analogues suggest the lead compounds are worthy of further development and optimization as potential drugs for novel anti-cancer and antimalarial strategies.


Assuntos
Amidinas/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Furanos/farmacologia , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Amidinas/síntese química , Amidinas/química , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
18.
Bioorg Med Chem ; 24(4): 661-71, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26740154

RESUMO

Several galactonoamidines were previously identified as very potent competitive inhibitors that exhibit stabilizing hydrophobic interactions of the aglycon in the active site of ß-galactosidase (Aspergillus oryzae). To elucidate the contributions of the glycon to the overall inhibition ability of the compounds, three glyconoamidine derivatives with alteration in the glycon at C-2 and C-4 were synthesized and evaluated herein. All amidines are competitive inhibitors of ß-galactosidase (Escherichia coli) and show significantly reduced inhibition ability when compared to the parent. The results highlight strong hydrogen-bonding interactions between the hydroxyl group at C-2 of the amidine glycon and the active site of the enzyme. Slightly weaker H-bonds are promoted through the hydroxyl group at C-4. The inhibition constants were determined to be picomolar for the parent galactonoamidine, and nanomolar for the designed derivatives rendering all glyconoamidines very potent inhibitors of glycosidases albeit the derivatized amidines show up to 700-fold lower inhibition activity than the parent.


Assuntos
Amidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , beta-Galactosidase/antagonistas & inibidores , Amidinas/síntese química , Amidinas/química , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligações de Hidrogênio , Estrutura Molecular , Relação Estrutura-Atividade , beta-Galactosidase/metabolismo
19.
J Pharm Biomed Anal ; 120: 419-24, 2016 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-26689740

RESUMO

Nitric Oxide Synthase (NOS) inhibitors could play a powerful role in inflammatory and neurodegenerative diseases. In this work, novel acetamidine derivatives of NOS were synthesized and the inhibitor activity was evalued. To screen the activity and selectivity, the l-citrulline residue, after the enzymatic NOS assay, was derivatized with o-phthaldialdehyde/N-acetyl cysteine (OPA/NAC) and then evaluated by RP-HPLC method with fluorescence detection. All compounds did not affect the activity of endothelial and neuronal isoforms, while nine of them possessed a percentage of iNOS activity at 10µM lower than 50%, and were selected for IC50 evaluation. Among them, a compound emerged as a very potent (IC50 of 53nM) and selective iNOS inhibitor.


Assuntos
Amidinas/síntese química , Inibidores Enzimáticos/análise , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/análise , Amidinas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacocinética , Óxido Nítrico Sintase Tipo II/metabolismo
20.
Angew Chem Int Ed Engl ; 54(49): 14715-8, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26458230

RESUMO

Protein arginine phosphorylation is a post-translational modification (PTM) that is important for bacterial growth and virulence. Despite its biological relevance, the intrinsic acid lability of phosphoarginine (pArg) has impaired studies of this novel PTM. Herein, we report for the first time the development of phosphonate amidines and sulfonate amidines as isosteres of pArg and then use these mimics as haptens to develop the first high-affinity sequence independent anti-pArg specific antibody. Employing this anti-pArg antibody, we further showed that arginine phosphorylation is induced in Bacillus subtilis during oxidative stress. Overall, we expect this antibody to see widespread use in analyzing the biological significance of arginine phosphorylation. Additionally, the chemistry reported here will facilitate the generation of pArg mimetics as highly potent inhibitors of the enzymes that catalyze arginine phosphorylation/dephosphorylation.


Assuntos
Amidinas/imunologia , Anticorpos/imunologia , Especificidade de Anticorpos , Arginina/análogos & derivados , Organofosfonatos/imunologia , Amidinas/síntese química , Amidinas/química , Arginina/química , Arginina/imunologia , Arginina/metabolismo , Bacillus subtilis/metabolismo , Haptenos/química , Haptenos/imunologia , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Compostos Organofosforados/química , Compostos Organofosforados/imunologia , Compostos Organofosforados/metabolismo , Estresse Oxidativo , Fosforilação
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