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1.
Top Curr Chem (Cham) ; 378(2): 22, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32030596

RESUMO

Heterocyclic compounds having a nitrogen atom in the ring exhibit very interesting biological activities. Indole is the core structure of many bioactive compounds owing to its high affinity to bind with most biological targets. Indole is an electron-rich compound and generally prefers electrophilic rather than nucleophilic substitution. Hence, many important indole derivatives are difficult to synthesize through the conventional reactivity of indole. This limitation can be avoided by using the umpolung, from the German word meaning polarity inversion. In umpolung, the indole molecule, especially the C2 and C3 positions, behave as an electrophile. As C2-functionalized indoles have substantial importance in synthetic and pharmaceutical chemistry, this review focuses on the C2 umpolung of indoles via the indirect approach which is less explored. Unlike direct approaches of indole umpolung, indirect methods have several advantages and therefore a number of research articles have been published in this field. But no review is available up till now. This is the first review on this topic and we believe that it will surely motivate the readers to work in this area further.


Assuntos
Carbono/química , Indóis/química , Alcaloides/síntese química , Alcaloides/química , Catálise , Ciclização , Iodo/química , Quinolinas/síntese química , Quinolinas/química , Ácidos Sulfínicos/química
2.
J Enzyme Inhib Med Chem ; 35(1): 584-597, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31992093

RESUMO

NorA is the most studied efflux pump of Staphylococcus aureus and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative 37a showed an improved EPI activity (16-fold) with respect to the starting hit 1. Moreover, compound 37a exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (norA+). Also, 37a exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of "selectivity index" in comparison to 1.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Quinolinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Quinolinas/síntese química , Quinolinas/química , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
3.
Exp Parasitol ; 206: 107756, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494217

RESUMO

Toxoplasma gondii is a widely distributed protozoan parasite, which affects worm-blooded animals including human. The commonest chemotherapeutics used for treatment of symptomatic toxoplasmosis have numerous adverse effects. Thus there is an eminent need to develop new therapeutic agents. Here we described the therapeutic efficacy of 4-(2-chloroquinolin-3-yl)-6-(2,5-dimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (PPQ-8); a quinoline-related compound in a mouse model of acute and chronic toxoplasmosis. In acute infection, PPQ-8 decreased the parasite load in liver and spleen with amelioration of the hepatic and splenic pathology. In addition, recovered tachyzoites showed distorted shapes, reduced sizes, irregularities, surface protrusions, erosions and peeling besides apical region distortion when seen by scanning electron microscopy. In chronic toxoplasmosis, PPQ-8 produced degeneration and reduction of the brain cysts without stimulating a damaging inflammatory response within the brain. In both models acute and chronic, PPQ-8 prolonged the survival time of mice. These findings hold promise for the development of a novel anti-toxoplasmosis drug using PPQ-8, but further in vivo studies should be carried out to elucidate PPQ-8 mechanism of action and to report its efficacy in combination with other anti-toxoplasmosis agents.


Assuntos
Quinolinas/uso terapêutico , Toxoplasma/patogenicidade , Toxoplasmose Animal/tratamento farmacológico , Doença Aguda , Análise de Variância , Animais , Líquido Ascítico/parasitologia , Encéfalo/parasitologia , Encéfalo/patologia , Doença Crônica , Feminino , Estimativa de Kaplan-Meier , Fígado/parasitologia , Fígado/patologia , Camundongos , Microscopia Eletrônica de Varredura , Distribuição Normal , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Distribuição Aleatória , Baço/parasitologia , Baço/patologia , Toxoplasma/efeitos dos fármacos , Toxoplasma/ultraestrutura , Toxoplasmose Animal/parasitologia
4.
Arch Pharm (Weinheim) ; 352(9): e1900101, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31414521

RESUMO

Based on the cabozantinib scaffold, novel c-Met inhibitors were rationalized from the limited knowledge of structure-activity relationships for the quinoline 6-position. Emphasis was given to modifications capable of engaging in additional polar interactions with the c-Met active site. In addition, ortho-fluorinations of the terminal benzene ring were explored. Fifteen new molecules were synthesized and evaluated in a c-Met enzymatic binding assay. A wide range of substituents were tolerated in the quinoline 6-position, while the ortho-fluorinations performed were shown to give considerable reductions in the c-Met binding affinity. The antiproliferative effects of the compounds were evaluated in the NCI60 cancer cell line panel. Most notably, compounds 15b and 18b were able to inhibit cell proliferation more efficiently than cabozantinib in leukemia, CNS, and breast cancer cell lines. The in vitro data agreed well with the in silico docking results, where additional hydrogen bonding was identified in the enzymatic pocket for the para-amino substituted 15b and 18b.


Assuntos
Anilidas/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridinas/química , Quinolinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Desenho de Drogas , Humanos , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/química , Quinolinas/farmacologia
5.
Eur J Med Chem ; 182: 111592, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421632

RESUMO

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 106 and 1.43 × 105, respectively, and DNA binding mode by intercalation. The IC50 values were obtained between 0.81 and 1.48 µM and topoisomerase inhibition results in 10 µM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Quinolinas/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Viscosidade
6.
Nat Commun ; 10(1): 3820, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444349

RESUMO

The bottom-up synthesis of structurally well-defined motifs of graphitic materials is crucial to understanding their physicochemical properties and to elicit new functions. Herein, we report the design and synthesis of TriQuinoline (TQ) as a molecular model for pyridinic-nitrogen defects in graphene sheets. TQ is a trimer of quinoline units concatenated at the 2- and 8-positions in a head-to-tail fashion, whose structure leads to unusual aromatisation behaviour at the final stage of the synthesis. The central atomic-sized void endows TQ with high proton affinity, which was confirmed empirically and computationally. TQ•H+ is a two-dimensional cationic molecule that displays both π-π and CH-π contact modes, culminating in the formation of the ternary complex ([12]cycloparaphenylene(CPP) ⊃ (TQ•H+/coronene)) that consists of TQ•H+, coronene (flat), and [12]cycloparaphenylene ([12]CPP) (ring). The water-miscibility of TQ•H+ allows it to serve as an efficient DNA intercalator for e.g. the inhibition of topoisomerase I activity.


Assuntos
Técnicas de Química Sintética , Grafite/química , Polímeros/síntese química , Quinolinas/síntese química , Modelos Moleculares
7.
Eur J Med Chem ; 180: 449-456, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31330446

RESUMO

Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds < 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 µM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 µM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Movimento Celular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
8.
Eur J Med Chem ; 180: 134-142, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31302446

RESUMO

In order to expand the arsenal of biologically active substances of anticonvulsive action by the interaction of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic acid with the corresponding amines in the presence of N,N'-carbonyldiimidazole in the dioxane medium, a systematic series of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-R-acetamides was obtained. A novel approach to synthesis of the key intermediate - 2-(2,4-dioxo-1,4-dihydro-quinazolin-3(2H)-yl)acetic acid was developed. The structure and purity of the resulting substances was confirmed by elemental analysis, 1H NMR, 13C NMR spectroscopy and LC/MS. Based on the results of docking studies using SCIGRESS software, selected compounds with the best affinity for anticonvulsant protein biomes (PDB codes: 4COF, 3F8E and 1 EOU) are promising for experimental studies of anticonvulsant activity. A comparative analysis of the results of molecular docking and in vivo results suggests that there is a positive correlation between scoring protein inhibition and experimental data. Pharmacological studies have revealed the leader compound 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(2,4-dichlorophenyl)methyl]acet-amide, which improved all the experimental convulsive syndrome rates in mice without motor coordination impairment and may be recommended for further research. The lowest values of the scoring function of the ligand-peptide interaction are obtained for the synthesized compound and сarbonic anhydrase II (gene name CA2) (PDB code 1 EOU), so its inhibition is proposed by us as the most probable mechanism of the anticonvulsive effect of the leader compound.


Assuntos
Acetamidas/farmacologia , Anticonvulsivantes/farmacologia , Quinolinas/farmacologia , Convulsões/tratamento farmacológico , Acetamidas/síntese química , Acetamidas/química , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
9.
Org Biomol Chem ; 17(24): 5943-5950, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31157811

RESUMO

We have synthesised a range of thiazole orange (TO) functionalised oligonucleotides for nucleic acid detection in which TO is attached to the nucleobase or sugar of thymidine. The properties of duplexes between TO-probes and their DNA and RNA targets strongly depend on the length of the linker between TO and the oligonucleotide, the position of attachment of TO to the nucleotide (major or minor groove) and the mode of attachment of thiazole orange (via benzothiazole or quinoline moiety). This information can be used to design probes for detection of target nucleic acids by fluorescence or duplex melting. With cellular imaging in mind we show that 2'-OMe RNA probes with TO at the 5-position of uracil or the 2'-position of the ribose sugar are particularly effective, exhibiting up to 44-fold fluorescence enhancement against DNA and RNA, and high duplex stability. Excellent mismatch discrimination is achieved when the mispaired base is located adjacent to the TO-modified nucleotide rather than opposite to it. The simple design, ease of synthesis and favourable properties of these TO probes suggest applications in fluorescent imaging of DNA and RNA in a cellular context.


Assuntos
Benzotiazóis/síntese química , DNA/análise , Fluorescência , Sondas de Oligonucleotídeos/síntese química , Quinolinas/síntese química , RNA/análise , Benzotiazóis/química , Sondas de Oligonucleotídeos/química , Quinolinas/química
10.
Eur J Med Chem ; 177: 247-258, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158742

RESUMO

Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-ß (Aß) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Aß aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models.


Assuntos
Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Nootrópicos/farmacologia , Quinolinas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/química , Animais , Barreira Hematoencefálica/metabolismo , Quelantes/síntese química , Quelantes/farmacocinética , Quelantes/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/toxicidade , Desenho de Drogas , Canal de Potássio ERG1/antagonistas & inibidores , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Nootrópicos/síntese química , Nootrópicos/farmacocinética , Nootrópicos/toxicidade , Fragmentos de Peptídeos/química , Multimerização Proteica/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Peixe-Zebra
11.
Eur J Med Chem ; 177: 338-349, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158748

RESUMO

A series of styrylquinolines was designed and synthesized based on the four main quinoline scaffolds including oxine, chloroxine and quinolines substituted with a hydroxyl group or chlorine atom at the C4 position. All of the compounds were tested for their anticancer activity on wild-type colon cancer cells (HCT 116) and those with a p53 deletion. Analysis of SAR revealed the importance of electron-withdrawing substituents in the styryl part and chelating properties in the quinoline ring. The compounds that were more active were also tested on a panel of four cancer cell lines with mutations in TP53 tumor suppressor gene. The results suggest that styrylquinolines induce cell cycle arrest and activate a p53-independent apoptosis. The apparent mechanism of action was studied for the most promising compounds, which produced reactive oxygen species and changed the cellular redox balance.


Assuntos
Antineoplásicos/farmacologia , Quinolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estirenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Heme Oxigenase-1/metabolismo , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerase-1/metabolismo , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/química , Estirenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo
12.
Molecules ; 24(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197105

RESUMO

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI50 than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI50 < 10 nM).


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase II/farmacologia , Moduladores de Tubulina/farmacologia , Amidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/genética , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Neoplasias/genética , Podofilotoxina/farmacologia , Piridinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/química , Quinases Associadas a rho/genética
13.
Eur J Med Chem ; 178: 154-167, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181480

RESUMO

A series of new quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 11p, 11s, 11v, 11x and 11y exhibited potent antiproliferative activity with IC50 value of lower than 10 µM against seven human tumor cell lines, and N-(3-methoxyphenyl)-7- (3-phenylpropoxy)quinolin-4-amine 11x was found to be the most potent antiproliferative agent against HCT-116, RKO, A2780 and Hela cell lines with an IC50 value of 2.56, 3.67, 3.46 and 2.71 µM, respectively. The antitumor efficacy of the representative compound 11x in mice was also evaluated, and the results showed that compound 11x effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 11x could inhibit colorectal cancer growth through ATG5-depenent autophagy pathway. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Quinolinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Dalton Trans ; 48(28): 10505-10515, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31211317

RESUMO

Different N3-substituted derivatives of the new ligand 3H-imidazo[4,5-f]quinolin-5-ol were synthesized. The three pKa values of its nucleoside derivative 1 were determined as 2.72 ± 0.09, 5.2 ± 0.2 and 9.7 ± 0.2. Sophisticated computational methods were used to explain these experimental acidity constants. The artificial nucleoside analogue 1 containing the new ligand was introduced into various DNA duplexes. Upon the addition of Cu(ii) ions to the DNA, highly stabilizing 1-Cu(ii)-1 base pairs were formed, with an increase in the DNA melting temperature upon Cu(ii) insertion of up to 38 °C. The ligand represents the largest artificial nucleobase used for Cu(ii)-mediated base pairing. It was also applied in Cu(ii)-mediated base pairing with the smallest Cu(ii)-binding nucleoside 2, involving the ligand 4-carboxyimidazole. The thermal duplex stabilization upon 2-Cu(ii)-1 base pair formation is smaller than that of 1-Cu(ii)-1 and comes close to that of the previously reported 2-Cu(ii)-2. Important design principles for Cu(ii)-mediated base pairs can be derived by comparing the homoleptic complexes of the largest and the smallest Cu(ii)-binding nucleosides with the heteroleptic complexes comprising both nucleosides.


Assuntos
Cobre/química , DNA/química , Quinolinas/química , Pareamento de Bases , Ligantes , Estrutura Molecular , Quinolinas/síntese química
15.
Eur J Med Chem ; 179: 109-122, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247373

RESUMO

Toll-like receptors (TLRs) are promising targets for treatment of viral infections, autoimmune diseases, and cancers. Here, two new series of selective small-molecule TLR7 agonists with novel scaffolds and good selectivity over TLR8 are described, some with potencies in the low micromolar range. 8-Hydroxy-1-isobutylchromeno[3,4-d]imidazol-4(1H)-one (26) from the first series was designed and synthesized on the basis of previously described TLR7 antagonist 2, and is shown to be a selective TLR7 agonist (EC50, 1.8 µM). The second series was based on 2-(trifluoromethyl)quinolin-4-amine and 2-(trifluoromethyl)quinazolin-4-amine scaffolds, which were defined according to our in-house ligand-based virtual screening protocol. Further synthesis of a focused library of analogs, biological evaluation, and docking studies provided systematic exploration of the structure-activity relationships, which indicate that a secondary or tertiary amine with smaller flexible alkyl substituents up to three carbon atoms in length, or bulkier rigid aliphatic rings is required at position 4 on 2-(trifluoromethyl)quinoline/quinazoline scaffold for potent TLR7 agonist activity. The influence of selected TLR7 agonists on cytokine production is also reported showing that N-cyclopropyl-2-(trifluoromethyl)quinazolin-4-amine (46) is able to induce increased levels of IL-6 and IL-8. These data demonstrate successful in-silico definition of novel TLR7 versus TLR8-selective compounds as promising chemical probes for further development of potent small-molecule immunomodulators.


Assuntos
Imidazóis/farmacologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Citocinas/análise , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismo
16.
Arch Pharm (Weinheim) ; 352(7): e1800355, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31081954

RESUMO

New quinolines substituted with various heterocycles and chalcone moieties were synthesized and evaluated as antitumor agents. All the synthesized compounds were in vitro screened against 60 human cancer cell lines. Compound 13 showed the highest cytotoxicity toward 58 cell lines, exhibiting distinct growth inhibition values (GI50 ) against the majority of them, including SR, HL-60 (TB) strains (leukemia), and MDA-MB-435 strains (melanoma), with GI50 values of 0.232, 0.260, and 0.300 µM, respectively. It exhibited great selectivity toward cancer cell lines, with less toxic effect against normal cells represented by skin fibroblast (BJ) and breast epithelial cell lines (MCF-10F). The enzyme inhibitory activity of compound 13 was evaluated against topoisomerase 1 (Topo 1), epidermal growth factor receptor and vascular endothelial growth factor receptor 2, where it displayed worthy Topo 1 inhibition activity with an IC50 value of 0.278 µM compared with camptothecin as a reference drug (IC50 0.224 µM). Docking studies were performed to investigate the recognition profile of compound 13 with the Topo 1 enzyme binding site.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Desenho de Drogas , Simulação de Acoplamento Molecular , Quinolinas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Software , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química
17.
Eur J Med Chem ; 175: 201-214, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078867

RESUMO

Herein we report the design, synthesis, molecular docking study and evaluation of antimicrobial activity of ten new dithioloquinolinethiones. The structures of compounds were confirmed by 1H NMR, 13C NMR and HPLC-HRMS. Before evaluation of their possible antimicrobial activity prediction of toxicity was performed. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. All compounds appeared to be more active than ampicillin and almost all than streptomycin. The best antibacterial activity was observed for compound 8c 4,4,8-trimethyl-5-{[(4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)thio]acetyl}-4,5-dihydro-1H-[1,2]dithiolo[3,4c]quino lone-1-thione). The most sensitive bacterium En.cloacae followed by S. aureus, while L.monocytogenes was the most resistant. All compounds were tested for antifungal activity also against eight fungal species. The best activity was expressed by compound 8d (5-[(4,5-Dihydro-1,3-thiazol-2-ylthio)acetyl]-4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione). The most sensitive fungal was T. viride, while P. verrucosum var. cyclopium was the most resistant one. All compounds were more potent as antifungal agent than reference compound bifonazole and ketoconazole. The docking studies indicated a probable involvement of E. coli DNA GyrB inhibition in the anti-bacterial mechanism, while CYP51ca inhibition is probably responsible for antifungal activity of tested compounds. It is interesting to mention that docking results coincides with experimental.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida de Alta Pressão , Desenho de Drogas , Fungos/classificação , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Quinolinas/síntese química , Relação Estrutura-Atividade
18.
Chem Rec ; 19(12): 2436-2479, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31021524

RESUMO

Among different metallic nanoparticles, sliver nanoparticles (Ag NPs) are one of the most essential and fascinating nanomaterials. Importantly, among the metal based nanoparticles, Ag NPs play a key role in various fields such as biomedicine, biosensors, catalysis, pharmaceuticals, nanoscience and nanotechnology, particularly in nanomedicine. A main concern about the chemical synthesis of Ag NPs is the production of hazardous chemicals and toxic wastes. To overcome this problem, many research studies have been carried out on the green synthesis of Ag NPs using green sources such as plant extracts, microorganisms and some biopolymers without formation of hazardous wastes. Among green sources, plants could be remarkably valuable to exploring the biosynthesis of Ag NPs. In this review, the green synthesis of Ag-based nanocatalysts such as Ag NPs, AgPd NPs, Au-Ag NPs, Ag/AgPd NPs, Ag/Cu NPs, Ag@AgCl NPs, Au-Ag@AgCl nanocomposite, Ag-Cr-AC nanocomposite and Ag NPs immobilized on various supports such as Natrolite zeolite, bone, ZnO, seashell, hazelnut shell, almond shell, SnO2 , perlite, ZrO2 , TiO2 , α-Al2 O3 , CeO2 , reduced graphene oxide (rGO), h-Fe2 O3 @SiO2 , and Fe3 O4 using numerous plant extracts as reducing and stabilizing agents in the absence of hazardous surfactant and capping agents has been focused. This work describes the state of the art and future challenges in the biosynthesis of Ag-based nanocatalysts. The fact about the application of living plants in metal nanoparticle (MNPs) industry is that it is a more economical and efficient biosynthesis biosynthetic procedure. In addition, the catalytic activities of the synthesized, Ag-based recyclable nanocatalysts using various plant extracts in several chemical reactions such as oxidation, reduction, coupling, cycloaddition, cyanation, epoxidation, hydration, degradation and hydrogenation reactions have bben extensively discussed.


Assuntos
Antibacterianos/biossíntese , Química Verde/métodos , Nanopartículas Metálicas/química , Plantas/química , Prata/química , Antibacterianos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Catálise , Extratos Vegetais/química , Plantas/metabolismo , Quinolinas/síntese química , Quinolinas/química , Dióxido de Silício/química
19.
Arch Pharm (Weinheim) ; 352(5): e1800281, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30994941

RESUMO

Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4-aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC50 values ranging from 3.84 to 10 µM. A structure-activity relationship analysis gave evidence that a piperidine or a morpholine attached as N-alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC50 ranging from 69 to >250 µM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony-resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism-of-action studies and molecular docking simulations were performed for the most active 4-aminoquinoline.


Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Leishmania/efeitos dos fármacos , Quinolinas/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/química , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 170: 28-44, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878830

RESUMO

Pancreatic cancer is one of the most deadly neoplasm with a 5-year survival rate of less than 6% owing to its remarkable tolerance to nutrient starvation, and new drugs and treatment strategies are urgently needed. During a project aiming at discovery of anticancer agents, we performed a structure modification on polycyclic polyprenylated acylphloroglucinols (PPAPs) skeleton, and discovered that PPAP rearranged to a tetrahydroquinolin-2(1H)-one feature. Here, series of tetrahydroquinolin-2(1H)-one derivatives were designed, synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (PANC-1), and the structure-activity relationship was also discussed. Among them, derivative 11k showed the most potent inhibitory activity with an IC50 value of 4.9 µM under nutrient-deprived condition. In contrast, all these derivatives exhibited low cytotoxicity against PANC-1 cells under normal nutrient condition, suggesting that the derivatives appeared to allow alternative tumor cell death mechanisms, and led to less toxicity. Further evaluations demonstrated that 11k decreased colony formation and induced the apoptosis of PANC-1 under nutrient-deprived condition in a concentration dependent manner. In in vivo study, 11k significantly suppressed the tumor development and weight in nude mice. Preliminary mechanism research revealed that 11k clearly downregulated LC3-II expression and increased the level of p62, two key autophagy markers and critical signals for pancreatic tumor growth and progression. Our current findings demonstrated that 11k might be a promising candidate for the new chemotherapeutic molecule of pancreatic cancer, and deserve further study.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Quinolinas/química , Quinolinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos Nus , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Quinolinas/síntese química , Quinolinas/farmacologia
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