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1.
Chembiochem ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32347622

RESUMO

The synthesis, characterization, photophysical and biological properties of 13 new conjugate coumarin-diruthenium(II)⋅arene complexes against Toxoplasma gondii are presented. For all conjugate organometallic unit/coumarins, an almost complete loss of fluorescence efficacy was observed. However, the nature of the fluorophore, the type of bonding, the presence and length of a linker between the coumarin dye and the ruthenium(II) moiety, and the number of dye units influenced their biological properties. The in vitro activity against a transgenic T. gondii strain grown in human foreskin fibroblasts (HFF) leads to IC50 values for T. gondii ß-gal from 105 to 735 nM. Of note is that nine compounds displayed lower IC50 than the standard drug pyrimethamine. One compound applied at its IC50 did not affect B-cell proliferation but had an impact on T-cell proliferation in murine splenocyte cultures. Transmission electron microscopy of T. gondii ß-gal-infected HFF showed that treatment predominantly affected the parasites' mitochondrion.

2.
Inorg Chem ; 56(16): 9617-9633, 2017 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-28758743

RESUMO

Dinuclear metal complexes have emerged as a promising class of anticancer compounds with the ability to cross-link biomolecular targets. Here, we describe two novel series of phosphine-linked dinuclear ruthenium(II) p-cymene and gold(I) complexes, in which the length of the connecting poly(ethylene glycol) chain has been systematically modified. The impact of the multinuclearity, lipophilicity, and linker length on the antiproliferative activity of the compounds on tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines was assessed. The dinuclear ruthenium(II) complexes were considerably more cytotoxic than their mononuclear counterparts, and a correlation between the lipophilicity of the linker and the cytotoxicity was observed, whereas the cytotoxicity of the gold(I) series is independent of these factors.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Auranofina/química , Auranofina/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cimenos , Humanos , Estrutura Molecular , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Relação Estrutura-Atividade
3.
J Inorg Biochem ; 175: 198-207, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28779652

RESUMO

Following the identification of a ruthenium(II)-arene complex with an ethacrynic acid-modified imidazole ligand, which inhibits glutathione transferase (GST) and is cytotoxic to chemo-resistant cancer cells, a series of structurally related ruthenium(II)- and osmium(II)-p-cymene compounds have been prepared. In these complexes the ethacrynic acid is linked to the metals via appropriately modified pyridine ligands. The influence of the metal center and the metal:ethacrynic acid ratio on the cytotoxicity of the compounds was evaluated with the derivatives with one metal center and two ethacrynic acid moieties being the most potent against chemo-resistant A2780cisR cells (human ovarian cancer cells with acquired resistance to cisplatin). Moreover, compared to a complex with an ethacrynic acid-modified imidazole ligand (RAIMID-EA, Figure 2), these complexes display a significant degree of cancer cell specificity.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos , Ácido Etacrínico , Compostos Organometálicos , Osmio , Neoplasias Ovarianas/tratamento farmacológico , Rutênio , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácido Etacrínico/química , Ácido Etacrínico/farmacologia , Feminino , Glutationa Transferase/antagonistas & inibidores , Humanos , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Osmio/química , Osmio/farmacologia , Neoplasias Ovarianas/enzimologia , Rutênio/química , Rutênio/farmacologia
4.
Inorg Chem ; 55(4): 1788-808, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26824462

RESUMO

Compounds that combine metal-based drugs with covalently linked targeted organic agents have been shown, in some instances, to exhibit superior anticancer properties compared to the individual counterparts. Within this framework, we prepared a series of organometallic ruthenium(II)- and osmium(II)-p-cymene complexes modified with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and diclofenac. The NSAIDs are attached to the organometallic moieties via monodentate (pyridine/phosphine) or bidentate (bipyridine) ligands, affording piano-stool Ru(II) and Os(II) arene complexes of general formula [M(η(6)-p-cymene)Cl2(N)], where N is a pyridine-based ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate}, [M(η(6)-p-cymene)Cl2(P)], where P is a phosphine ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-4-(diphenylphosphanyl)benzoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl-4-(diphenylphosphanyl)benzoate, and [M(η(6)-p-cymene)Cl(N,N')][Cl], where N,N' is a bipyridine-based ligand, (4'-methyl-[2,2'-bipyridin]-4-yl)methyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate), (4'-methyl-[2,2'-bipyridin]-4-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate), (bis(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate), or (bis(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate). The antiproliferative properties of the complexes were assessed in human ovarian cancer cells (A2780 and A2780cisR, the latter being resistant to cisplatin) and nontumorigenic human embryonic kidney (HEK-293) cells. Some of the complexes are considerably more cytotoxic than the original drugs and also display significant cancer cell selectivity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Compostos Organometálicos/farmacologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
5.
Inorg Chem ; 54(21): 10504-12, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26465973

RESUMO

Ionic liquids doped with I2, usually resulting in the formation of polyiodide anions, are extensively used as electrolytes and in iodination reactions. Herein, NMR spectroscopy and single-crystal X-ray diffraction were used to rationalize the structures of imidazolium-based polyiodide ionic liquids in the liquid and solid states. Combined, these studies show that extensive interactions between the imidazolium cation and the resulting polyiodide anion are present, which have the net effect of lengthening, polarizing, and weakening the I-I bonds in the anion. This bond weakening rationalizes the high conductivity and reactivity of ionic liquids doped with I2.

6.
ChemMedChem ; 10(9): 1539-47, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26190176

RESUMO

Osmium compounds are attracting increasing attention as potential anticancer drugs. In this context, a series of bifunctional organometallic osmium(II)-p-cymene complexes functionalized with alkyl or perfluoroalkyl groups were prepared and screened for their antiproliferative activity. Three compounds from the series display selectivity toward cancer cells, with moderate cytotoxicity observed against human ovarian carcinoma (A2780) cells, whereas no cytotoxicity was observed on non-cancerous human embryonic kidney (HEK-293) cells and human endothelial (ECRF24) cells. Two of these three cancer-cell-selective compounds induce cell death largely via apoptosis and were also found to disrupt vascularization in the chicken embryo chorioallantoic membrane (CAM) model. Based on these promising properties, these compounds have potential clinical applications.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Compostos de Ósmio/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Técnicas de Química Sintética , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Cristalografia por Raios X , Cimenos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células Endoteliais/efeitos dos fármacos , Células HEK293/efeitos dos fármacos , Humanos , Monoterpenos/química , Compostos de Ósmio/química , Rutênio/química
7.
Mol Pharm ; 12(8): 3089-96, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-26158308

RESUMO

Two bifunctional ruthenium(II)-p-cymene complexes with perfluorinated side chains, attached via pyridine ligands, have been evaluated in a series of in vitro and in vivo assays. Their effects on human endothelial (ECRF24 and HUVEC) cells, noncancerous human embryonic kidney (HEK-293) cells, and various human tumor cells were investigated. The complex with the shorter chain, 1, inhibits the proliferation of the tumor cell lines and ECRF24, whereas 2 selectively inhibits ECRF24 and HUVEC proliferation. Neither inhibits the migration of ECRF24 cells whereas both compounds inhibit sprout formation in HUVEC cells. Using three preclinical models, i.e., vasculature formation in the chorioallantoic membrane (CAM) of the chicken embryo, human A2780 ovarian carcinoma tumors xenografted on the CAM, and human LS174T colorectal adenocarcinoma tumors grown in athymic mice, the angiostatic and anticancer activities of these two complexes were studied. Overall, 1 inhibited tumor growth predominantly through an anticancer effect whereas 2 inhibited tumor growth predominately via an antiangiogenic mechanism.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Monoterpenos/química , Compostos Organometálicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Rutênio/química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Cimenos , Ensaios de Seleção de Medicamentos Antitumorais , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Células HEK293 , Humanos , Técnicas Imunoenzimáticas , Camundongos , Modelos Moleculares , Neovascularização Patológica/prevenção & controle , Compostos Organometálicos/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade
8.
Inorg Chem ; 54(13): 6504-12, 2015 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-26073654

RESUMO

Pyridine- and phosphine-based ligands modified with ethacrynic acid (a broad acting glutathione transferase inhibitor) were prepared and coordinated to ruthenium(II)-arene complexes and to a ruthenium(III) NAMI-A type complex. All the compounds (ligands and complexes) were fully characterized by analytical and spectroscopic methods and, in one case, by single-crystal X-ray diffraction. The in vitro anticancer activity of the compounds was studied, with the compounds displaying moderate cytotoxicity toward the human ovarian cancer cell lines. All the complexes led to similar levels of residual GST activity in the different cell lines, irrespective of the stability of the Ru-ligand bond.

9.
ACS Med Chem Lett ; 6(3): 313-7, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25815152

RESUMO

Dasatinib is an orally active nonselective tyrosine kinase inhibitor used to treat certain types of adult leukemia. By inhibiting PDGFR-ß and SFKs in both tumor cells and tumor-associated endothelial cells, dasatinib inhibits tumor growth and angiogenesis. Herein, dasatinib derivatives modified with hydrophobic chains were prepared and evaluated for their in vitro antiproliferative selectivity and their in vivo antiangiogenic activity. For one of the derivatives, modified with a long perfluorinated chain, a significant enhancement in antiangiogenic activity was observed. Combined, these results suggest a possible generic route to modulate the angiostatic activity of drugs.

10.
J Med Chem ; 58(8): 3356-65, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25812075

RESUMO

Following the identification of [Ru(η(6)-p-cymene)Cl2(1H,1H,2H,2H-perfluorodecyl-3-(pyridin-3-yl)propanoate)], a ruthenium(II)-arene complex with a perfluoroalkyl-modified ligand that displays remarkable in vitro cancer cell selectivity, a series of structurally related compounds were designed. In the new derivatives, the p-cymene ring and/or the chloride ligands are substituted by other ligands to modulate the steric bulk or aquation kinetics. The new compounds were evaluated in both in vitro (cytotoxicity and migration assays) and in vivo (chicken chorioallantoic membrane) models and were found to exhibit potent antivascular effects.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Monoterpenos/química , Monoterpenos/farmacologia , Rutênio/química , Rutênio/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Cimenos , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico
11.
Chem Sci ; 6(5): 2795-2801, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28706667

RESUMO

Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers. Currently, the small molecule drugs used in combination with hyperthermia were not designed for this application. Herein, we report the evaluation of a chlorambucil and a ruthenium compound modified with a long fluorous chain, which exhibit thermoresponsive activity in colorectal adenocarcinoma xenografts in athymic mice in combination with mild hyperthermia (42 °C). Intraperitoneal injection of the derivatives followed by local hyperthermia showed a synergistic tumor growth reduction by 79% and 90% for the chlorambucil and ruthenium-based derivatives, respectively, with the latter exhibiting a higher synergy in combination with hyperthermia compared to the monotherapies. Histological analysis shows that both derivatives in combination with hyperthermia significantly decrease the number of proliferating tumor cells.

12.
J Med Chem ; 57(8): 3546-58, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24669938

RESUMO

A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 µM, and no cytotoxic effect was observed on nontumorigenic (HEK-293) cells at concentrations up to 500 µM (the maximum concentration tested). Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and noncancerous cell lines. The lead compound was then evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed.


Assuntos
Inibidores da Angiogênese/síntese química , Antineoplásicos/síntese química , Compostos Organometálicos/síntese química , Compostos de Rutênio/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Embrião de Galinha , Descoberta de Drogas , Células HEK293 , Humanos , Compostos Organometálicos/farmacologia , Compostos de Rutênio/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Phys Chem B ; 117(30): 9094-105, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23822750

RESUMO

Hydrogen bonding in ionic liquids based on the 1-(2'-hydroxylethyl)-3-methylimidazolium cation ([C2OHmim](+)) and various anions ([A](-)) of differing H-bond acceptor strength, viz. hexafluorophosphate [PF6](-), tetrafluoroborate [BF4](-), bis(trifluoromethanesulfonimide) [Tf2N](-), trifluoromethylsulfonate [OTf](-), and trifluoroacetate [TFA](-), was studied by a range of spectroscopic and computational techniques and, in the case of [C2OHmim][PF6], by single crystal X-ray diffraction. The first quantitative estimates of the energy (E(HB)) and the enthalpy (-ΔH(HB)) of H-bonds in bulk ILs were obtained from a theoretical analysis of the solid-state electron-density map of crystalline [C2OHmim][PF6] and an analysis of the IR spectra in crystal and liquid samples. E(HB) for OH···[PF6](-) H-bonds amounts to ~3.4-3.8 kcal·mol(-1), whereas weaker H-bonds (2.8-3.1 kcal·mol(-1)) are formed between aromatic C2H group of imidazolium ring and the [PF6](-) anion. The enthalpy of the OH···[A](-) H-bonds follows the order: [PF6] (2.4 kcal·mol(-1)) < [BF4] (3.3 kcal·mol(-1)) < [Tf2N] (3.4 kcal·mol(-1)) < [OTf] (4.7 kcal·mol(-1)l) < [TFA] (6.2 kcal·mol(-1)). The formation of aggregates of self-associated [C2OHmim](+) cations is present in liquid [C2OHmim][PF6], [C2OHmim][BF4], and [C2OHmim][Tf2N], with the energy of the OH···OH H-bonds amounting to ~6 kcal·mol(-1). Multiple secondary interactions in the bulk ILs influence their structure, vibrational spectra, and H-bond strength. In particular, these interactions can blue-shift the stretching frequencies of the CH groups of the imidazolium ring in spite of red-shifting CH···[A](-) H-bonds. They also weaken the H-bonding in the IL relative to the isolated ion pairs, with these anticooperative effects amounting to ca. 50% of the E(HB) value.

14.
Chem Biol Interact ; 203(1): 81-4, 2013 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-23111374

RESUMO

Organophosphorus nerve agents (OPNAs) are highly toxic compounds that represent a threat to both military and civilian populations. They cause an irreversible inhibition of acetylcholinesterase (AChE), by the formation of a covalent P-O bond with the catalytic serine. Among the present treatment of nerve agents poisoning, pyridinium and bis-pyridinium aldoximes are used to reactivate this inhibited enzyme but these compounds do not readily cross the blood brain barrier (BBB) due to their permanent cationic charge and thus cannot efficiently reactivate cholinesterases in the central nervous system (CNS). In this study, a series of seven new uncharged oximes reactivators have been synthesized and their in vitro ability to reactivate VX and tabun-inhibited human acetylcholinesterase (hAChE) has been evaluated. The dissociation constant K(D) of inhibited enzyme-oxime complex, the reactivity rate constant kr and the second order reactivation rate constant k(r2) have been determined and have been compared to reference oximes HI-6, Obidoxime and 2-Pralidoxime (2-PAM). Regarding the reactivation of VX-inhibited hAChE, all compounds show a better reactivation potency than those of 2-PAM, nevertheless they are less efficient than obidoxime and HI-6. Moreover, one of seven described compounds presents an ability to reactivate tabun-inhibited hAChE equivalent to those of 2-PAM.


Assuntos
Acetilcolinesterase/metabolismo , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/síntese química , Reativadores da Colinesterase/farmacologia , Compostos Organofosforados/toxicidade , Reativadores da Colinesterase/química , Avaliação Pré-Clínica de Medicamentos , Eletroquímica , Proteínas Ligadas por GPI/metabolismo , Humanos , Estrutura Molecular , Cloreto de Obidoxima/farmacologia , Oximas/síntese química , Oximas/química , Oximas/farmacologia , Compostos de Pralidoxima/farmacologia , Compostos de Piridínio/farmacologia , Proteínas Recombinantes/metabolismo
15.
Chemistry ; 16(11): 3510-23, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20143367

RESUMO

A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the P-S bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated P-Oaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated P-Salkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V-type nerve agents. A preliminary screening, realised on a small alpha-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, alpha-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers.


Assuntos
Substâncias para a Guerra Química/química , Compostos Organofosforados/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Corantes Fluorescentes/química , Ensaios de Triagem em Larga Escala
16.
ChemMedChem ; 4(4): 549-61, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19212949

RESUMO

The prophylactic administration of amodiaquine (AQ), a 4-aminoquinoline antimalarial drug, has been associated with side effects such as agranulocytosis and liver damage. The toxicity of this drug is mediated by amodiaquine quinone-imine, an electrophilic metabolite. Replacement of the 4'-hydroxy function of AQ with various alkyl, aryl, or heteroaryl substituents would provide analogues that avoid metabolism to potentially toxic derivatives. Following a multistep procedure, 33 compounds containing hydrophobic groups at the 4'-position were synthesized using Csp(2)-Csp(2) and Csp(2)-Csp(3) Suzuki-Miyaura cross-coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)-sensitive and CQ-resistant strains of P. falciparum, with IC(50) values in the range of 7-200 nM. Alkyl analogues are more efficient than aryl or heteroaryl derivatives. All compounds were also assessed for their cytotoxicity and ability to inhibit beta-hematin formation in vitro. A detailed investigation of the structure-activity relationships for these new compounds was carried out; the 4'-methyl compound showed interesting in vivo antimalarial activity.


Assuntos
Amodiaquina/síntese química , Amodiaquina/farmacologia , Antimaláricos/síntese química , Antimaláricos/farmacologia , Amodiaquina/química , Animais , Antimaláricos/química , Linhagem Celular , Cristalização , Cristalografia por Raios X , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Elétrons , Humanos , Hidroxilação , Iminas/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Plasmodium falciparum/efeitos dos fármacos
17.
Eur J Med Chem ; 43(2): 252-60, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17485145

RESUMO

In order to determine the real significance of the 4'-phenolic group in the antimalarial activity and/or cytotoxicity of amodiaquine (AQ), analogues for which this functionality was shifted or modified were synthesized. Good in vitro antimalarial activity was obtained for compounds unable to form intramolecular hydrogen bond. Among the compounds synthesized, new amino derivative 5 displayed the greatest selectivity index towards the most CQ-resistant strain tested and was active in mice infected by Plasmodium berghei.


Assuntos
Amodiaquina/síntese química , Amodiaquina/farmacologia , Antimaláricos/síntese química , Antimaláricos/farmacologia , Amodiaquina/química , Animais , Antimaláricos/química , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Camundongos , Plasmodium berghei/efeitos dos fármacos
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