RESUMEN

The aim of this work was to obtain and evaluate, as antiprotozoals, new derivatives of benzoate imidazo-1,3,4-thiadiazole 18-23 based on the concepts of molecular repositioning and hybridization. In the design of these compounds, two important pharmacophoric subunits of the fexnidazole prototype were used: metronidazole was used as a repositioning molecule, p-aminobenzoic acid was incorporated as a bridge group, and 1,3,4-thiadiazole group was incorporated as a second pharmacophore, which at position 5 has an aromatic group with different substituents incorporated. The final six compounds were obtained through a five-step linear route with moderate to good yields. The biological results demonstrated the potential of this new class of compounds, since three of them 19-21 showed inhibitory activity on proliferation, in the order of 50%, in the in vitro assay against epimastigotes of T. cruzi (Strain Y sensitive to nifurtimox and benznidazole) and promastigotes of L. donovani, at a single concentration of 50 µM.

Asunto(s)

Imidazoles , Leishmania donovani , Tiadiazoles , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Leishmania donovani/efectos de los fármacos , Leishmania donovani/crecimiento & desarrollo , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , Relación Estructura-Actividad , Estructura Molecular

RESUMEN

Leishmania amazonensis and L. braziliensis are the main etiological agents of the American Tegumentary Leishmaniasis (ATL). Taking into account the limited effectiveness and high toxicity of the current drug arsenal to treat ATL, novel options are urgently needed. Inspired by the fact that gold-based compounds are promising candidates for antileishmanial drugs, we studied the biological action of a systematic series of six (1)-(6) symmetric Au(I) benzyl and aryl-N-heterocyclic carbenes. All compounds were active at low micromolar concentrations with 50% effective concentrations ranging from 1.57 to 8.30 µM against Leishmania promastigotes. The mesityl derivative (3) proved to be the best candidate from this series, with a selectivity index ~13 against both species. The results suggest an effect of the steric and electronic parameters of the N-substituent in the activity. Intracellular infections were drastically reduced after 24h of (2)-(5) incubation in terms of infection rate and amastigote burden. Further investigations showed that our compounds induced significant parasites' morphological alterations and membrane permeability. Also, (3) and (6) were able to reduce the residual activity of three Leishmania recombinant cysteine proteases, known as possible targets for Au(I) complexes. Our promising results open the possibility of exploring gold complexes as leishmanicidal molecules to be further screened in in vivo models of infection.

Asunto(s)

Imidazoles/farmacología , Compuestos Orgánicos de Oro/farmacología , Tripanocidas/farmacología , Animales , Membrana Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Femenino , Oro/química , Imidazoles/síntesis química , Leishmania braziliensis/efectos de los fármacos , Ratones Endogámicos BALB C , Estructura Molecular , Compuestos Orgánicos de Oro/síntesis química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/síntesis química

RESUMEN

Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs. To address this issue, a large number of diverse heterocyclic compounds were prepared. Straightforward synthetic approaches tolerated pre-functionalized structures, giving rise to a structurally diverse set of analogs. We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 29 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei, respectively (antitrypanosomal activities <10 µM). The present work discusses the structure-activity relationships of new fused-ring scaffolds based on imidazopyridine/pyrimidine and furopyridine cores. This library of compounds shows significant potential for anti-trypanosomiases drug discovery.

Asunto(s)

Imidazoles/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Tripanosomiasis/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Piridinas/síntesis química , Piridinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química

RESUMEN

A one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes. This methodology afforded twenty-nine disubstituted NH-imidazoles (23%-85% yield). A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation-condensation protocol, followed by bromination and Suzuki coupling in the imidazole ring to yield trisubstituted NH-imidazoles (23%-69%, three steps). This approach was also employed in the synthesis of known inhibitor GSK3037619A.

Asunto(s)

Aldehídos/química , Imidazoles/química , Imidazoles/síntesis química , Cetonas/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Oxidación-Reducción

RESUMEN

More than 100 years after being first described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, which is caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continents but has become a global health threat. Current therapies, i.e., nifurtimox and benznidazole (Bz), are far from being adequate, due to their undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypic evaluation in T. cruzi of a new class of imidazole compounds, which were discovered in a previous phenotypic screen against different trypanosomatids and were designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to that of Bz prompted a synthesis program of hit optimization and extended structure-activity relationship aimed at improving drug-like properties such as aqueous solubility, which resulted in additional hits with 50% inhibitory concentration (IC50) values similar to that of Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC50 concentration, that were consistent with induced autophagy and osmotic stress, mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP levels, confirming that inhibition of T. cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T. cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.

Asunto(s)

3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Antiparasitarios/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Imidazoles/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Células Cultivadas , Descubrimiento de Drogas , Imidazoles/síntesis química , Ratones , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad

RESUMEN

A convenient one-pot synthesis of 4-aryl-2-methyl-N-phenacylimidazoles (4) through a microwave-assisted pseudo-tricomponent reaction of α-bromoacetophenones (1) with acetamidine hydrochloride (2) is reported. Ketones (4) were successfully used as substrates for the preparation of the respective N-(2-hydroxyethyl)imidazoles (5) with yields up to 87%. The synthesized compounds were characterized by NMR and high-resolution mass spectrometry analyses, and several structures were confirmed and studied by single-crystal X-ray diffraction. The analysis of the whole-of-molecule interactions shows that, despite the difference in the atom-atom contacts forming the crystals, dispersion energies make the largest contribution to the formation of the solids, giving an isotropic tendency in the topology of the energy framework diagrams for pairs of molecules. In addition, the in vitro antifungal activity of both families of compounds [ketones (4) and alcohols (5)] against Candida albicans and Cryptococcus neoformans was evaluated, where the 2,4-dichlorophenyl-substituted alcohol (5f), an isomer of the drug miconazole, showed the highest activity (IC50 = 7.8 µg ml-1 against C. neoformans).

Asunto(s)

Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Imidazoles/farmacología , Termodinámica , Antifúngicos/síntesis química , Antifúngicos/química , Cristalización , Relación Dosis-Respuesta a Droga , Imidazoles/síntesis química , Imidazoles/química , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Relación Estructura-Actividad

RESUMEN

Nematode parasites cause substantial morbidity to billions of people and considerable losses in livestock and food crops. The repertoire of effective anthelmintic compounds for treating these parasitoses is very limited, as drug development has been delayed for decades. Moreover, resistance has become a global concern in livestock parasites and is an emerging issue for human helminthiasis. Therefore, anthelmintics with novel mechanisms of action are urgently needed. Taking advantage of Caenorhabditis elegans as an established model system, we here screened the nematicidal potential of novel imidazolium and imidazole derivatives. One of these derivatives, diisopropylphenyl-imidazole (DII), is lethal to C. elegans at both mature and immature stages. This lethal effect appears to be specific because DII concentrations which prove to be toxic to C. elegans do not induce significant lethality on bacteria, Drosophila melanogaster, and HEK-293 cells. Our analysis of DII action on C. elegans mutant strains determined that, in the adult stage, null mutants of unc-29 are resistant to the drug. Muscle expression of this gene completely restores DII sensitivity. UNC-29 has been largely reported as an essential constituent of the levamisole-sensitive muscle nicotinic receptor (L-AChR). Nevertheless, null mutants in unc-63 and lev-8 (essential and non-essential subunits of L-AChRs, respectively) are as sensitive to DII as the wild-type strain. Therefore, our results suggest that DII effects on adult nematodes rely on a previously unidentified UNC-29-containing muscle AChR, different from the classical L-AChR. Interestingly, DII targets appear to be different between larvae and adults, as unc-29 null mutant larvae are sensitive to the drug. The existence of more than one target could delay resistance development. Its lethality on C. elegans, its harmlessness in non-nematode species and its novel and dual mechanism of action make DII a promising candidate compound for anthelmintic therapy.

Asunto(s)

Antihelmínticos/farmacología , Caenorhabditis elegans/efectos de los fármacos , Imidazoles/farmacología , Animales , Antihelmínticos/síntesis química , Antihelmínticos/química , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Supervivencia Celular/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Femenino , Células HEK293 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Masculino , Estructura Molecular , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo

RESUMEN

The crystal structures of 2-methyl-4-phenyl-1H-imidazole, C10H10N2, (3a), 4-(4-chlorophenyl)-2-methyl-1H-imidazole hemihydrate, C10H9ClN2·0.5H2O, (3b), and 4-(4-methoxyphenyl)-2-methyl-1H-imidazole, C11H12N2O, (3c), have been analyzed. It was found that the electron-donating/withdrawing tendency of the substituent groups in the aryl ring influence the acid-base properties of the 2-methylimidazole nucleus, changing the strength of the intermolecular N-H...N interactions. This behaviour not only influences the crystal structure but also seems to have an important effect on the antifungal activity. Considering the substituent groups, that is, H in (3a), Cl in (3b) and OMe in (3c), the formation of strong N-H...N connections has the probability (3a) > (3b) > (3c), while compound (3c) proves to be more active than (3a) and (3b) at all concentrations against C. neoformans.

Asunto(s)

Antifúngicos/farmacología , Imidazoles/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Candida albicans/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Cristalografía por Rayos X , Enlace de Hidrógeno , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular

RESUMEN

Keeping in mind the concept of green chemistry, this research aims to synthesize and characterize new ionic liquids (ILs) derived from N-cinnamyl imidazole with different sizes of alkyl chains (1, 6, 8, and 10 carbon atoms), and evaluate their antibacterial activity against Skin and soft tissue infections (SSTIs) causative bacteria. The antibacterial screening was carried out by agar well diffusion and the Minimum Inhibitory Concentration (MIC) and Half Maximum Inhibitory Concentration (IC50) of the different ILs were determined by microdilution in broth, also Molecular dynamics simulations were performed to study the interaction mechanism between ILs and membranes. The MIC value in Gram-positive bacteria showed that as the hydrocarbon chain increases, the MIC value decreases with a dose-dependent effect. Furthermore, Gram-negative bacteria showed high MIC values, which were also evidenced in the antibacterial screening. The molecular dynamics showed an incorporation of the ILs with the longer chain (10 C), corresponding to a passive diffusion towards the membrane surface, for its part, the ILs with the shorter chain due to its lack of hydrophobicity was not incorporated into the bilayer. Finally, the new ILs synthesized could be an alternative for the treatment of Gram-positive bacteria causative of SSTIs.

Asunto(s)

Antibacterianos/química , Antibacterianos/síntesis química , Imidazoles/síntesis química , Líquidos Iónicos/síntesis química , Animales , Antibacterianos/farmacología , Relación Dosis-Respuesta a Droga , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Tecnología Química Verde , Humanos , Imidazoles/química , Imidazoles/farmacología , Líquidos Iónicos/química , Líquidos Iónicos/farmacología , Pruebas de Sensibilidad Microbiana , Simulación de Dinámica Molecular , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico

RESUMEN

Although inflammation is a biological phenomenon that exists to protect the host against infections and/or related problems, its unceasing activation results in the aggravation of several medical conditions. Imidazoles, whether natural or synthetic, are molecules related to a broad spectrum of biological effects, including anti-inflammatory properties. In this study, we screened eight novel small molecules of the imidazole class synthesized by our research group for their in vitro anti-inflammatory activity. The effect of the selected molecules was confirmed in an in vivo inflammatory model. We also analyzed whether the effects were caused by inhibition of nuclear factor kappa B (NF-κB) transcription factor transmigration. Of the eight imidazoles tested, methyl 1-allyl-2-(4-fluorophenyl)-5-phenyl-1H-imidazole-4-acetate (8) inhibited nitric oxide metabolites and pro-inflammatory cytokine (TNF-α, IL-6, and IL-1ß) secretion in J774 macrophages stimulated with LPS. It also attenuated leukocyte migration and exudate formation in the pleural cavity of mice challenged with carrageenan. Furthermore, imidazole 8 reverted the oxidative stress pattern triggered by carrageenan in the pleural cavity by diminishing myeloperoxidase, superoxide dismutase, catalase, and glutathione S-transferase activities and reducing the production of nitric oxide metabolites and thiobarbituric acid-reactive substances. Finally, these effects can be attributed, at least in part, to the ability of this compound to prevent NF-κB transmigration. In this context, our results demonstrate that imidazole 8 has promising potential as a prototype for the development of a new anti-inflammatory drug to treat inflammatory conditions in which NF-κB and oxidative stress play a prominent role. Graphical Abstract ᅟ.

Asunto(s)

Antiinflamatorios/síntesis química , Diseño de Fármacos , Imidazoles/farmacología , Animales , Línea Celular , Imidazoles/síntesis química , Imidazoles/química , Ratones , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-Actividad

RESUMEN

Alkylimidazolium salts are an important class of ionic liquids (ILs) due to their self-assembly capacity when in solution and due to their potential applications in chemistry and materials science. Therefore, detailed knowledge of the physicochemical properties of this class of ILs and their mixtures with natural polymers is highly desired. This work describes the interactions between a homologous series of mono- (CnMIMBr) and dicationic imidazolium (Cn(MIM)2Br2) ILs with cellulose ethers in aqueous medium. The effects of the alkyl chain length (n = 10, 12, 14, and 16), type, and concentration range of ILs (below and above their cmc) on the binding to methylcellulose (MC) were evaluated. The thermodynamic parameters showed that the interactions are favored by the increase of the IL hydrocarbon chain length, and that the binding of monocationic ILs to MC is driven by entropy. The monocationic ILs bind more effectively on the methoxyl group of MC when compared to dicationic ILs, and this outcome may be rationalized by considering the structural difference between the conventional (CnMIMBr) and the bolaform (Cn(MIM)2Br2) surfactant ILs. The C16MIMBr interacts more strongly with hydroxypropylcellulose when compared to methylcellulose, indicating that the strength of the interaction also depends on the hydrophobicity of the cellulose ethers. Our findings highlight that several parameters should be taken into account when designing new complex formulations.

Asunto(s)

Imidazoles/química , Líquidos Iónicos/química , Metilcelulosa/química , Tensoactivos/química , Sitios de Unión , Calorimetría , Cationes/síntesis química , Cationes/química , Conductividad Eléctrica , Imidazoles/síntesis química , Líquidos Iónicos/síntesis química , Tensión Superficial , Tensoactivos/síntesis química , Termodinámica

RESUMEN

Pregnane derivatives are studied as agents for the treatment of different hormone-dependent diseases. The biological importance of these steroids is based on their potential use against cancer. In this study, we report the synthesis, characterization and biological activity of two pregnane derivatives with a triazole (3ß-hydroxy-21-(1H-1,2,4-triazol-1-yl)pregna-5,16-dien-20-one; T-OH) or imidazole (3ß-hydroxy-21-(1H-imidazol-1-yl)pregna-5,16-dien-20-one; I-OH) moieties at C-21. These derivatives were synthesized from 16-dehydropregnenolone acetate. The activity on cell proliferation of the compounds was measured on three human cancer cells lines: prostate cancer (PC-3), breast cancer (MCF7) and lung cancer (SK-LU-1). The cytotoxic and antiproliferative effects of T-OH and I-OH were assessed by using SBR and XTT methods, respectively. The gene expressions were evaluated by real time PCR. In addition, results were complemented by docking studies and transactivation assays using an expression vector to progesterone and androgen receptor. Results show that the two compounds inhibited the three cell lines proliferation in a dose-dependent manner. Compound I-OH downregulated the gene expression of the cyclins D1 and E1 in PC-3 and MFC7 cells; however, effect upon Ki-67, EAG1, BIM or survivin genes was not observed. Docking studies show poor interaction with the steroid receptors. Nevertheless, the transactivation assays show a weak antagonist effect of I-OH on progesterone receptor but not androgenic or antiandrogenic actions. In conclusion, the synthesized compounds inhibited cell proliferation as well as genes key to cell cycle of PC-3 and MCF7 cell lines. Therefore, these compounds could be considered a good starting point for the development of novel therapeutic alternatives to treat cancer.

Asunto(s)

Antineoplásicos/síntesis química , Imidazoles/síntesis química , Pregnadienos/síntesis química , Triazoles/síntesis química , Antineoplásicos/farmacología , Apoptosis , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Pregnadienos/farmacología , Triazoles/farmacología , Vitamina D3 24-Hidroxilasa/metabolismo

RESUMEN

Four novel miconazole analogues (8-11) were synthetized and evaluated for activity against four filamentous fungi (Mucor hiemalis, Aspergillus fumigatus, Trichosporon cutaneum, and Rhizopus oryzae) and eight species of Candida as yeast specimens. Compounds 9 and 10 showed very good activity when evaluated in yeast (MIC 0.112 and 0.163 µg/mL) compared to the reference compound, itraconazole (MIC 0.067 µg/mL). The best antifungal activity in filamentous strains was shown by compound 9. Hence compounds 9 and 10 represent new leads for further pharmacomodulation in this series.

Asunto(s)

Antifúngicos/síntesis química , Antifúngicos/farmacología , Benzoatos/síntesis química , Benzoatos/farmacología , Hongos/efectos de los fármacos , Imidazoles/síntesis química , Imidazoles/farmacología , Metanol/análogos & derivados , Miconazol/química , Micosis/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Metanol/síntesis química , Metanol/farmacología , Pruebas de Sensibilidad Microbiana , Micosis/microbiología

RESUMEN

Fused heterobicyclic systems have gained much importance in the field of medicinal chemistry because of their broad spectrum of physiological activities. Among the heterocyclic rings containing bridgehead nitrogen atom, imidazothiazoles derivatives are especially attractive because of their different biological activities. Since many imidazothiazoles derivatives are effective for treating several diseases, is interesting to analyze the behavior of some isosteric related heterocycles, such as pirrolothiazoles, imidazothiadiazoles and imidazotriazoles. In this context, this review summarizes the current knowledge about the syntheses and biological behavior of these families of heterocycles. Traditional synthetic methodologies as well as alternative synthetic procedures are described. Among these last methodologies, the use of multicomponent reaction, novel and efficient coupling reagents, and environmental friendly strategies, like microwave assistance and solvent-free condition in ionic liquids are also summarized. This review includes the biological assessments, docking research and studies of mechanism of action performed in order to obtain the compounds leading to the development of new drugs.

Asunto(s)

Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Proliferación Celular/efectos de los fármacos , Compuestos Heterocíclicos/química , Humanos , Imidazoles/química , Tiazoles/química

RESUMEN

The water-soluble and visible luminescent complexes cis-[Ru(L-L)2(L)2](2+) where L-L = 2,2-bipyridine and 1,10-phenanthroline and L= imidazole, 1-methylimidazole, and histamine have been synthesized and characterized by spectroscopic techniques. Spectroscopic (circular dichroism, saturation transfer difference NMR, and diffusion ordered spectroscopy NMR) and isothermal titration calorimetry studies indicate binding of cis-[Ru(phen)2(ImH)2](2+) and human serum albumin occurs via noncovalent interactions with K(b) = 9.8 × 10(4) mol(-1) L, ΔH = -11.5 ± 0.1 kcal mol(-1), and TΔS = -4.46 ± 0.3 kcal mol(-1). High uptake of the complex into HCT116 cells was detected by luminescent confocal microscopy. Cytotoxicity of cis-[Ru(phen)2(ImH)2](2+) against proliferation of HCT116p53(+/+) and HCT116p53(-/-) shows IC50 values of 0.1 and 0.7 µmol L(-1). Flow cytometry and western blot indicate RuphenImH mediates cell cycle arrest in the G1 phase in both cells and is more prominent in p53(+/+). The complex activates proapoptotic PARP in p53(-/-), but not in p53(+/+). A cytostatic mechanism based on quantification of the number of cells during the time period of incubation is suggested.

Asunto(s)

Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Sustancias Luminiscentes/síntesis química , Rutenio , 2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/síntesis química , 2,2'-Dipiridil/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Histamina/análogos & derivados , Histamina/síntesis química , Histamina/farmacología , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Sustancias Luminiscentes/farmacología , Fenantrolinas/síntesis química , Fenantrolinas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Unión Proteica , Albúmina Sérica/metabolismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/metabolismo

RESUMEN

Herein, we report the design, synthesis and trypanocidal activity of some novel trisubstituted imidazole derivatives. These heterocyclic derivatives were structurally planned by exploring the concept of molecular hybridisation between two arylhydrazones derived from megazol, which has potent trypanocidal activity. The trypanocidal activity of these triarylimidazole derivatives was evaluated against infective trypomastigote forms of T. cruzi and the derivative 2'-(4-bromophenyl)-1-methyl-5'-phenyl-1H,3'H-2,4'-biimidazol-3'-ol showed moderate biological activity (IC50 = 23.9 µM) when compared to benznidazole, a standard trypanocidal drug. These compounds did not present cytotoxic effects at concentrations near the trypanocidal IC50, being considered a good starting point for the development of new anti-Chagas drug candidates.

Asunto(s)

Imidazoles/síntesis química , Tripanocidas/síntesis química , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Hidrazonas/química , Imidazoles/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos

RESUMEN

Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 µg/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes.

Asunto(s)

Antituberculosos/síntesis química , Antituberculosos/farmacología , Azoles/farmacología , Imidazoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Naftoquinonas/farmacología , Oxazoles/farmacología , Antituberculosos/química , Azoles/síntesis química , Azoles/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Naftoquinonas/síntesis química , Naftoquinonas/química , Oxazoles/síntesis química , Oxazoles/química , Relación Estructura-Actividad

RESUMEN

Two series of imidazo[2,1-b]thiazoles substituted on C-3 or C-5 with an unprotected carbohydrate moiety were synthesized. Different protective groups for position 3 of the carbohydrate moiety were tested (acetyl, tert-butyldimethylsilyl (TBDMS), and p-methoxybenzyl (PMB)) and the latter turn out to be the best strategy to obtain the desired products. Full deprotection of the carbohydrate was performed successfully in only one step.

Asunto(s)

Carbohidratos/química , Imidazoles/síntesis química , Tiazoles/síntesis química , Imidazoles/química , Estructura Molecular , Estereoisomerismo , Tiazoles/química

RESUMEN

A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC(50) values ranging from 15 to 60 µM. The reference drug pentamidine presented IC(50)=10 µM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.

Asunto(s)

Antiprotozoarios/síntesis química , Imidazoles/síntesis química , Pirazoles/síntesis química , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Imidazoles/química , Imidazoles/farmacología , Imidazoles/uso terapéutico , Leishmania/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Ratones , Pirazoles/química , Pirazoles/farmacología , Pirazoles/uso terapéutico , Relación Estructura-Actividad

RESUMEN

The synthesis and antimicrobial profile of imidazolium ionic liquids containing selenium are described herein. Minimum inhibitory concentration revealed that these compounds are especially active against algae, and their activity is modulated by substituents attached to the selenium moiety as well as by the counterion.

Asunto(s)

Antiinfecciosos/síntesis química , Imidazoles/síntesis química , Líquidos Iónicos/química , Selenio/química , Antiinfecciosos/farmacología , Imidazoles/farmacología , Viabilidad Microbiana/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad