RESUMEN
In this study, an efficient one-pot procedure for preparing a new series of pyrazolo[3,4-b]pyridine-fused pyrimidines was described. The target hybrids were developed through a three-component reaction of 3-amino-1H-pyrazolo[3,4-b]pyridine, benzaldehydes, and acetophenones (molar ratio 1 : 1 : 1). The best conditions for the previous reaction were 2.5â equivalents of barium hydroxide in DMF at 150 °C for 6â h. New bis(pyrimidines) were synthesized in high yields using a similar one-pot reaction protocol with some modifications. Thus, two equivalents of each of the appropriate acetophenones and 3-aminopyrazolopyridine were reacted with one equivalent of the appropriate bis(aldehydes). The reaction was carried out at 150 °C for 8â h using 4.5â equivalents of barium hydroxide in DMF. Repeating the previous reaction with the appropriate bis(acetyl) derivatives and benzaldehydes resulted in good yields of the target bis(pyrimidines). The inâ vitro cytotoxic activity of new pyrimidines against the MCF-7, HEPG2, and Caco2 cell lines was evaluated using the reference doxorubicin (IC50 values of 4.34-6.97â µM). Hybrid 6h had the best activity against Caco2 and MCF-7 cell lines, IC50 values of 12.62 and 14.50â µM, respectively. The IC50 values for hybrids 6c, 6e, and 6f against MCF-7 and Caco2 cell lines were 23.99-41.69 and 33.14-43.33â µM, respectively. Furthermore, hybrid 6e displayed IC50 value of 20.06â µM HEPG2 cell lines, while the hybrids 6c, 6f and 6h exhibited IC50 values ranging between 26.29-50.51â µM. Furthermore, hybrid 6e had an IC50 value of 20.06â µM for the HEPG2 cell lines, whereas hybrids 6c, 6f, and 6h had IC50 values ranging from 26.29 to 50.51â µM.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos de Bario/química , Pirazoles/química , Piridinas/química , Pirimidinas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Pectin is widely used in food and pharmaceutical industries. However, due to its polysaccharide nature it lacks antimicrobial activity. In the current work, new pectin derivatives with interesting optical and antimicrobial properties were prepared via supramolecular chemistry utilizing Fe- or Cu-terpyridine (Tpy-Fe and Tpy-Cu) motifs. To proof derivatization of pectin, ultraviolet-visible spectroscopy (UV-Vis) and Fourier Transform infrared (FTIR) were used. In addition, the prepared pectin derivatives retained the known emulsification activity of the non-modified sugar beet pectin as seen from the particle size analysis of oil-in-water emulsions. The prepared derivatives showed antibacterial activity toward selected Gram-positive and Gram-negative bacteria. In addition, cytotoxicity test showed that the Tpy-Fe-pectin derivative was non-toxic to cells of human hepatocarcinoma, breast adenocarcinoma MCF7, and colorectal carcinoma cells at concentrations up to 100 µg/ml, while Tpy-Cu-pectin had moderate toxicity toward the aforementioned cells at the same concentration levels. The prepared derivatives could have potential applications in emulsions with antibacterial activity.
Asunto(s)
Antibacterianos/farmacología , Complejos de Coordinación/farmacología , Emulsionantes/farmacología , Pectinas/farmacología , Piridinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Beta vulgaris/química , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/toxicidad , Cobre/química , Cobre/toxicidad , Emulsionantes/síntesis química , Emulsionantes/toxicidad , Escherichia coli/efectos de los fármacos , Humanos , Hierro/química , Hierro/toxicidad , Ligandos , Pruebas de Sensibilidad Microbiana , Pectinas/síntesis química , Pectinas/toxicidad , Piridinas/síntesis química , Piridinas/toxicidad , Staphylococcus aureus/efectos de los fármacosRESUMEN
For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 µM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Simulación por Computador , Piridinas/síntesis química , Piridinas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Antimaláricos/química , Antimaláricos/farmacocinética , Sitios de Unión , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Plasmodium falciparum/efectos de los fármacos , Piridinas/química , Piridinas/farmacocinética , Sulfonamidas/química , Sulfonamidas/farmacocinética , Triazoles/química , Triazoles/farmacocinéticaRESUMEN
Immune checkpoint blockade of the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway via an antibody is a potent strategy for T cell remodeling. Nevertheless, the potency of the antibody is partly compromised by its high price, instability, risk of autoimmune disease, and so forth. Small-molecule inhibitors are interesting alternatives to antibodies. However, tumor-specific delivery of small-molecule inhibitors to the target site for boosting the interruption of the PD-L1/PD-1 pathway is rarely reported. Herein, we designed a tumor-specific delivery nanoplatform that could efficiently deliver the small-molecule inhibitor to the precise target site, greatly enhancing the blocking effect of the PD-L1/PD-1 pathway. Hyaluronic acid (HA) was conjugated with chlorin e6 (Ce6), resulting in a HA-Ce6 conjugate (HC). The nanoplatform was constructed by the HC micelles with the encapsulation of small-molecule inhibitor, BMS 202 (BMS), to form BMS/HC micelles. The target property of HA, combined with the hyaluronidase-induced degradation of HA in the tumor site, enables the as-prepared micelles with tumor-specific delivery of BMS for blocking the PD-L1/PD-1 pathway. With cooperative treatment with the photosensitizer Ce6, the present therapeutic nanoplatform demonstrated excellent photoimmunotherapy for tumor regression in distant tumors and lung metastasis. This strategy of tumor-specific delivery of small-molecule inhibitors provides an effective pathway to strengthen the blocking efficacy of PD-L1/PD-1 on effective photoimmunotherapy.
Asunto(s)
Acetamidas/farmacología , Inmunoterapia , Melanoma Experimental/tratamiento farmacológico , Nanopartículas/química , Fototerapia , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Acetamidas/síntesis química , Acetamidas/química , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Clorofilidas , Femenino , Ácido Hialurónico/química , Ácido Hialurónico/metabolismo , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Micelas , Tamaño de la Partícula , Porfirinas/química , Piridinas/síntesis química , Piridinas/química , Especies Reactivas de Oxígeno/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC50 values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors (5e and 5d) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta (ßA) aggregation and ß-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Piridinas/farmacología , Tacrina/farmacología , Acetilcolinesterasa/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Butirilcolinesterasa/efectos de los fármacos , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Piridinas/síntesis química , Piridinas/química , Tacrina/síntesis química , Tacrina/químicaRESUMEN
Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Piridinas/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzofuranos/farmacología , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Fenilpropionatos/química , Piridinas/efectos adversos , Piridinas/farmacocinética , Ratas Sprague-Dawley , Sulfonas/farmacologíaRESUMEN
Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and immunohistochemical labelling of synaptic proteins were the gold-standard methods for such analyses. Over the last decade, several PET radiotracers for the synaptic vesicle 2A protein have been developed to achieve in vivo synapses visualization and quantification. Different strategies were used, namely radiolabelling with either 11C or 18F, preclinical development in rodent and non-human primates, and binding quantification with different kinetic modelling methods. This review provides an overview of these PET tracers and underlines their perspectives and limitations by focusing on radiochemical aspects, as well as preclinical proof-of-concept and the main clinical outcomes described so far.
Asunto(s)
Encéfalo/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Piridinas/farmacocinética , Pirrolidinas/farmacocinética , Pirrolidinonas/farmacocinética , Vesículas Sinápticas/patología , Animales , Encéfalo/metabolismo , Radioisótopos de Carbono , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Radioisótopos de Flúor , Humanos , Macaca mulatta , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/metabolismo , Neuronas/patología , Tomografía de Emisión de Positrones/normas , Prueba de Estudio Conceptual , Piridinas/síntesis química , Pirrolidinas/síntesis química , Pirrolidinonas/síntesis química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Roedores , Vesículas Sinápticas/metabolismoRESUMEN
Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [18F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [18F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs 1 and 2 were synthesized and their MCT1 inhibition was estimated by [14C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds 1 and 2 showed lower MCT1 inhibitory potencies than FACH (IC50 = 11 nM) by factors of 11 and 25, respectively, 1 (IC50 = 118 nM) could still be a suitable PET candidate. Therefore, 1 was selected for radiosynthesis of [18F]1 and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D7.4 result for [18F]1 agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [18F]1 compared to [18F]FACH, the in vivo brain uptake of [18F]1 was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain.
Asunto(s)
Encéfalo/diagnóstico por imagen , Transportadores de Ácidos Monocarboxílicos/metabolismo , Tomografía de Emisión de Positrones/métodos , Piridinas/síntesis química , Radiofármacos/síntesis química , Simportadores/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Línea Celular , Ácidos Cumáricos/farmacología , Evaluación Preclínica de Medicamentos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Radioisótopos de Flúor , Ligandos , Ratones , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Piridinas/farmacocinética , Radiofármacos/farmacocinética , Ratas , Simportadores/antagonistas & inhibidoresRESUMEN
A library of novel pyrazole-imidazo[1,2-α]pyridine scaffolds was designed and synthesized through a one-pot three-component tandem reaction. The structures of synthesized conjugates were confirmed by spectroscopic techniques (NMR, IR and HRMS). In vitro antibacterial evaluation of the twelve synthesized molecules (7a, 8a-k) against methicillin-resistant Staphylococcus aureus and normal strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa established 8b, 8d, 8e, 8h and 8i as potent antibacterial agents with superior minimum bactericidal concentration, compared with standard drug ciprofloxacin. Molecular docking studies of all active compounds into the binding site of glucosamine-6-phosphate synthase were further performed in order to have a comprehensive understanding of putative binding modes within the active sites of the receptor.
Asunto(s)
Antibacterianos/síntesis química , Inhibidores Enzimáticos/química , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/química , Pirazoles/síntesis química , Piridinas/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Ciprofloxacina/farmacología , Ciprofloxacina/normas , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/antagonistas & inhibidores , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/farmacología , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
AIM: Aiming to produce pyridine azo disperse dyes with good fastness properties and promising antimicrobial activity, a number of novel systems of polyfunctionalized pyridine azo dyes and their selenium nanoparticles (SeNPs) were synthesized. MATERIALS AND METHODS: The synthesized products were formed by the reaction of diazotized aniline derivatives or diazotized amino antipyrene with any of dibenzoyl methane or benzoyl acetone and cyanoacetamide in boiling ethanolic sodium ethoxide. The structures of the newly synthesized compounds were elucidated by elemental analysis and spectral data. Moreover, (SeNPs) of the pyridine azo disperse dyes were characterized by Ultra-Violet -Visible spectrophotometry, dynamic light scattering , X-ray diffraction, and transmission electron microscope analysis. On the other hand, the synthesized dyes and its (SeNPs) were applied for disperse dyeing of nylon 66 and their fastness properties were measured, such as washing, rubbing, perspiration, and light fastness. In addition, the antimicrobial activities for all the synthesized compounds and for (SeNPs) prepared compounds (2bN, 2cN, 2fN, 2gN, 2hN) were evaluated. RESULTS: Compounds 2bN, 2c, 2cN, 2fN, 2gN, 2h, 2hN, and 2i were the most active compounds against all Gram-positive and Gram-negative bacterial species. While, compounds 2b, 2f, 2g, and 5b were the most active toward some of the bacterial strains (at least two from the selected four strains). Moreover, compounds 2bN, 2cN, 2fN, 2gN, 2h, 2hN showed higher activity toward the fungal strain. Also, the minimal inhibitory concentrations for all the most active compounds were determined. CONCLUSION: Finally, all the (SeNPs) compounds revealed higher activity against bacterial and fungal strains than the other synthesized compounds.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Compuestos Azo/química , Compuestos Azo/síntesis química , Nanopartículas del Metal/química , Piridinas/química , Piridinas/síntesis química , Selenio/química , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Nanopartículas del Metal/ultraestructura , Pruebas de Sensibilidad Microbiana , Difracción de Rayos XRESUMEN
New series of fused pyrazolopyridines were prepared and assessed for antimicrobial, antiquorum-sensing and antitumor activities. Antimicrobial evaluation toward selected Gram-positive bacteria, Gram-negative bacteria and fungi indicated that 5-phenylpyrazolopyridotriazinone 4a has good and broad-spectrum antimicrobial activity. In addition, 5-(4-chlorophenyl)pyrazolopyridotriazinone 4b and 5-(4-(dimethylamino)phenyl)pyrazolopyridotriazinone 4c exhibited good activity against the selected Gram-positive bacteria and A. fumigatus, whereas 5-amino-4-phenylpyrazolopyridopyrimidine 6a demonstrated good activity against B. cereus and P. aeruginosa. Furthermore, 6-amino-5-imino-4-phenylpyrazolopyridopyrimidine 7a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b demonstrated promising activity against the tested Gram-negative bacteria and fungi, and moderate activity against Gram-positive bacteria. Antiquorum-sensing screening over C. violaceum illustrated that 4a, 6a and 7a-c have strong activity. In vitro antiproliferative assessment of the new derivatives against HepG2, HCT-116 and MCF-7 cancer cells revealed that 7a is the most active analog against all tested cell lines. Likewise, 3,7-dimethyl-4-phenylpyrazolopyridopyrimidinone 2a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b manifested strong activity against all examined cell lines. In vivo antitumor testing of 2a, 7a and 7b against EAC cells in mice indicated that 7a has the highest activity. Cytotoxicity toward WI38 and WISH normal cells was also assessed and results assured that all of the investigated analogs have lower cytotoxicity than doxorubicin. DNA-binding affinity and topoisomerase IIß inhibitory activity were evaluated, and results revealed that 5b, 7a and 7b bind strongly to DNA; in addition, 2a, 4a, 7a and 7b manifested higher topoisomerase IIß inhibitory activity than that of doxorubicin. Analogs 5b, 7a and 7b were docked into topoisomerase IIß, and results indicated that 7a and 7b have the highest binding affinity toward topoisomerase IIß. In silico simulation studies referred that most of the new analogs comply with the optimum needs for good oral absorption. Also, computational carcinogenicity evaluation was predicted.
Asunto(s)
Antiinfecciosos/síntesis química , Antineoplásicos/síntesis química , Pirazoles/síntesis química , Piridinas/síntesis química , Animales , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Bacterias/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , ADN/química , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , Proteínas de Unión al ADN/química , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/farmacología , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3'-indoline]-2',5(3H)-dione analogues were synthesized and evaluated as potent dengue virus inhibitors. Throughout a structure-activity relationship exploration on the amide of the indolone moiety, a wide range of substitutions were found to be well tolerated for chemical optimization at this position. Among these compounds, 15 (JMX0254) displayed the most potent and broad inhibitory activities, effective against DENV-1 to -3 with EC50 values of 0.78, 0.16, and 0.035 µM, respectively, while compounds 16, 21, 27-29, 47, and 70 exhibited relatively moderate to high activities with low micromolar to nanomolar potency against all four serotypes. The biotinylated compound 73 enriched NS4B protein from cell lysates in pull-down studies, and the findings together with the mutation investigations further validated dengue NS4B protein as the target of this class of compounds. More importantly, compound 15 exhibited good in vivo pharmacokinetic properties and efficacy in the A129 mouse model, indicating its therapeutic potential against the dengue virus infection as a drug candidate for further preclinical development.
Asunto(s)
Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Dengue/tratamiento farmacológico , Diseño de Fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dengue/metabolismo , Virus del Dengue/enzimología , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Masculino , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Distribución Tisular , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
2-(piperazin-1-yl)N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid ß aggregation inhibitors. Formation of synthesized compounds (P1P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aß aggregation and Cu(II)-mediated Aß aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50â¯=â¯4.8â¯nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced ß-amyloid (Aß) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aß1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aß disaggregation, antioxidation, metal-chelation activity.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Pirazoles/química , Pirazoles/uso terapéutico , Piridinas/química , Piridinas/uso terapéutico , Acetilcolinesterasa/efectos de los fármacos , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/ultraestructura , Antioxidantes/farmacología , Hidrolasas de Éster Carboxílico/efectos de los fármacos , Quelantes/uso terapéutico , Inhibidores de la Colinesterasa/uso terapéutico , Cobre/química , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Microscopía Electrónica de Transmisión , Simulación del Acoplamiento Molecular , Pirazoles/síntesis química , Piridinas/síntesis química , Espectrometría de FluorescenciaRESUMEN
With the aim of discovering novel IDO1 inhibitors, a combined similarity search and molecular docking approach was employed to the discovery of 32 hit compounds. Testing the screened hit compounds has led to several novel submicromolar inhibitors. Especially for compounds LVS-019 with cyanopyridine scaffold, showed good IDO1 inhibitory activity. To discover more compounds with similar structures to LVS-019, a shape-based model was then generated on the basis of it and the second-round virtual screening was carried out leading to 23 derivatives. Molecular docking studies suggested a possible binding mode of LVS-019, which provides a good starting point for the development of cyanopyridine scaffold compounds as potent IDO1 inhibitor. To improve potency of these hits, we further designed and synthesised another 14 derivatives of LVS-019. Among these compounds, LBJ-10 showed improved potency compared to the hits and displayed comparable potency to the control GDC-0919 analogue. LBJ-10 can serve as ideal leads for further modifications as IDO1 inhibitors for cancer treatment.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Piridinas/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G2/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of ß-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit ß-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Piridinas/farmacología , Pirimidinas/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ensayo de Inmunoadsorción Enzimática , Células HCT116 , Células HL-60 , Humanos , Células MCF-7 , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Polimerizacion/efectos de los fármacos , Piridinas/síntesis química , Piridinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Tubulina (Proteína)/biosíntesisRESUMEN
The rise of antimicrobial resistance (AMR) worldwide and the increasing spread of multi-drug-resistant organisms expressing metallo-ß-lactamases (MBL) require the development of efficient and clinically available MBL inhibitors. At present, no such inhibitor is available, and research is urgently needed to advance this field. We report herein the development, synthesis, and biological evaluation of chemical compounds based on the selective zinc chelator tris-picolylamine (TPA) that can restore the bactericidal activity of Meropenem (MEM) against Pseudomonas aeruginosa and Klebsiella pneumoniae expressing carbapenemases Verona integron-encoded metallo-ß-lactamase (VIM-2) and New Delhi metallo-ß-lactamase 1 (NDM-1), respectively. These adjuvants were prepared via standard chemical methods and evaluated in biological assays for potentiation of MEM against bacteria and toxicity (IC50) against HepG2 human liver carcinoma cells. One of the best compounds, 15, lowered the minimum inhibitory concentration (MIC) of MEM by a factor of 32-256 at 50 µM within all tested MBL-expressing clinical isolates and showed no activity toward serine carbapenemase expressing isolates. Biochemical assays with purified VIM-2 and NDM-1 and 15 resulted in inhibition kinetics with kinact/ KI of 12.5 min-1 mM-1 and 0.500 min-1 mM-1, respectively. The resistance frequency of 15 at 50 µM was in the range of 10-7 to 10-9. 15 showed good tolerance in HepG2 cells with an IC50 well above 100 µM, and an in vivo study in mice showed no acute toxic effects even at a dose of 128 mg/kg.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Quelantes/síntesis química , Quelantes/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/farmacología , Antibacterianos/química , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Quelantes/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Meropenem/farmacología , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Piridinas/química , Zinc/química , Zinc/metabolismo , Inhibidores de beta-Lactamasas/química , beta-Lactamasas/química , beta-Lactamasas/metabolismoRESUMEN
Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeutics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with antiarenaviral activity that could serve as probes to identify arenavirus-host interactions suitable for targeting, as well as lead compounds to develop future antiarenaviral drugs. Screening of a combinatorial library of Krönhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[ b][1,4] dioxin-6-yl)-4'-methoxy-[1,1'-biphenyl]-3-yl)thiophene-2-carboxamide] as having strong anti-lymphocytic choriomeningitis virus (LCMV) activity in cultured cells. KP-146 did not inhibit LCMV cell entry but rather interfered with the activity of the LCMV ribonucleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Kröhnke pyridine scaffold as a valuable source to identify compounds that could serve as tools to dissect arenavirus-host interactions, as well as lead candidate structures to develop antiarenaviral drugs.
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Antivirales/farmacología , Arenavirus/efectos de los fármacos , Minería de Datos , Descubrimiento de Drogas , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas , Animales , Antivirales/síntesis química , Antivirales/química , Infecciones por Arenaviridae/tratamiento farmacológico , Infecciones por Arenaviridae/virología , Arenavirus/fisiología , Línea Celular , Técnicas de Química Sintética , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Virus de la Coriomeningitis Linfocítica/efectos de los fármacos , Piridinas/síntesis química , Piridinas/química , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
An expeditious catalyst-free heteroannulation reaction for imidazo[1,2- a]pyridines/pyrimidines/pyrazines was developed in green solvent under microwave irradiation. Using H2O-IPA as the reaction medium, various substituted 2-aminopyridines/pyrazines/pyrimidines underwent annulation reaction with α-bromoketones under microwave irradiation to provide the corresponding imidazo[1,2- a]pyridines/pyrimidines/pyrazines in excellent yields. The synthetic methodology appears to be very simple and superior to the already reported procedures with the high abundance of commercial reagents and great ability in expanding the molecular diversity. The present synthetic sequence is visualized as an environmentally benign process which allows the introduction of three points of structural diversity to expand chemical space with excellent purity and yields. The anti-inflammatory and antimicrobial activities of the derivatives were evaluated. Screening results uncovered three derivatives with strong inhibition of albumin denaturation and two derivatives were active on Proteus and Klebsiella bacteria. These positive bioassay results implied that the library of potential anti-inflammatory agents could be rapidly prepared in an ecofriendly manner, and provided new insights into drug discovery for medicinal chemists.
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Imidazoles/síntesis química , Pirazinas/síntesis química , Piridinas/síntesis química , Pirimidinas/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Catálisis , Técnicas Químicas Combinatorias/métodos , Evaluación Preclínica de Medicamentos/métodos , Tecnología Química Verde/métodos , Humanos , Microondas , Estructura Molecular , Desnaturalización Proteica , Bibliotecas de Moléculas Pequeñas/síntesis química , Solventes , Relación Estructura-ActividadRESUMEN
Retinoic acid receptor-related-orphan-receptor-C (RORγt) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORγt in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight RORγt inverse agonist. The compound binds to the ligand binding domain (LBD) of RORγt leading to displacement of a co-activator peptide. We show for the first time that a RORγt inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORγt-dependent genes. Consistent with this, the compound effectively reduced IL-17A production by polarized human T-cells and γδT-cells and attenuated transcription of RORγt target genes. The inhibitor showed good in vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex vivo recall assays. In summary, we demonstrate that inhibiting RORγt by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.
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Artritis Experimental/tratamiento farmacológico , Imidazoles/farmacología , Interleucina-17/antagonistas & inhibidores , Linfocitos Intraepiteliales/efectos de los fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Piridinas/farmacología , Pirimidinas/farmacología , Células Th17/efectos de los fármacos , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/patología , Línea Celular Tumoral , Femenino , Regulación de la Expresión Génica , Células HEK293 , Humanos , Imidazoles/síntesis química , Interleucina-17/genética , Interleucina-17/inmunología , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/patología , Cinética , Masculino , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Regiones Promotoras Genéticas , Unión Proteica , Piridinas/síntesis química , Pirimidinas/síntesis química , Ratas , Ratas Endogámicas Lew , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Transducción de Señal , Células Th17/inmunología , Células Th17/patologíaRESUMEN
The synthesis, photophysics, and biochemical utility of a fluorescent NAD+ analogue based on an isothiazolo[4,3-d]pyrimidine core (NtzAD+) are described. Enzymatic reactions, photophysically monitored in real time, show NtzAD+ and NtzADH to be substrates for yeast alcohol dehydrogenase and lactate dehydrogenase, respectively, with reaction rates comparable to that of the native cofactors. A drop in fluorescence is seen as NtzAD+ is converted to NtzADH, reflecting a complementary photophysical behavior to that of the native NAD+/NADH. NtzAD+ and NtzADH serve as substrates for NADase, which selectively cleaves the nicotinamide's glycosidic bond yielding tzADP-ribose. NtzAD+ also serves as a substrate for ribosyl transferases, including human adenosine ribosyl transferase 5 (ART5) and Cholera toxin subunit A (CTA), which hydrolyze the nicotinamide and transfer tzADP-ribose to an arginine analogue, respectively. These reactions can be monitored by fluorescence spectroscopy, in stark contrast to the corresponding processes with the nonemissive NAD+.