RESUMEN

Alzheimer's disease is age-related multifactorial neurodegenerative disease manifested by gradual loss of memory, cognitive decline and changes in personality. Due to rapid and continuous growth of its prevalence, the treatment of Alzheimer's disease calls for development of new and efficacies drugs, especially those that could be able to simultaneously act on more than one of possible targets of action. Aminoquinolines have proven to be a highly promising structural scaffold in the design of such a drug as cholinesterases and ß-secretase 1 inhibitors. In this study, we synthesised twenty-two new 4-aminoquinolines with different halogen atom and its position in the terminal N-benzyl group or with a trifluoromethyl or a chlorine as C(7)-substituents on the quinoline moiety. All compounds were evaluated as multi-target-directedligands by determining their inhibition potency towards human acetylcholinesterase, butyrylcholinesterase and ß-secretase 1. All of the tested derivatives were very potent inhibitors of human acetylcholinesterase and butyrylcholinesterase with inhibition constants (Ki) in the nM to low µM range. Most were estimated to be able to cross the blood-brain barrier by passive transport and were nontoxic toward cells that represented the main models of individual organs.

Asunto(s)

Acetilcolinesterasa , Aminoquinolinas , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Humanos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Aminoquinolinas/farmacología , Aminoquinolinas/química , Aminoquinolinas/síntesis química , Butirilcolinesterasa/metabolismo , Relación Estructura-Actividad , Acetilcolinesterasa/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Estructura Molecular , Halógenos/química , Relación Dosis-Respuesta a Droga

RESUMEN

Antimalarial drug resistance is a major obstacle in the ongoing quest against malaria. The disease affects half of the world's population. The majority of them are toddlers and pregnant women. Needed a potent compound to act on drug-resistant Pf at appropriate concentrations without endangering the host. Envisaged solving this issue through rational drug design by creating a novel hybrid drug possessing two pharmacophores that can act on two marvellous and independent aims within the cell. Synthesized a new series of substituted 4-phenyl-1,2,3,6-tetrahydropyridine (THP) 8-Aminoquinoline-based hybrid analogs which have been integrated with quinoline, chloroquine, pamaquine, and primaquine, which exhibited antimalarial activity against Pf. Out of thirteen 4-phenyl-1,2,3,6-THP appended 8-Aminoquinoline derivatives, the compounds 1j, 1e, 1b, and 1l have exhibited good antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strain with the minimum inhibitory concentration. Compound 1b was the most effective and showed consistently good potency against the drug-resistant (RKL-9) strain, although all other arrays showed good antimalarial efficacy. Additional docking and molecular dynamics studies were carried out at several targeting sites to quantify the structural parameters necessary for the activity.

Asunto(s)

Aminoquinolinas , Antimaláricos , Diseño de Fármacos , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum , Humanos , Aminoquinolinas/química , Aminoquinolinas/farmacología , Aminoquinolinas/síntesis química , Antimaláricos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos , Piridinas/química , Piridinas/farmacología , Piridinas/síntesis química , Relación Estructura-Actividad

RESUMEN

Patents tend to define a huge chemical space described by the combinatorial nature of Markush structures. However, the optimization of new principal active ingredient is frequently driven by a simple Free Wilson approach. This procedure leads to a highly focused study on the chemical space near a hit compound leaving many unexplored regions that may present highly biological active reservoirs. This study aims to demonstrate that this unveiled chemical space can hide compounds with interesting potential biological activity that would be worth pursuing. This underlines the value and necessity of broadening an approach beyond conventional strategies. Hence, we advocate for an alternative methodology that may be more efficient in the early drug discovery stages. We have selected the case of Tafenoquine, a single-dose treatment for the radical cure of P. vivax malaria approved by the FDA in 2018, as an example to illustrate the process. Through the deep exploration of the Tafenoquine chemical space, seven compounds with potential antimalarial activity have been rationally identified and synthesized. This small set is representative of the chemical diversity unexplored by the 58 analogs reported to date. After biological assessment, results evidence that our approach for rational design has proven to be a very efficient exploratory methodology suitable for the early drug discovery stages.

Asunto(s)

Aminoquinolinas , Antimaláricos , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , Aminoquinolinas/química , Aminoquinolinas/farmacología , Aminoquinolinas/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Parasitaria , Plasmodium vivax/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos

RESUMEN

The hydrogen bonding interaction between an amide N-H and the amide N of the preceding residue is prevalent in proline-containing proteins and peptides. However, the N-H⋅⋅⋅N hydrogen bonding interaction is rare in non-prolyl natural peptides due to restricted dihedral angles. Herein, we stabilize this type of interaction in 8-aminoquinoline appended non-prolyl peptides through bifurcated N⋅⋅⋅H⋅⋅⋅N hydrogen bond. The 8-aminoquinoline-incorporated model peptides 2 a-i were designed, synthesized, and the crystal structures of 2 a-c and 2 i were solved. Analysis of crystal data reveals that the amide N-H of aminoquinoline is involved in bifurcated hydrogen bonding interaction with the nitrogen of the preceding amino acid residue and the nitrogen in quinoline. Analysis of crystal packing, Hirshfeld surface and fingerprint plots confirms that the intermolecular O⋅⋅⋅H contacts significantly contribute to stabilizing bifurcated N⋅⋅⋅H⋅⋅⋅N hydrogen bonding interaction. Furthermore, NMR experiments and CD spectroscopy were conducted to examine the preferred conformation in solution, and the data corroborate with the crystal structure conformation.

Asunto(s)

Aminoquinolinas , Enlace de Hidrógeno , Péptidos , Péptidos/química , Péptidos/síntesis química , Aminoquinolinas/química , Aminoquinolinas/síntesis química , Cristalografía por Rayos X , Modelos Moleculares

RESUMEN

The biphenyl scaffold represents a prominent privileged structure within the realms of organic chemistry and drug development. Biphenyl derivatives have demonstrated notable biological activities, including antimicrobial, anti-inflammatory, anti-HIV, and the treatment of neuropathic pain. Importantly, their anticancer abilities should not be underestimated. In this context, the present study involves the design and synthesis of a series of biphenyl derivatives featuring an additional privileged structure, namely the quinoline core. We have also diversified the substituents attached to the benzyloxy group at either the meta or para position of the biphenyl ring categorized into two distinct groups: [4,3']biphenylaminoquinoline-substituted and [3,3']biphenylaminoquinoline-substituted compounds. We embarked on an assessment of the cytotoxic activities of these derivatives in colorectal cancer cell line SW480 and prostate cancer cell line DU145 for exploring the structure-activity relationship. Furthermore, we determined the IC50 values of selected compounds that exhibited superior inhibitory effects on cell viability against SW480, DU145 cells, as well as MDA-MB-231 and MiaPaCa-2 cells. Notably, [3,3']biphenylaminoquinoline derivative 7j displayed the most potent cytotoxicity against these four cancer cell lines, SW480, DU145, MDA-MB-231, and MiaPaCa-2, with IC50 values of 1.05 µM, 0.98 µM, 0.38 µM, and 0.17 µM, respectively. This highly promising outcome underscores the potential of [3,3']biphenylaminoquinoline 7j for further investigation as a prospective anticancer agent in future research endeavors.

Asunto(s)

Antineoplásicos , Compuestos de Bifenilo , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Relación Estructura-Actividad , Línea Celular Tumoral , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Ensayos de Selección de Medicamentos Antitumorales , Aminoquinolinas/química , Aminoquinolinas/farmacología , Aminoquinolinas/síntesis química , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos

RESUMEN

Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity relationships led to novel submicromolar inhibitors of MtInhA and potent antitubercular agents. The lead compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals, satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-aminoquinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug-resistant tuberculosis treatments.

Asunto(s)

Aminoquinolinas , Antituberculosos , Inhibidores Enzimáticos , Mycobacterium tuberculosis , Oxidorreductasas de Alcohol Dependientes de NAD (+) y NADP (+) , Animales , Ratones , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Antituberculosos/síntesis química , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Oxidorreductasas de Alcohol Dependientes de NAD (+) y NADP (+)/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Tuberculosis/tratamiento farmacológico , Modelos Animales de Enfermedad

RESUMEN

Malignant gliomas are the most common brain tumors, with generally dismal prognosis, early clinical deterioration and high mortality. Recently, 2-aminoquinoline scaffold derivatives have shown pronounced activity in central nervous system disorders. We herein reported a series of 2-aminoquinoline-3-carboxamides as novel non-alkylator anti-glioblastoma agents. The synthesized compounds showed comparable activity to cisplatin against glioblastoma cell line U87 MG in vitro. Among them, we found that 6a displayed good inhibitory activity against A172 and U118 MG glioblastoma cell lines and induced cell cycle arrest in the G2/M phase and apoptosis in U87 MG by flow cytometry analysis. Additionally, 6a displayed low cytotoxicity to several normal human cell lines. In silico study showed 6a had promising physicochemical properties and was predicted to cross the blood-brain barrier. Moreover, preliminary structure-activity relationships are also investigated, shedding light on further modifications towards more potent agents on this series of compounds. Our results suggest this compound has a promising potential as an anti-glioblastoma agent with a differential effect between tumor and non-malignant cells.

Asunto(s)

Aminoquinolinas/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Diseño de Fármacos , Glioblastoma/tratamiento farmacológico , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

The tumor microenvironment contains high concentrations of TGFß, a crucial immunosuppressive cytokine. TGFß stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack. Small-molecule inhibitors of TGFßR1 are a prospective method for next-generation immunotherapies. In the present study, we identified selective 4-aminoquinoline-based inhibitors of TGFßR1 through structural and rational-based design strategies. This led to the identification of compound 4i, which was found to be selective for TGFßR1 with the exception of MAP4K4 in the kinase profiling assay. The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression. Optimization efforts led to compound 4s that inhibited TGFßR1 at an IC50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4. Compound 4s represents a highly selective TGFßR1 inhibitor that has potential applications in immuno-oncology.

Asunto(s)

Aminoquinolinas/farmacología , Descubrimiento de Drogas , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/inmunología , Estructura Molecular , Proteínas Serina-Treonina Quinasas/inmunología , Receptor Tipo I de Factor de Crecimiento Transformador beta/inmunología , Relación Estructura-Actividad

RESUMEN

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aß42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Aminoquinolinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/metabolismo , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Simulación de Dinámica Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo

RESUMEN

We have previously reported the unique features of dimeric bisaminoquinolines as anticancer agents and have identified their cellular target as PPT1, a protein palmitoyl-thioesterase. We now report a systematic study on the role of the linker in these constructs, both with respect to the distance between the heterocycles, the linker hydrophobicity and the methylation status (primary vs. secondary vs. tertiary) of the central nitrogen atom on the observed biological activity.

Asunto(s)

Aminoquinolinas/farmacología , Antineoplásicos/farmacología , Aminoquinolinas/síntesis química , Antineoplásicos/síntesis química , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Proteínas de la Membrana/antagonistas & inhibidores , Estructura Molecular , Tioléster Hidrolasas/antagonistas & inhibidores

RESUMEN

Quinoline and 1,2,3-triazoles are well-known nitrogen-based heterocycles presenting diverse pharmacological properties, although their antileishmanial activity is still poorly exploited. As an effort to contribute with studies involving these interesting chemical groups, in the present study, a series of compounds derived from 4-aminoquinoline and 1,2,3-triazole were synthetized and biological studies using L. amazonensis species were performed. The results pointed that the derivative 4, a hybrid of 4-aminoquinoline/1,2,3-triazole exhibited the best antileishmanial action, with inhibitory concentration (IC50) values of ~1 µM against intramacrophage amastigotes of L. amazonensis , and being 16-fold more active to parasites than to the host cell. The mechanism of action of derivative 4 suggest a multi-target action on Leishmania parasites, since the treatment of L. amazonensis promastigotes caused mitochondrial membrane depolarization, accumulation of ROS products, plasma membrane permeabilization, increase in neutral lipids, exposure of phosphatidylserine to the cell surface, changes in the cell cycle and DNA fragmentation. The results suggest that the antileishmanial effect of this compound is primarily altering critical biochemical processes for the correct functioning of organelles and macromolecules of parasites, with consequent cell death by processes related to apoptosis-like and necrosis. No up-regulation of reactive oxygen and nitrogen intermediates was promoted by derivative 4 on L. amazonensis -infected macrophages, suggesting a mechanism of action independent from the activation of the host cell. In conclusion, data suggest that derivative 4 presents selective antileishmanial effect, which is associated with multi-target action, and can be considered for future studies for the treatment against disease.

Asunto(s)

Aminoquinolinas/farmacología , Antiprotozoarios/farmacología , Leishmania mexicana/efectos de los fármacos , Triazoles/farmacología , Aminoquinolinas/síntesis química , Animales , Antiprotozoarios/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Membrana Celular/química , Membrana Celular/metabolismo , Fragmentación del ADN/efectos de los fármacos , Femenino , Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos/parasitología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Orgánulos/efectos de los fármacos , Fosfatidilserinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Triazoles/síntesis química

RESUMEN

Literature conclusively shows that one of the quinolinequinone analogs (6-anilino-5,8-quinolinequinone), referred to as LY83583 hereafter, an inhibitor of guanylyl cyclase, was used as the inhibitor of the cell proliferation in cancer cells. In the present work, a series of analogs of the LY83583 containing alkoxy group(s) in aminophenyl ring (AQQ1-15) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against four different cancer cell lines (K562, Jurkat, MT-2, and HeLa) and human peripheral blood mononuclear cells (PBMCs) by MTT assay. The analog (AQQ13) was identified to possess the most potent cytotoxic activity against K562 human chronic myelogenous (CML) cell line (IC50 = 0.59 ± 0.07 µM) with significant selectivity (SI = 4.51) compared to imatinib (IC50 = 5.46 ± 0.85 µM; SI = 4.60). Based on its superior cytotoxic activity, the analog AQQ13 was selected for further mechanistic studies including determination of its apoptotic effects on K562 cell line via annexin V/ethidium homodimer III staining potency, ABL1 kinase inhibitory activity, and DNA cleaving capacity. Results ascertained that the analog AQQ13 induced apoptosis in K562 cell line with notable DNA-cleaving activity. However, AQQ13 demonstrated weak ABL1 inhibition indicating the correlation between anti-K562 and anti-ABL1 activities. In continuance, respectively conducted in silico molecular docking and Absorption, Distribution, Metabolism, and Excretion (ADME) studies drew attention to enhanced binding interactions of AQQ13 towards DNA and its high compatibility with the potential limits of specified pharmacokinetic parameters making it as a potential anti-leukemic drug candidate. Our findings may provide a new insight for further development of novel quinolinequinone-based anticancer analogs against CML.

Asunto(s)

Aminoquinolinas/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , División del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-abl/metabolismo , Relación Estructura-Actividad

RESUMEN

Quinone-based small molecules are the promising structures for antiproliferative drug design and can induce apoptosis in cancer cells. Among them, one of the quinolinequinones, named as 6-anilino-5,8-quinolinequinone, LY83583 has the ability to inhibit the growth of cancer cells as an inhibitor of cyclase. The biological potential of all synthesized compounds as the analogs of the identified lead molecule LY83583 that possessed the antiproliferative efficiency was determined. The two series of the LY83583 analogs containing electron-withdrawing or electron-donating group(s) were synthesized and subsequently in vitro evaluated for their cytotoxic activity against K562, Jurkat, MT-2, and HeLa cell lines using MTT assay. All the LY83583 analogs showed antiproliferative activity with good IC50 values (less than positive control imatinib). Four analogs from each series were also selected for the determination of selectivity against human peripheral blood mononuclear cells (PBMCs). The analog AQQ15 showed high potency towards all cancer cell lines with almost similar selectivity of imatinib. In order to get a better insight into cytotoxic effects of the analog AQQ15 in K562 cells, further apoptotic effects due to annexin V/ethidium homodimer III staining, ABL1 kinase inhibition, and DNA cleaving ability were examined. The analog AQQ15 induced apoptotic cell death in K562 cells with 34.6% compared to imatinib (6.5%). This analog showed no considerable ABL1 kinase inhibitory activity but significant DNA cleavage activity indicating DNA fragmentation-induced apoptosis. Besides, molecular docking studies revealed that the analog AQQ15 established proper interactions with the deoxyribose sugar attached with the nucleobases adenine and guanidine respectively, in the minor groove of the double helix of DNA. In silico predicted pharmacokinetic parameters of this analog were found to comply with the standard range making it an efficient anticancer drug candidate for further research.

Asunto(s)

Aminoquinolinas/química , Aminoquinolinas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Aminoquinolinas/síntesis química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Técnicas de Química Sintética , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico

RESUMEN

In search of new environmentally friendly and effective antifungal agents, a series of 4-aminoquinolines bearing a 1,3-benzodioxole moiety were prepared and their structures were fully elucidated by spectroscopic analyses. The antifungal activities of all the target compounds against five phytopathogenic fungi were evaluated in vitro. The results revealed that most of the newly synthesized compounds exhibited obvious inhibitory activities at the concentration of 50 µg/mL. Among them, 6-(furan-2-yl)-N-(4-methylphenyl)-2H-[1,3]dioxolo[4,5-g]quinolin-8-amine hydrochloride (7m) displayed more promising antifungal potency with EC50 values of 10.3 and 14.0 µg/mL against C. lunata and A. alternate, respectively. Particularly, the EC50 value of 7m against C. lunata was 7.3-fold as potent as the standard azoxystrobin. There were some significant morphological alterations in the mycelia of C. lunata when treated with 7m at 50 µg/mL. Additionally, the preliminary structure-activity relationships (SARs) were also discussed. Thus, this study suggests that 4-aminoquinolines bearing a 1,3-benzodioxole moiety are interesting scaffolds for the development of novel antifungal agents.

Asunto(s)

Aminoquinolinas/farmacología , Antifúngicos/farmacología , Dioxoles/farmacología , Hongos/efectos de los fármacos , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Antifúngicos/síntesis química , Antifúngicos/química , Dioxoles/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular

RESUMEN

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

Asunto(s)

Aminoquinolinas/uso terapéutico , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Nucleósidos/uso terapéutico , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Aminoquinolinas/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Femenino , Humanos , Ratones SCID , Simulación del Acoplamiento Molecular , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/metabolismo , Unión Proteica , Proteína-Arginina N-Metiltransferasas/metabolismo , Relación Estructura-Actividad

RESUMEN

Alzheimer's disease (AD) is one of the most common types of dementia, especially in elderly, with an increasing number of people suffering from this disease worldwide. There are no available disease-modifying therapies and only four drugs are approved for the relief of symptoms. Currently, the therapeutic approach used for AD treatment is based on single target drugs, which are not capable to stop its progression. To address this issue, multi-target compounds, combining two or more pharmacophores in a single molecular entity, have gained increasing interest to deal with the multiple factors related to AD. The exact cause of AD is not yet completely disclosed, and several hallmarks have been associated to this neurodegenerative disease. Even though, the accumulation of both amyloid-ß plaques (Aß) and neurofibrillary tangles (NFTs) are fully accepted as the main AD hallmarks, being object of lots of research for early-stage diagnosis and pharmacological therapy. In this context, this review summarizes the state-of-the-art in the field of dual-target inhibitors of both Aß and tau aggregation simultaneously, including the design and synthetic strategy of the dual-target compounds, as well as a brief structure-activity relationships (SAR) analysis.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Aminoquinolinas/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Curcumina/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Tacrina/farmacología , Proteínas tau/antagonistas & inhibidores , Enfermedad de Alzheimer/metabolismo , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Péptidos beta-Amiloides/metabolismo , Curcumina/síntesis química , Curcumina/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tacrina/síntesis química , Tacrina/química , Proteínas tau/metabolismo

RESUMEN

The ligand-activated transcription factor nuclear receptor related-1 (Nurr1) exhibits great potential for neurodegenerative disease treatment, but potent Nurr1 modulators to further probe and validate the nuclear receptor as a therapeutic target are lacking. We have systematically studied the structure-activity relationship of the 4-amino-7-chloroquinoline scaffold contained in Nurr1 activators amodiaquine and chloroquine and discovered fragment-like analogues that activated Nurr1 in several cellular settings. The most active descendants promoted the transcriptional activity of Nurr1 on human response elements as monomer, homodimer, and heterodimer and markedly enhanced Nurr1-dependent gene expression in human astrocytes. As a tool to elucidate mechanisms involving in Nurr1 activation, these Nurr1 agonists induced robust recruitment of NCoR1 and NCoR2 co-regulators to the Nurr1 ligand binding domain and promoted Nurr1 dimerization. These findings provide important insights in Nurr1 regulation. The fragment-sized Nurr1 agonists are appealing starting points for medicinal chemistry and valuable early Nurr1 agonist tools for pharmacology and chemical biology.

Asunto(s)

Aminoquinolinas/farmacología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/agonistas , Aminoquinolinas/síntesis química , Astrocitos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Estructura Molecular , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Relación Estructura-Actividad

RESUMEN

A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a cultured T. b. rhodesiense STIB900 strain. Several of these compounds (4a-g) displayed good antiplasmodium activities (IC50 = 0.20-0.62 µM) that were comparable to the reference drugs, while their antitrypanosomal activity was moderate (<20 µM). Compound 4e was 2-fold more active than primaquine and was also the most active (IC50 = 7.01 µM) against T. b. rhodesiense and also exhibited excellent aqueous solubility (>200 µM) at pH 7.

Asunto(s)

Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Lactamas/química , Tetrazoles/química , Aminoquinolinas/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Técnicas de Química Sintética , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Trypanosoma brucei rhodesiense/efectos de los fármacos

RESUMEN

To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC50 = 0.18 ± 0.03 µM, hBChE IC50 = 0.32 ± 0.07 µM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aß1-42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aß1-42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T1/2, and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.

Asunto(s)

Aminoquinolinas/farmacología , Bencimidazoles/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuroprotectores/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/metabolismo , Aminoquinolinas/toxicidad , Animales , Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Bencimidazoles/toxicidad , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Inhibidores de la Colinesterasa/toxicidad , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/toxicidad , Unión Proteica , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/toxicidad

RESUMEN

BACKGROUND: α2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α2A-AR subtype of traditional drugs greatly limits their clinic usage. METHODS: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism. RESULTS: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α2A-AR over α2B- and α2C-ARs. Besides, the affinities are of similar linker length-dependence for each α2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α2A-AR (pKi=-7.45±0.62), which is 12-fold and 60-fold selective over α2B-AR and α2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and "allosteric" sites of the α2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99. CONCLUSION: The specificity of C10 for the α2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α2A-AR subtype selective compounds.

Asunto(s)

Aminoquinolinas/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Humanos , Modelos Moleculares , Estructura Molecular