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1.
Molecules ; 28(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37049810

RESUMO

Despite the significant outcomes attained by scientific research, breast cancer (BC) still represents the second leading cause of death in women. Estrogen receptor-positive (ER+) BC accounts for the majority of diagnosed BCs, highlighting the disruption of estrogenic signalling as target for first-line treatment. This goal is presently pursued by inhibiting aromatase (AR) enzyme or by modulating Estrogen Receptor (ER) α. An appealing strategy for fighting BC and reducing side effects and resistance issues may lie in the design of multifunctional compounds able to simultaneously target AR and ER. In this paper, previously reported flavonoid-related potent AR inhibitors were suitably modified with the aim of also targeting ERα. As a result, homoisoflavone derivatives 3b and 4a emerged as well-balanced submicromolar dual acting compounds. An extensive computational study was then performed to gain insights into the interactions the best compounds established with the two targets. This study highlighted the feasibility of switching from single-target compounds to balanced dual-acting agents, confirming that a multi-target approach may represent a valid therapeutic option to counteract ER+ BC. The homoisoflavone core emerged as a valuable natural-inspired scaffold for the design of multifunctional compounds.


Assuntos
Inibidores da Aromatase , Aromatase , Neoplasias da Mama , Desenho de Fármacos , Receptor alfa de Estrogênio , Flavonoides , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Flavonoides/síntese química , Flavonoides/química , Flavonoides/farmacologia , Humanos , Feminino , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Simulação de Dinâmica Molecular , Aromatase/química , Aromatase/metabolismo , Termodinâmica , Concentração Inibidora 50 , Simulação de Acoplamento Molecular
2.
Bioorg Chem ; 129: 106152, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36155094

RESUMO

The complexity of neurodegenerative diseases, among which Alzheimer's disease plays a pivotal role, poses one of the tough therapeutic challenges of present time. In this perspective, a multitarget approach appears as a promising strategy to simultaneously interfere with different defective pathways. In this paper, a structural simplification plan was performed on our previously reported multipotent polycyclic compounds, in order to obtain a simpler pharmacophoric central core with improved pharmacokinetic properties, while maintaining the modulating activity on neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3ß), as validated targets to combat Alzheimer's disease. The molecular pruning approach applied here led to tetrahydroisoindole-dione (1), tetrahydromethanoisoindole-dione (2) and tetrahydroepoxyisoindole-dione (3) structures, easily affordable by Diels-Alder cycloaddition. Preliminary data indicated structure 3 as the most appropriate, thus a SAR study was performed by introducing different substituents, selected on the basis of the commercial availability of the furan derivatives required for the synthetic procedure. The results indicated compound 10 as a promising, structurally atypical, safe and BBB-penetrating Cav modulator, inhibiting both L- and N-calcium channels, likely responsible for the Ca2+ overload observed in Alzheimer's disease. In a multitarget perspective, compound 11 appeared as an effective prototype, endowed with improved Cav inhibitory activity, with respect to the reference drug nifedipine, and encouraging modulating activity on GSK-3ß.


Assuntos
Doença de Alzheimer , Humanos , Glicogênio Sintase Quinase 3 beta , Doença de Alzheimer/tratamento farmacológico , Simulação de Acoplamento Molecular , Canais de Cálcio , Neurônios
3.
Molecules ; 27(12)2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35744886

RESUMO

Osteosarcoma (OS) is a malignant disease characterized by poor prognosis due to a high incidence of metastasis and chemoresistance. Recently, Licochalcone A (Lic-A) has been reported as a promising agent against OS. Starting from chalcones selected from a wide in-house library, a new series was designed and synthetized. The antitumor activity of the compounds was tested on the MG63 OS cell line through the innovative Quantitative Phase Imaging technique and MTT assay. To further investigate the biological profile of active derivatives, cell cycle progression and apoptosis induction were evaluated. An earlier and more consistent arrest in the G2-M phase with respect to Lic-A was observed. Moreover, apoptosis was assessed by Annexin V staining as well as by the detection of typical morphological features of apoptotic cells. Among the selected compounds, 1e, 1q, and 1r proved to be the most promising antitumor molecules. This study pointed out that an integrated methodological approach may constitute a valuable platform for the rapid screening of large series of compounds.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Chalcona , Chalconas , Osteossarcoma , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Chalcona/farmacologia , Chalconas/farmacologia , Chalconas/uso terapêutico , Humanos , Osteossarcoma/patologia
4.
Bioorg Chem ; 106: 104460, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33229118

RESUMO

A small library of derivatives carrying a polycyclic scaffold recently identified by us as a new privileged structure in medicinal chemistry was designed and synthesized, aiming at obtaining potent MDR reverting agents also endowed with antitumor properties. In particular, as a follow-up of our previous studies, attention was focused on the role of the spacer connecting the polycyclic core with a properly selected nitrogen-containing group. A relevant increase in reverting potency was observed, going from the previously employed but-2-ynyl- to a pent-3-ynylamino moiety, as in compounds 3d and 3e, while the introduction of a triazole ring proved to differently impact on the activity of the compounds. The docking results supported the data obtained by biological tests, showing, for the most active compounds, the ability to establish specific bonds with P-glycoprotein. Moreover, a multifaceted anticancer profile and dual in vitro activity was observed for all compounds, showing both revertant and antitumor effects on leukemic cells. In this respect, 3c emerged as a "triple-target" agent, endowed with a relevant reverting potency, a considerable antiproliferative activity and a collateral sensitivity profile.


Assuntos
Antracenos/farmacologia , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Succinimidas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antracenos/síntese química , Antracenos/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Succinimidas/síntese química , Succinimidas/metabolismo
5.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299503

RESUMO

Naturally occurring flavonoids are found as secondary metabolites in a wide number of plants exploited for both medicine and food and have long been known to be endowed with multiple biological activities, making them useful tools for the treatment of different pathologies. Due to the versatility of the scaffolds and the vast possibilities of appropriate decoration, they have also been regarded as fruitful sources of lead compounds and excellent chemical platforms for the development of bioactive synthetic compounds. Flavone-8-acetic acid (FAA) and 5,6-dimethylxanthone acetic acid (DMXAA) emerged for their antitumour potential due to the induction of cytokines and consequent rapid haemorrhagic necrosis of murine tumour vasculature, and different series of derivatives have been designed thereafter. Although the promising DMXAA failed in phase III clinical trials because of strict species-specificity, a boost in research came from the recent identification of the stimulator of interferon genes (STING), responsible for supporting tumoural innate immune responses, as a possible biological target. Consequently, in the last decade a renewal of interest for these flavonoid-based structures was noticed, and novel derivatives have been synthesised and evaluated for a deeper understanding of the molecular features needed for affecting human cells. Undoubtedly, these natural-derived molecules deserve further investigation and still appear attractive in an anticancer perspective.


Assuntos
Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ensaios Clínicos Fase III como Assunto , Humanos , Xantenos/farmacologia , Xantonas/farmacologia
6.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071439

RESUMO

In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer's disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aß42) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aß42 self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation.


Assuntos
Canabinoides/química , Receptores Colinérgicos/química , Doença de Alzheimer/tratamento farmacológico , Amidoidrolases , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Carbamatos/farmacologia , Química Farmacêutica/métodos , Colinérgicos , Cumarínicos/uso terapêutico , Desenho de Fármacos , Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Receptores de Canabinoides , Rivastigmina/farmacologia
7.
Molecules ; 25(22)2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33207783

RESUMO

The current therapeutic approach for the treatment of hormone dependent breast cancer includes interference with estrogen receptors via either selective modulators or estrogens deprivation, by preventing their biosynthesis with aromatase inhibitors. Severe side effects and acquired resistance are drawbacks of both drug classes, and the efforts to overcome these issues still allow for research in this field to be animated. This review reports on recent findings that have opened new avenues for reconsidering the role of aromatase enzymes (and estrogen receptors) leading to the possibility of looking at well-known targets in a new perspective.


Assuntos
Inibidores da Aromatase/uso terapêutico , Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Terapia de Alvo Molecular , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Estrogênios/química , Estrogênios/metabolismo , Feminino , Humanos , Receptores de Estrogênio/metabolismo
8.
Molecules ; 25(13)2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32635622

RESUMO

The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, "privileged" synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound 1, bearing a para-fluoro phenyl moiety, showed low-micromolar potency against T acute lymphoblastic leukemia cell growth. More in-depth biologic studies demonstrated, for this analog, cell death-inducing properties associated with its capability to simultaneously activate both the receptor and the mitochondrial apoptosis cascades. This peculiar behavior offers promises for achieving an expanded anticancer effect, namely intense cytotoxic response coupled with reduced predisposition of chemoresistance insurgence. Altogether, this study allowed the identification of compound 1 as a lead compound worth to be progressed as an anticancer drug candidate.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Curcumina/farmacologia , Leucemia de Células T/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Triazóis/química , Antineoplásicos/química , Proliferação de Células , Curcumina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia de Células T/tratamento farmacológico , Estrutura Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Bioorg Chem ; 86: 401-409, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30769265

RESUMO

The inhibition of steroidogenic cytochrome P450 enzymes has been shown to play a central role in the management of life-threatening diseases such as cancer, and indeed potent inhibitors of CYP19 (aromatase) and CYP17 (17α hydroxylase/17,20 lyase) are currently used for the treatment of breast, ovarian and prostate cancer. In the last few decades CYP11B1 (11-ß-hydroxylase) and CYP11B2 (aldosterone synthase), key enzymes in the biosynthesis of cortisol and aldosterone, respectively, have been also investigated as targets for the identification of new potent and selective agents for the treatment of Cushing's syndrome, impaired wound healing and cardiovascular diseases. In an effort to improve activity and synthetic feasibility of our different series of xanthone-based CYP11B1 and CYP11B2 inhibitors, a small series of imidazolylmethylbenzophenone-based compounds, previously reported as CYP19 inhibitors, was also tested on these new targets, in order to explore the role of a more flexible scaffold for the inhibition of CYP11B1 and -B2 isoforms. Compound 3 proved to be very potent and selective towards CYP11B1, and was thus selected for further optimization via appropriate decoration of the scaffold, leading to new potent 4'-substituted derivatives. In this second series, 4 and 8, carrying a methoxy group and a phenyl ring, respectively, proved to be low-nanomolar inhibitors of CYP11B1, despite a slight decrease in selectivity against CYP11B2. Moreover, unlike the benzophenones of the first series, the 4'-substituted derivatives also proved to be selective for CYP11B enzymes, showing very weak inhibition of CYP19 and CYP17. Notably, the promising result of a preliminary scratch test performed on compound 8 confirmed the potential of this compound as a wound-healing promoter.


Assuntos
Benzofenonas/farmacologia , Inibidores Enzimáticos/farmacologia , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Cicatrização/efeitos dos fármacos , Xantonas/farmacologia , Benzofenonas/síntese química , Benzofenonas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Esteroide 11-beta-Hidroxilase/metabolismo , Relação Estrutura-Atividade , Xantonas/química
10.
Bioorg Chem ; 86: 538-549, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30782572

RESUMO

Breast cancer is the most diagnosed type of cancer among women for which an exhaustive cure has not been discovered yet. Nowadays, tamoxifen still represents the gold standard for breast cancer therapy; it acts on both estrogen receptor-positive and estrogen receptor-negative breast cancers. Unfortunately, its toxicity and the related chemoresistance undermine its antitumor potential. In this paper, new tamoxifen-based derivatives with a rigid structural motif in their structure were designed, synthesized, and evaluated to assess their antitumor behavior. All the tested compounds affected estrogen receptor-positive tumor (MCF-7) cell growth, even with different extents, among which, the most active ones proved also to induce mitochondria-mediated apoptosis through activation of PARP cleavage, decrease in Bax/Bcl-2 ratio and increase in Bim gene expression levels. Here we found that the compound 1, carrying a rigid xanthene core, turned out to be the most promising of the set showing an activity profile comparable to that of tamoxifen. Furthermore, a more favorable genotoxic profile than tamoxifen made compound 1 a promising candidate for further studies.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Tamoxifeno/farmacologia , Xantenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Tamoxifeno/química , Células Tumorais Cultivadas , Xantenos/química
11.
Molecules ; 24(2)2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669643

RESUMO

The occurrence of invasive fungal infections represents a substantial threat to human health that is particularly serious in immunocompromised patients. The limited number of antifungal agents, devoid of unwanted toxic effects, has resulted in an increased demand for new drugs. Herein, the chalcone framework was functionalized to develop new antifungal agents able to interfere with cell growth and with the infection process. Thus, a small library of chalcone-based analogues was evaluated in vitro against C. albicans ATCC 10231 and a number of compounds strongly inhibited yeast growth at non-cytotoxic concentrations. Among these, 5 and 7 interfered with the expression of two key virulence factors in C. albicans pathogenesis, namely, hyphae and biofilm formation, while 28 emerged as a potent and broad spectrum antifungal agent, enabling the inhibition of the tested Candida spp. and non-Candida species. Indeed, these compounds combine two modes of action by selectively interfering with growth and, as an added value, weakening microbial virulence. Overall, these compounds could be regarded as promising antifungal candidates worthy of deeper investigation. They also provide a chemical platform through which to perform an optimization process, addressed at improving potency and correcting liabilities.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Chalconas/química , Fungos/efeitos dos fármacos , Chumbo/química , Chumbo/farmacologia , Animais , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Fungos/fisiologia , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células Vero , Fatores de Virulência , Leveduras/efeitos dos fármacos
12.
Molecules ; 23(12)2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30486354

RESUMO

As a follow-up to our previous studies on differently substituted 1,4-dihydropyridines endowed with a peculiar cardiac selectivity, in this paper, a small series of hybrid compounds bearing the pharmacophore fragment of lidoflazine in position 2 or 3 on a 4-(xanthen-9-one)-dihydropyridine core was reported. Lidoflazine was selected due to our promising previously reported data, and the xanthen-9-one substituent was introduced in position 4 of the dihydropyridine scaffold based on the cardiac selectivity observed in several of our studies. The new hybrid compounds were tested to assess cardiac and vascular activities, and the data were evaluated in comparison with those previously obtained for 4-(xanthen-9-one)-dihydropyridines and lidoflazine⁻nifedipine hybrid compounds. The functional studies indicated an interesting peculiar selectivity for the cardiac parameter inotropy, in particular when the lidoflazine fragment was introduced in position 2 of the dihydropyridine scaffold (4a⁻e), and thus a possible preferential binding with the Cav 1.2 isoform of l-type calcium channels, which are mainly involved in cardiac contractility.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Di-Hidropiridinas , Lidoflazina , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Xantonas , Animais , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Feminino , Cobaias , Lidoflazina/síntese química , Lidoflazina/química , Lidoflazina/farmacologia , Masculino , Xantonas/síntese química , Xantonas/química , Xantonas/farmacologia
13.
Molecules ; 23(8)2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30061534

RESUMO

Alzheimer's disease still represents an untreated multifaceted pathology, and drugs able to stop or reverse its progression are urgently needed. In this paper, a series of naturally inspired chalcone-based derivatives were designed as structural simplification of our previously reported benzofuran lead compound, aiming at targeting both acetyl (AChE)- and butyryl (BuChE) cholinesterases that, despite having been studied for years, still deserve considerable attention. In addition, the new compounds could also modulate different pathways involved in disease progression, due to the peculiar trans-α,ß-unsaturated ketone in the chalcone framework. All molecules presented in this study were evaluated for cholinesterase inhibition on the human enzymes and for antioxidant and neuroprotective activities on a SH-SY5Y cell line. The results proved that almost all the new compounds were low micromolar inhibitors, showing different selectivity depending on the appended substituent; some of them were also effective antioxidant and neuroprotective agents. In particular, compound 4, endowed with dual AChE/BuChE inhibitory activity, was able to decrease ROS formation and increase GSH levels, resulting in enhanced antioxidant endogenous defense. Moreover, this compound also proved to counteract the neurotoxicity elicited by Aß1⁻42 oligomers, showing a promising neuroprotective potential.


Assuntos
Acetilcolinesterase/química , Antioxidantes/síntese química , Butirilcolinesterase/química , Chalconas/síntese química , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Nootrópicos/síntese química , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/farmacologia , Antioxidantes/farmacologia , Butirilcolinesterase/genética , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Glutationa/agonistas , Glutationa/metabolismo , Humanos , Simulação de Acoplamento Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
14.
Molecules ; 21(5)2016 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-27196880

RESUMO

Alzheimer's disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aß protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aß generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the "pharmacophores combination" strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu(2+)-induced ROS formation without any direct neurotoxic effect.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Chalcona/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Agregação Patológica de Proteínas/tratamento farmacológico , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/química , Ácido Aspártico Endopeptidases/química , Chalcona/química , Quelantes/administração & dosagem , Quelantes/química , Combinação de Medicamentos , Humanos , Íons/química , Ligantes , Metais/química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
15.
Bioorg Med Chem Lett ; 25(14): 2804-8, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26003339

RESUMO

In recent years, a progressive increase in age-related disorders could be observed in most western countries, among which Alzheimer's disease (AD) is one of the most challenging. BACE1 could be seen as an attractive target to develop disease-modifying compounds, and in this context, a new series of hybrid molecules was designed and synthesized, based on a previously identified multitarget lead compound. In particular, the amino side chain was appropriately modified to fit BACE1 as additional target. In vitro testing results pointed out compound 8 (IC50=2.49±0.08 µM), bearing the bulky bis(4-fluorophenyl)methyl)piperazine substituent, as the most potent BACE1 inhibitor of the series.


Assuntos
Acetilcolinesterase/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores da Colinesterase/química , Indanos/química , Inibidores de Proteases/química , Acetilcolinesterase/metabolismo , Aminas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Desenho de Fármacos , Humanos , Indanos/síntese química , Indanos/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 266: 116138, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38219658

RESUMO

As a new approach to the management of inflammatory disorders, a series of chromone-based derivatives containing a (carbamate)hydrazone moiety was designed and synthesized. The compounds were assessed for their ability to inhibit COX-1/2, 15-LOX, and mPGES-1, as a combination that should effectively impede the arachidonate pathway. Results revealed that the benzylcarbazates (2a-c) demonstrated two-digit nanomolar COX-2 inhibitory activities with reasonable selectivity indices. They also showed appreciable 15-LOX inhibition, in comparison to quercetin. Further testing of these compounds for mPGES-1 inhibition displayed promising activities. Intriguingly, compounds 2a-c were capable of suppressing edema in the formalin-induced rat paw edema assay. They exhibited an acceptable gastrointestinal safety profile regarding ulcerogenic liabilities in gross and histopathological examinations. Additionally, upon treatment with the test compounds, the expression of the anti-inflammatory cytokine IL-10 was elevated, whereas that of TNF-α, iNOS, IL-1ß, and COX-2 were downregulated in LPS-challenged RAW264.7 macrophages. Docking experiments into the three enzymes showed interesting binding profiles and affinities, further substantiating their biological activities. Their in silico physicochemical and pharmacokinetic parameters were advantageous.


Assuntos
Anti-Inflamatórios , Inibidores de Lipoxigenase , Ratos , Animais , Ciclo-Oxigenase 2/metabolismo , Inibidores de Lipoxigenase/química , Ciclo-Oxigenase 1/metabolismo , Anti-Inflamatórios/farmacologia , Ácidos Araquidônicos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Simulação de Acoplamento Molecular , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Araquidonato 5-Lipoxigenase/metabolismo , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 252: 115297, 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-36996713

RESUMO

Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aß protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aß protein oligomerisation and the consequent neurotoxic events. Interestingly, from in vitro studies, analogues 3 and 4, bearing a substituted triazole moiety, emerged as multifunctional agents able to counteract Aß aggregation, neuroinflammation and oxidative stress. In vivo proof-of-concept evaluations, performed in a Drosophila oxidative stress model, allowed us to identify compound 4 as a promising lead candidate.


Assuntos
Doença de Alzheimer , Curcumina , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Curcumina/farmacologia , Curcumina/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Doenças Neuroinflamatórias , Estresse Oxidativo
18.
Curr Med Chem ; 29(28): 4796-4830, 2022 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34781863

RESUMO

Pharmacological treatment of complex pathologies, such as neurodegenerative diseases still represents a major challenge, due to the networked pathways involved in their onset and progression that may require equally complex therapeutic approaches. Polypharmacology, based on the simultaneous modulation of multiple targets involved in the disease, may offer the potential to increase effectiveness and reduce the drawbacks related to the use of drug combinations. Clearly, this approach requires both the knowledge of the systems responsible for disease development and the discovery of new attractive targets to be exploited to design a multitarget drug. Over the last years, an ever increasing interest has focused on the endocannabinoid system, implicated in the modulation of several physiological functions, among which neuroinflammation, a crucial process for most neurodegenerative diseases. In this respect, the cannabinoid receptor subtype 2 represents a promising therapeutic target, being overexpressed in microglia cells and thus involved in neuroinflammation. The indirect modulation of this system through the inhibition of the main enzymes responsible for endocannabinoids metabolism, namely fatty acid amide hydrolase and monoacylglycerol lipase, may also significantly affect neurodegenerative processes. The aim of this review is to give an overview of the opportunities posed by the endocannabinoid system for neurodegenerative diseases management, mainly focusing on the potential for a multitarget strategy.


Assuntos
Endocanabinoides , Doenças Neurodegenerativas , Amidoidrolases/metabolismo , Endocanabinoides/metabolismo , Humanos , Monoacilglicerol Lipases/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Polifarmacologia
19.
Eur J Med Chem ; 244: 114802, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36240547

RESUMO

The most frequently diagnosed breast cancer (BC) type in women expresses estrogen receptor (ER) and depends on estrogens for its growth, being classified as ER positive (ER+). The gold standard therapy for the treatment of this tumor relies on the inhibition of the aromatase enzyme, which catalyzes estrogen biosynthesis. Despite the clinical success of current aromatase inhibitors (AIs), after prolonged therapeutic regimens, BC ER + patients experience acquired resistance and disease relapse. This points up the urgent need for a newer generation of AIs able to overcome resistance issues, while mitigating toxicity and side effects of current therapies. Here we performed the synthesis, biological evaluation, and extensive structural characterization by advanced molecular simulation methods of a new generation of dualsteric non-steroidal AIs, which simultaneously target the enzyme's active and allosteric sites. Notably, 3d, the most active AI of the series, exhibits a single-digit nM potency (IC50 2 nM). A detailed inspection of its binding mode reveals that the ancillary alkoxy chain predatorily takes advantage of the small hydrophobic cavities lining the allosteric site, triggering a remodeling of its residues and completely sealing the active site access-channel. As a result, the inhibitor is effectively locked in. This study sets a conceptual basis to develop a new generation of AIs exploiting a dualsteric targeting strategy.


Assuntos
Aromatase , Neoplasias da Mama , Humanos , Feminino , Aromatase/metabolismo , Domínio Catalítico , Inibidores da Aromatase/química , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/patologia
20.
Future Med Chem ; 14(24): 1865-1880, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36622669

RESUMO

Background: Malaria represents the major parasitic disease in tropical regions, and the development of new potent drugs is of pivotal importance. In this study, a series of hybrid molecules were designed by linking the 7-chloroquinoline core of chloroquine to different fluorinated flavonoid-related scaffolds. Materials & methods: Compounds were prepared by exploiting the click chemistry approach, allowing the introduction of a 1,2,3-triazole, a privileged structural motif in antiparasitic dug discovery. Results: Compounds 1b and 1c were the most interesting and were endowed with the highest in vitro activity, mainly against a resistant Plasmodium falciparum strain. They also inhibited hemozoin formation, and 1c was more effective than chloroquine against stage V gametocytes. Conclusion: The homoisoflavone core is a new, promising antimalarial scaffold that deserves further investigation.


Assuntos
Antimaláricos , Malária , Humanos , Antimaláricos/química , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Triazóis/química , Cloroquina/química , Malária/tratamento farmacológico , Plasmodium falciparum
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