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1.
Eur J Med Chem ; 266: 116094, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38219660

RESUMO

In an effort to develop new potent anticancer agents, two Schiff base rhenium(I) tricarbonyl complexes, containing the ubiquitous aminoquinoline scaffold, were synthesized. Both aminoquinoline ligands and Re(I) complexes showed adequate stability over a 48-h incubation period. Furthermore, the cytotoxic activity of the precursor ligands and rhenium(I) complexes were evaluated against the hormone-dependent MCF-7 and hormone-independent triple negative MDA-MB-231 breast cancer cell lines. Inclusion of the [Re(CO)3Cl]+ entity significantly enhanced the cytotoxicity of the aminoquinoline Schiff base ligands against the tested cancer cell lines. Remarkably, the incorporation of the Schiff-base iminoquinolyl entity notably enhanced the cytotoxic activity of the Re(I) complexes, in comparison with the iminopyridyl entity. Notably, the quinolyl-substituted complex showed up to three-fold higher activity than cisplatin against breast cancer cell lines, underpinning the significance of the quinoline pharmacophore in rational drug design. In addition, the most active Re(I) complex showed better selectivity towards the breast cancer cells over non-tumorigenic FG-0 cells. Western blotting revealed that the complexes increased levels of γH2AX, a key DNA damage response protein. Moreover, apoptosis was confirmed in both cell lines due to the detection of cleaved PARP. The complexes show favourable binding affinities towards both calf thymus DNA (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions align with their cytotoxic effects. The in silico molecular simulations of the complexes were also performed with CT-DNA and BSA targets.


Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Rênio , Humanos , Feminino , Bases de Schiff/farmacologia , Bases de Schiff/química , Rênio/química , DNA/metabolismo , Células MCF-7 , Soroalbumina Bovina/química , Hormônios , Aminoquinolinas/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Antineoplásicos/química , Ligantes
2.
Eur J Med Chem ; 264: 116043, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38118392

RESUMO

Amongst heterocyclic compounds, quinoline and its derivatives are advantaged scaffolds that appear as a significant assembly motif for developing new drug entities. Aminoquinoline moiety has gained significant attention among researchers in the 21stcentury. Considering the biological and pharmaceutical importance of aminoquinoline derivatives, herein, we review the recent developments (since 2019) in various biological activities of the 4-aminoquinoline scaffold hybridized with diverse heterocyclic moieties such as quinoline, pyridine, pyrimidine, triazine, dioxine, piperazine, pyrazoline, piperidine, imidazole, indole, oxadiazole, carbazole, dioxole, thiazole, benzothiazole, pyrazole, phthalimide, adamantane, benzochromene, and pyridinone. Moreover, by gaining knowledge about SARs, structural insights, and molecular targets, this review may help medicinal chemists design cost-effective, selective, safe, and more potent 4-aminoquinoline hybrids for diverse biological activities.


Assuntos
Antimaláricos , Quinolinas , Plasmodium falciparum , Antimaláricos/farmacologia , Aminoquinolinas/farmacologia , Aminoquinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade
3.
Future Med Chem ; 15(17): 1569-1582, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37728024

RESUMO

Background: The aminoquinoline core exhibits versatile pharmacological properties, particularly in the area of anticancer activity. This study was designed to investigate the potential of the 4-aminoquinoline scaffold in the development of anticancer agents by targeting the HIF-1α signaling pathway. Methodology: The authors synthesized multiple derivatives of 4-aminoquinoline containing heterocyclic rings by a microwave reactor and assessed the cytotoxicity and inhibitory effects of these derivatives on the HIF-1α signaling pathway. Conclusion: Compound 3s was identified as the most promising HIF-1α inhibitor due to its exceptional antiproliferative effects, with IC50 values of 0.6 and 53.3 nM observed in MiaPaCa-2 and MDA-MB-231 cells, respectively. Furthermore, compound 3s was found to inhibit HIF-1α expression by decreasing the level of HIF-1α mRNA.


Assuntos
Antineoplásicos , Transdução de Sinais , Antineoplásicos/farmacologia , Aminoquinolinas/farmacologia , RNA Mensageiro , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Linhagem Celular Tumoral
4.
J Biol Chem ; 299(9): 105151, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37567479

RESUMO

Hepatitis B virus (HBV) is a hepatotropic DNA virus that has a very compact genome. Due to this genomic density, several distinct mechanisms are used to facilitate the viral life cycle. Recently, accumulating evidence show that G-quadruplex (G4) in different viruses play essential regulatory roles in key steps of the viral life cycle. Although G4 structures in the HBV genome have been reported, their function in HBV replication remains elusive. In this study, we treated an HBV replication-competent cell line and HBV-infected cells with the G4 structure stabilizer pyridostatin (PDS) and evaluated different HBV replication markers to better understand the role played by the G4. In both models, we found PDS had no effect on viral precore RNA (pcRNA) or pre-genomic RNA (pgRNA), but treatment did increase HBeAg/HBc ELISA reads and intracellular levels of viral core/capsid protein (HBc) in a dose-dependent manner, suggesting post-transcriptional regulation. To further dissect the mechanism of G4 involvement, we used in vitro-synthesized HBV pcRNA and pgRNA. Interestingly, we found PDS treatment only enhanced HBc expression from pgRNA but not HBeAg expression from pcRNA. Our bioinformatic analysis and CD spectroscopy revealed that pgRNA harbors a conserved G4 structure. Finally, we introduced point mutations in pgRNA to disrupt its G4 structure and observed the resulting mutant failed to respond to PDS treatment and decreased HBc level in in vitro translation assay. Taken together, our data demonstrate that HBV pgRNA contains a G4 structure that plays a vital role in the regulation of viral mRNA translation.


Assuntos
Quadruplex G , Vírus da Hepatite B , Hepatite B , Humanos , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Hepatite B/virologia , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Proteínas do Core Viral/química , Proteínas do Core Viral/metabolismo , Replicação Viral/genética , Linhagem Celular , Quadruplex G/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Mutação , Aminoquinolinas/farmacologia
5.
Int J Mol Sci ; 24(13)2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37446011

RESUMO

Cutaneous cancers are, by far, the most common malignant neoplasms of the human being. Due to the great array of clinical conditions, their worldwide increasing incidence and the steady ageing of the population, non-invasive treatments modalities that show a good clinical response, a proper benefit-risk ratio and cosmetic results are becoming increasingly important in the clinical setting. Imiquimod is a topically applied immunomodulator which is often used in the management of several premalignant and malignant cutaneous disorders. This article is a review of the current literature on its mechanism of action, pharmacokinetics, and therapeutical effects.


Assuntos
Antineoplásicos , Lesões Pré-Cancerosas , Neoplasias Cutâneas , Humanos , Imiquimode/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/epidemiologia , Adjuvantes Imunológicos/uso terapêutico , Pele/patologia , Lesões Pré-Cancerosas/tratamento farmacológico , Administração Cutânea , Imunoterapia , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
6.
Neurotoxicology ; 98: 9-15, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37429421

RESUMO

OBJECTIVE: Activity or expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) is diminished in some disease states such as cardiac failure and diabetes mellitus. A newly developed activator of SERCA, CDN1163, reportedly rescued or alleviated pathological conditions attributed to dysfunctional SERCA. We examined whether CDN1163 could relieve mouse neuronal N2A cell growth inhibition caused by cyclopiazonic acid (CPA, SERCA inhibitor). We also examined how CDN1163 affected cytosolic Ca2+, mitochondrial Ca2+ and mitochondrial membrane potential. METHODS: Cell viability was measured by MTT assay and trypan blue exclusion test. Cytosolic Ca2+, mitochondrial Ca2+ and mitochondrial membrane potential were measured using fura 2, Rhod-2 and JC-1, respectively, as fluorescent probes. RESULTS: CDN1163 (10 µM) itself suppressed cell proliferation, and did not alleviate CPA's inhibitory effect (and vice versa). Cell cycle was arrested at the G1 phase after CDN1163 treatment. CDN1163 treatment caused a slow yet persistent cytosolic [Ca2+] elevation partly due to Ca2+ release from an internal store other than the CPA-sensitive endoplasmic reticulum (ER). Treatment with CDN1163 for 3 h raised mitochondrial Ca2+ level and such increase was suppressed by MCU-i4 (an inhibitor of mitochondria Ca2+ uniporter, MCU), suggesting Ca2+ entered the mitochondrial matrix through MCU. Treatment of cells with CDN1163 up to 2 days resulted in mitochondrial hyperpolarization. CONCLUSION: CDN1163 caused internal Ca2+ leak, cytosolic Ca2+ overload, mitochondrial Ca2+ elevation and hyperpolarization, cell cycle arrest and cell growth inhibition.


Assuntos
Retículo Endoplasmático , Mitocôndrias , Camundongos , Animais , Mitocôndrias/metabolismo , Retículo Endoplasmático/metabolismo , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Pontos de Checagem do Ciclo Celular , Cálcio/metabolismo
7.
Chem Biol Interact ; 382: 110620, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37406982

RESUMO

The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of ß-secretase 1 (BACE1) and their antioxidant capacity. All of the tested derivatives were very potent inhibitors of human AChE and BChE with inhibition constants (Ki) ranging from 0.0023 to 1.6 µM. Most of the compounds were estimated to be able to cross the blood-brain barrier (BBB) by passive transport and were nontoxic to human neuronal, kidney and liver cells in concentrations in which they inhibit cholinesterases. Generally, newly synthesised compounds were weak reductants compared to standard antioxidants, but all possessed a certain amount of antioxidant activity compared to tacrine. Of the eleven most potent cholinesterase inhibitors, eight compounds also inhibited BACE1 activity at 10-18%. Based on our overall results, compounds 8 with 3-fluorobenzyl, 11 with 3-chlorobenzyl and 17 with 3-metoxy benzyl substituents on the terminal amino group stood out as the most promising for the treatment of AD; they strongly inhibited AChE and BChE, were non-toxic on HepG2, HEK293 and SH-SY5Y cells, had the potential to cross the BBB and possessed the ability to chelate biometals and/or inhibit the activity of BACE1 within a range close to the therapeutically desired degree of inhibition.


Assuntos
Doença de Alzheimer , Neuroblastoma , Oligoelementos , Humanos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Ligantes , Células HEK293 , Simulação de Acoplamento Molecular , Ácido Aspártico Endopeptidases/metabolismo , Aminoquinolinas/farmacologia , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 256: 115458, 2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37163950

RESUMO

Malaria is the fifth most lethal parasitic infection in the world. Antimalarial medications have played a crucial role in preventing and eradicating malaria. Numerous heterocyclic moieties have been incorporated into the creation of effective antimalarial drugs. The 4-aminoquinoline moiety is favoured in antimalarial drug discovery due to the diverse biological applications of its derivative. Since the 1960s, 4-aminoquinoline has been an important antimalarial drug due to its low toxicity, high tolerability, and rapid absorption after administration. This review focused on the antimalarial efficacy of the 4-aminoquinoline moiety hybridised with various heterocyclic scaffolds developed by scientists since 2018 against diverse Plasmodium clones. It could aid in the future development of more effective antimalarial agents.


Assuntos
Antimaláricos , Malária , Humanos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Plasmodium falciparum , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Malária/tratamento farmacológico , Malária/parasitologia
9.
Sci Rep ; 13(1): 8435, 2023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-37225786

RESUMO

Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14-18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.


Assuntos
Adamantano , Glioblastoma , Antagonistas do Receptor Purinérgico P2X , Humanos , Adamantano/análogos & derivados , Adamantano/farmacologia , Aminoquinolinas/farmacologia , Glioblastoma/tratamento farmacológico , Receptores Purinérgicos P2X7 , Temozolomida/farmacologia , Microambiente Tumoral , Antagonistas do Receptor Purinérgico P2X/farmacologia
10.
Acta Trop ; 242: 106924, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37037291

RESUMO

Atorvastatin (AVA) is a third-generation statin with several pleiotropic effects, considered the last synthetic pharmaceutical blockbuster. Recently, our group described the effects of AVA on DNA damage prevention and against Trypanosoma cruzi infection. In this study, our aim was to evaluate the efficacy, safety, and in silico pharmacokinetic profile of four hybrids of aminoquinolines with AVA 4a-d against T. cruzi using in vitro and in silico models. These synthetic compounds were designed by hybridization of the pentapyrrolic moiety of AVA with the aminoquinolinic unit of chloroquine or primaquine. Pharmacokinetics (ADME) and toxicity parameters were predicted by SwissADME, admetSAR and LAZAR in silico algorithms. The trypanocidal activity of AVA-quinoline hybrids were evaluated in vitro against amastigotes and trypomastigotes of T. cruzi, from Y (Tc II) and Tulahuen (Tc VI) strains. In vitro cardiocytotoxicity was assessed using primary cultures of mouse embryonic cardiac cells and in vitro hepatocytotoxicity on bidimensional and 3D-cultured HepG2 cells. Genotoxicity was evaluated by Ames test and micronucleus assay. Despite the overall good in silico ADMET profile, all tested compounds were predicted to be hepatotoxic. All hybrid derivatives presented high trypanocidal activity, against both trypomastigote and intracellular forms of T. cruzi, presenting EC50's lower than 1 µM besides superior selectivity than the reference drug, without evidences of cardiotoxicity in vitro. The compounds 4a and 4b presented a time-dependent toxicity in monolayer culture of HepG2 but no detectable toxic effects in their spheroids, opposing to the in silico prediction. We can conclude that the AVA-aminoquinoline hybrids presented a hit profile as antiparasitic agents in synthetic pharmaceutical innovation platforms.


Assuntos
Antimaláricos , Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Doença de Chagas/parasitologia , Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Dano ao DNA , Preparações Farmacêuticas , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
11.
Curr Top Med Chem ; 23(5): 403-414, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36694313

RESUMO

BACKGROUND: Polypharmacology means drugs having interactions with multiple targets of a unique disease or many disease pathways. This concept has been greatly appreciated against complex diseases, such as oncology, CNS disorders, and anti-infectives. METHODS: The integration of diverse compounds available on public databases initiates polypharmacological drug discovery research. Immunocompromised patients may suffer from complex diseases. Multiple-component drug formulations may produce side effects and resistance issues due to unintended drug-target interactions. RESULTS: Polypharmacology remains a novel avenue to propose a more effective and less toxic treatment. The 4-amino quinoline scaffold has become an important construction motif for the development of new drugs against lifestyle diseases like cancer and infectious diseases like tuberculosis and malaria. CONCLUSION: The present study is an attempt to explore the polypharmacological effects of 4- aminoquinoline drugs to combat malaria, cancer, and tuberculosis.


Assuntos
Malária , Neoplasias , Tuberculose , Humanos , Polifarmacologia , Tuberculose/tratamento farmacológico , Aminoquinolinas/farmacologia , Malária/tratamento farmacológico
12.
Biochem Biophys Res Commun ; 644: 55-61, 2023 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-36630735

RESUMO

RNA structure plays an important role in regulating cellular function and there is a significant emerging interest in targeting RNA for drug discovery. Here we report the identification of 4-aminoquinolines as modulators of RNA structure and function. Aminoquinolines have a broad range of pharmacological activities, but their specific mechanism of action is often not fully understood. Using electrophoretic mobility shift assays and enzymatic probing we identified 4-aminoquinolines that bind the stem-loop II motif (s2m) of SARS-CoV-2 RNA site-specifically and induce dimerization. Using fluorescence-based RNA binding and T-box riboswitch functional assays we identified that hydroxychloroquine binds the T-box riboswitch antiterminator RNA element and inhibits riboswitch function. Based on its structure and riboswitch dose-response activity we identified that the antagonist activity of hydroxychloroquine is consistent with it being a conformationally restricted analog of the polyamine spermidine. Given the known role that polyamines play in RNA function, the identification of an RNA binding ligand with the pharmacophore of a conformationally restricted polyamine has significant implications for further elucidation of RNA structure-function relationships and RNA-targeted drug discovery.


Assuntos
COVID-19 , Riboswitch , Humanos , Poliaminas , Farmacóforo , Hidroxicloroquina , RNA Viral , SARS-CoV-2/genética , Aminoquinolinas/farmacologia , RNA Bacteriano/genética , Conformação de Ácido Nucleico
13.
J Enzyme Inhib Med Chem ; 38(1): 282-293, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36408835

RESUMO

Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro, compound 14 exhibited high affinity (IC50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.


Assuntos
Aminoquinolinas , Inflamação , Humanos , Filogenia , Inflamação/tratamento farmacológico , Aminoquinolinas/farmacologia , Transdução de Sinais , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/farmacologia
14.
Eur J Med Chem ; 245(Pt 1): 114908, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36435016

RESUMO

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.


Assuntos
Aminoquinolinas , Antituberculosos , Inibidores Enzimáticos , Mycobacterium tuberculosis , Álcool Oxidorredutases Dependentes de NAD(+) e NADP(+) , Animais , Camundongos , Aminoquinolinas/síntese química , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antituberculosos/síntese química , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Álcool Oxidorredutases Dependentes de NAD(+) e NADP(+)/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Tuberculose/tratamento farmacológico , Modelos Animais de Doenças
15.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232533

RESUMO

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 µM and 28.37 ± 1.85 µM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 µM and 6.05 ± 1.17 µM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 µM). It is worth noting that 3-aminoquinoline derivatives 12a-12d exhibited better drug-like properties.


Assuntos
Doença de Alzheimer , Hidroxiquinolinas , Acetilcolinesterase/metabolismo , Aminas/farmacologia , Aminoquinolinas/farmacologia , Benzotiazóis , Carbono , Inibidores da Colinesterase/farmacologia , Galantamina , Humanos , Cinética , Simulação de Acoplamento Molecular , Morfolinas , Relação Estrutura-Atividade , Ácidos Sulfônicos
16.
ACS Infect Dis ; 8(8): 1700-1710, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35848708

RESUMO

Pyrido[1,2-a]benzimidazoles (PBIs) are synthetic antiplasmodium agents with potent activity and are structurally differentiated from benchmark antimalarials. To study the cellular uptake of PBIs and understand the underlying phenotype of their antiplasmodium activity, their antiparasitic activities were examined in chloroquine (CQ)-susceptible and CQ-resistant Plasmodium falciparumin vitro. Moreover, drug uptake and heme detoxification suppression were examined in Plasmodium berghei-infected mice. The in vitro potency of PBIs is comparable to most 4-aminoquinolines. They have a speed of action in vitro that is superior to that of atovaquone and an ability to kill rings and trophozoites. The antiparasitic effects observed for the PBIs in cell culture and in infected mice are similar in terms of potency and efficacy and are comparable to CQ but with the added advantage of demonstrating equipotency against both CQ susceptible and resistant parasite strains. PBIs have a high rate of uptake by parasite cells and, conversely, a limited rate of uptake by host cells. The mechanism of cellular uptake of the PBIs differs from the ion-trap mechanism typically observed for 4-aminoquinolines, although they share key structural features. The high cellular uptake, attractive parasiticidal profile, and susceptibility of resistant strains to PBIs are desirable characteristics for new antimalarial agents.


Assuntos
Antimaláricos , Antagonistas do Ácido Fólico , Malária , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antiparasitários/farmacologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Cloroquina/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Heme , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Plasmodium falciparum
17.
Molecules ; 27(8)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35458755

RESUMO

Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Aminoquinolinas/farmacologia , Antituberculosos/química , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico
18.
Exp Parasitol ; 236-237: 108249, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35318066

RESUMO

Significant overlaps in the geographical distribution of malaria and leishmaniasis increase the risk for comorbidity, which can affect treatment efficacy, cotreatment compatibility and disease progression. These concerns are also exacerbated by the existing shortcomings of malaria and leishmaniasis treatments. There is, therefore, a pressing need for new anti-infective drugs for both individual diseases and coinfections. The in vitro antileishmanial activity of previously synthesized antiplasmodial aminoquinoline-chalcone hybrids was evaluated. Hybrid 6, featuring a N-methyl-1,3-propylene diamine linker between pharmacophores, was 11-fold more potent in anti-amastigote activity against Leishmania major, responsible for cutaneous leishmaniasis, the most common form of the disease, in comparison to chloroquine. Hybrid 7, with a 2,2-(ethylenedioxy)bis(ethylamine) linker, was nearly 7-fold more active in anti-amastigote activity against Leishmania donovani, responsible for visceral leishmaniasis, the most lethal form of the infection. Although these two hybrids were less potent than the clinically used antileishmanial, amphotericin B, they still qualify as hits against both Plasmodium and Leishmania strains. Accordingly, this may lend them as potential agents against Leishmania-Plasmodium coinfections, which will require further investigation using in vitro co-cultures and subsequent in vivo testing for confirmation.


Assuntos
Antimaláricos , Antiprotozoários , Chalcona , Chalconas , Coinfecção , Leishmania donovani , Leishmaniose Cutânea , Malária , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Chalconas/uso terapêutico , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Malária/tratamento farmacológico
19.
Molecules ; 27(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35163977

RESUMO

COVID-19 has spread around the world and caused serious public health and social problems. Although several vaccines have been authorized for emergency use, new effective antiviral drugs are still needed. Some repurposed drugs including Chloroquine, Hydroxychloroquine and Remdesivir were immediately used to treat COVID-19 after the pandemic. However, the therapeutic effects of these drugs have not been fully demonstrated in clinical studies. In this paper, we found an antimalarial drug, Naphthoquine, showed good broad-spectrum anti-coronavirus activity. Naphthoquineinhibited HCoV-229E, HCoV-OC43 and SARS-CoV-2 replication in vitro, with IC50 = 2.05 ± 1.44 µM, 5.83 ± 0.74 µM, and 2.01 ± 0.38 µM, respectively. Time-of-addition assay was also performed to explore at which stage Naphthoquine functions during SARS-CoV-2 replication. The results suggested that Naphthoquine may influence virus entry and post-entry replication. Considering the safety of Naphthoquine was even better than that of Chloroquine, we think Naphthoquine has the potential to be used as a broad-spectrum drug for coronavirus infection.


Assuntos
1-Naftilamina/análogos & derivados , Aminoquinolinas/farmacologia , Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , 1-Naftilamina/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano NL63/efeitos dos fármacos , Coronavirus Humano OC43/efeitos dos fármacos , Humanos , Técnicas In Vitro , Células Vero , Replicação Viral/efeitos dos fármacos
20.
Sci Rep ; 12(1): 2928, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35190588

RESUMO

Biomarkers for treatment sensitivity or drug resistance used in precision medicine include prognostic and predictive molecules, critical factors in selecting appropriate treatment protocols and improving survival rates. However, identification of accurate biomarkers remain challenging due to the high risk of false-positive findings and lack of functional validation results for each biomarker. Here, we discovered a mechanical correlation between leucine proline-enriched proteoglycan 1 (LEPRE1) and pelitinib drug sensitivity using in silico statistical methods and confirmed the correlation in acute myeloid leukemia (AML) and A549 lung cancer cells. We determined that high LEPRE1 levels induce protein kinase B activation, overexpression of ATP-binding cassette superfamily G member 2 (ABCG2) and E-cadherin, and cell colonization, resulting in a cancer stem cell-like phenotype. Sensitivity to pelitinib increases in LEPRE1-overexpressing cells due to the reversing effect of ABCG2 upregulation. LEPRE1 silencing induces pelitinib resistance and promotes epithelial-to-mesenchymal transition through actin rearrangement via a series of Src/ERK/cofilin cascades. The in silico results identified a mechanistic relationship between LEPRE1 and pelitinib drug sensitivity, confirmed in two cancer types. This study demonstrates the potential of LEPRE1 as a biomarker in cancer through in-silico prediction and in vitro experiments supporting the clinical development of personalized medicine strategies based on bioinformatics findings.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminoquinolinas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Transição Epitelial-Mesenquimal/genética , Regulação Leucêmica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prolil Hidroxilases/genética , Prolil Hidroxilases/fisiologia , Proteoglicanas/genética , Proteoglicanas/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Neoplasias Pulmonares/diagnóstico
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