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1.
Int J Parasitol Drugs Drug Resist ; 24: 100525, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38359731

RESUMO

Leishmaniasis is a disease caused by Leishmania spp., affecting millions of people around the world. For decades, its treatment has been based on pentavalent antimonials, which notoriously cause toxic side effects in patients. In this study, epoxy-α-lapachone incorporated into an oil-in-water-type microemulsion (ELAP-ME) and meglumine antimoniate (MA) were assayed in monotherapy and in combination (ELAP-ME/MA) in BALB/c mice infected with Leishmania (Leishmania) amazonensis. In general, there was a reduction in paw lesion size (up to 37% reduction) and decreases of parasite loads in the footpad (∼40%) and lymph nodes (∼31%) of animals treated with ELAP-ME/MA, when compared to the non-treated control groups. Analyses of serum biochemical parameters revealed that the ELAP-ME/MA showed lower renal and hepatic toxicity when compared to MA 2-doses/week monotherapy. These findings indicate that the ELAP-ME/MA combination may be a promising approach for the treatment of cutaneous leishmaniasis.


Assuntos
Antiprotozoários , Leishmania , Leishmaniose Cutânea , Naftoquinonas , Compostos Organometálicos , Humanos , Animais , Camundongos , Antimoniato de Meglumina/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Meglumina/uso terapêutico , Compostos Organometálicos/uso terapêutico , Camundongos Endogâmicos BALB C
2.
Int J Pharm ; 636: 122864, 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-36934883

RESUMO

Epoxy-α-lapachone (ELAP), an oxirane-functionalized molecule synthesized from naturally occurring lapachol, has shown promising activity against murine infection with Leishmania (Leishmania) amazonensis. Herein, we report the successful development of oil-in-water-type (o/w) microemulsions (ME) loaded with ELAP (ELAP-ME) using Capmul MCM, Labrasol, and PEG 400. Stability studies revealed that ELAP-ME (100 µg/mL of ELAP), which was comprised of globule size smaller than 120.4 ± 7.7 nm, displayed a good stability profile over 73 days. ELAP-ME had an effect in BALB/c mice infected with L. (L.) amazonensis, causing reductions in paw lesions after two weeks of treatment (∼2-fold) when compared to untreated animals. Furthermore, there was also a reduction in the parasite load both in the footpad (60.3%) and in the lymph nodes (31.5%). Based on these findings, ELAP-ME emerges as a promising treatment for tegumentar leishmaniasis.


Assuntos
Leishmania , Leishmaniose , Animais , Camundongos , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Camundongos Endogâmicos BALB C , Pele/parasitologia , Inibidores da Topoisomerase II/uso terapêutico
3.
Molecules ; 28(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36677652

RESUMO

ATP acts in the extracellular environment as an important signal, activating a family of receptors called purinergic receptors. In recent years, interest in the potential therapeutics of purinergic components, including agonists and antagonists of receptors, has increased. Currently, many observations have indicated that ATP acts as an important mediator of inflammatory responses and, when found in high concentrations in the extracellular space, is related to the activation of the P2X7 purinergic receptor. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Sulfonamide derivatives have been reported to be potent inhibitors of P2X receptors. In this study, ten naphthoquinone sulfonamide derivatives and five naphthoquinone sulfonate ester derivatives were tested for their inhibitory activity on the P2X7 receptor expressed in peritoneal macrophages. Some compounds showed promising results, displaying IC50 values lower than that of A740003. Molecular docking and dynamic studies also indicated that the active compounds bind to an allosteric site on P2X7R. The binding free energy indicates that sulfonamides have an affinity for the P2X7 receptor similar to A740003. Therefore, the compounds studied herein present potential P2X7R inhibition.


Assuntos
Naftoquinonas , Antagonistas do Receptor Purinérgico P2X , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/química , Sulfonamidas/farmacologia , Simulação de Acoplamento Molecular , Naftoquinonas/farmacologia , Naftoquinonas/química , Receptores Purinérgicos P2X7 , Trifosfato de Adenosina/metabolismo
4.
Front Bioeng Biotechnol ; 11: 1284630, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38239922

RESUMO

Introduction: The use of chitosan in pharmaceutical formulations is an advantageous approach due to this compound intrinsic biodegradability and biocompatibility, as well as ready availability and low polymer cost. Methods: Herein, the naphthoquinones 3- chloromethylene-menadione (NQ1) and 2,3-dichloro-1,4-naphthoquinone (NQ2) were nanoencapsulated into chitosan (CNP) by the ionotropic gelatinization technique and characterized by DLS, FTIR, SEM, TGA and DSC, and their release profiles evaluated. The antimicrobial and wound healing activities were investigated. Results and Discussion: Homogeneous chitosan nanocapsulses of about 193 nm and Z potential ranging from +30.6 to +33.1 mV loaded with NQ1 (CNP-NQ1) or NQ2 (CNPQNQ2). With nanoencapsulation efficiencies of ≥ 96%, the solubility of naphthoquinones in aqueous environments was improved, making them suitable for biological system applications. The encapsulated naphthoquinones displayed a controlled release of approximately 80% for CNP-NQ1 and 90% for CNP-NQ2 over an 8 h period at 36°C. Both CNP-NQ1 and CNP-NQ2 retained the already established free naphthoquinone antimicrobial activity against two Staphylococcus aureus strains, Staphylococcus epidermidis, Streptococcus pyogenes and Pseudomonas aeruginosa. Although presenting low toxicity to healthy human cells, only CNP-NQ1 displayed therapeutic indices above 100 for S. aureus and S. epidermidis and above 27 for S. pyogenes and P. aeruginosa, allowing for safe use in human tissues. Furthermore, CNP-NQ1 did not impair the migration of human fibroblast cells in scratch assays, adding promising wound healing properties to this formulation. These findings emphasize that CNP-NQ1 may be useful in protecting injured skin tissue from bacterial contamination, avoiding skin infections not only by reducing bacterial loads but also by accelerating the healing process until complete dermal tissue recovery.

5.
Molecules ; 27(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36014389

RESUMO

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Naftoquinonas , Acridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Simulação de Acoplamento Molecular , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
6.
Pharmaceutics ; 14(6)2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35745879

RESUMO

Chitosan displays a dual function, acting as both an active ingredient and/or carrier for pharmaceutical bioactive molecules and metal ions. Its hydroxyl- and amino-reactive groups and acetylation degree can be used to adjust this biopolymer's physicochemical and pharmacological properties in different forms, including scaffolds, nanoparticles, fibers, sponges, films, and hydrogels, among others. In terms of pharmacological purposes, chitosan association with different polymers and the immobilization or entrapment of bioactive agents are effective strategies to achieve desired biological responses. Chitosan biocompatibility, water entrapment within nanofibrils, antioxidant character, and antimicrobial and anti-inflammatory properties, whether enhanced by other active components or not, ensure skin moisturization, as well as protection against bacteria colonization and oxidative imbalance. Chitosan-based nanomaterials can maintain or reconstruct skin architecture through topical or systemic delivery of hydrophilic or hydrophobic pharmaceuticals at controlled rates to treat skin affections, such as acne, inflammatory manifestations, wounds, or even tumorigenesis, by coating chemotherapy drugs. Herein, chitosan obtention, physicochemical characteristics, chemical modifications, and interactions with bioactive agents are presented and discussed. Molecular mechanisms involved in chitosan skin protection and recovery are highlighted by overlapping the events orchestrated by the signaling molecules secreted by different cell types to reconstitute healthy skin tissue structures and components.

7.
Pharmaceuticals (Basel) ; 15(1)2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35056112

RESUMO

Recently, the well-known geographically wide distribution of sporotrichosis in Brazil, combined with the difficulties of effective domestic feline treatment, has emphasized the pressing need for new therapeutic alternatives. This work considers a range of synthetic derivatives as potential antifungals against Sporothrix brasiliensis isolated from cats from the hyperendemic Brazilian region. Six S. brasiliensis isolates from the sporotrichotic lesions of itraconazole responsive or non-responsive domestic cats were studied. The minimum inhibitory concentrations (MICs) of three novel hydrazone derivatives and eleven novel quinone derivatives were determined using the broth microdilution method (M38-A2). In silico tests were also used to predict the pharmacological profile and toxicity parameters of these synthetic derivatives. MICs and MFCs ranged from 1 to >128 µg/mL. The ADMET computational analysis failed to detect toxicity while a good pharmacological predictive profile, with parameters similar to itraconazole, was obtained. Three hydrazone derivatives were particularly promising candidates as antifungal agents against itraconazole-resistant S. brasiliensis from the Brazilian hyperendemic region. Since sporotrichosis is a neglected zoonosis currently spreading in Latin America, particularly in Brazil, the present data can contribute to its future control by alternative antifungal drug design against S. brasiliensis, the most virulent and prevalent species of the hyperendemic context.

8.
Beilstein J Org Chem ; 18: 53-69, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35047082

RESUMO

Several low molecular weight naphthoquinones are very useful in organic synthesis. These compounds have given rise to thousands of other naphthoquinones that have been tested against various microorganisms and pharmacological targets, including being used in the preparation of several drugs that are on the pharmaceutical market. Among these naphthoquinones, the series of compounds prepared from 1,2-naphthoquinone-4-sulfonic acid salts (ß-NQS) stands out. In addition to being used in organic synthesis, they are excellent analytical derivatization reagents to spectrophotometrically determine drugs containing primary and secondary amino groups. This review summarizes the literature involving ß-NQS.

10.
J Bioenerg Biomembr ; 50(2): 81-91, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29473131

RESUMO

Chagas disease is one of the most relevant endemic diseases in Latin America caused by the flagellate protozoan Trypanosoma cruzi. Nifurtimox and benzonidazole are the drugs used in the treatment of this disease, but they commonly are toxic and present severe side effects. New effective molecules, without collateral effects, has promoted the investigation to develop new lead compounds with to advance for clinical trials. Previously, 3-nitro-1H-1,2,4-triazole-based amines and 1,2,3-triazoles demonstrated significant trypanocidal activity against T. cruzi. In this paper, we synthesized a new series of 92 examples of 1,2,3-triazoles. Six compounds exhibited antiparasitic activity, 14, 25, 27, 31 and 40, 43 and were effective against epimastigotes of two strains of T. cruzi (Y and Dm28-C) and 25, 27 and 31 exhibited trypanocidal activity similar to benzonidazole. Notably, the compound 25 compared to benzonidazole increase the toxicity against T. cruzi, with no apparent toxicity to the cell line of mice macrophages or primary mice peritoneal macrophages. As results, we calculated selectivity indexes up to 2000 to 25 and 31 in both T. cruzi strains. Derivative 14 caused a trypanostatic effect because it did not damage external epimastigote membrane. Triazoles 40 and 43 impaired parasites viability using a pathway not dependent on ROS production.


Assuntos
Doença de Chagas/tratamento farmacológico , Triazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiparasitários/química , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Linhagem Celular , Humanos , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Triazóis/uso terapêutico , Triazóis/toxicidade
11.
Molecules ; 22(10)2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28973960

RESUMO

Chagas disease is an endemic parasitic infection that occurs in 21 Latin American countries. New therapies for this disease are urgently needed, as the only two drugs available (nifurtimox and benznidazol) have high toxicity and variable efficacy in the disease's chronic phase. Recently, a new chemical entity (NCE) named Pyranaphthoquinone (IVS320) was synthesized from lawsone. We report herein, a detailed study of the physicochemical properties and in vitro trypanocidal activity of IVS320. A series of assays were performed for characterization, where thermal, diffractometric, and morphological analysis were performed. In addition, the solubility, permeability, and hygroscopicity of IVS320 were determined. The results show that its poor solubility and low permeability may be due to its high degree of crystallinity (99.19%), which might require the use of proper techniques to increase the IVS320's aqueous solubility and permeability. The trypanocidal activity study demonstrated that IVS320 is more potent than the reference drug benznidazole, with IC50/24 h of 1.49 ± 0.1 µM, which indicates that IVS320 has potential as a new drug candidate for the treatment of Chagas disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Naftoquinonas/química , Tripanossomicidas/química , Trypanosoma/efeitos dos fármacos , Sítios de Ligação , Humanos , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/farmacologia , Permeabilidade , Ligação Proteica , Solubilidade , Tripanossomicidas/farmacologia
12.
Dalton Trans ; 45(35): 13671-4, 2016 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-27488398

RESUMO

Three novel cobalt(iii)-triazole complexes with structural and redox properties suitable for hypoxia-activated drug delivery were obtained. A major influence of the ancillary ligands (TPA, py2en, py2enMe2) on the electronic properties and reactivity of their complexes was observed. An [O2]-dependent reduction to cobalt(ii) by ascorbic acid provided evidence of hypoxic selectivity.


Assuntos
Cobalto/química , Complexos de Coordenação/química , Sistemas de Liberação de Medicamentos/métodos , Modelos Biológicos , Oxigênio/química , Triazóis/química , Ácido Ascórbico/química , Complexos de Coordenação/síntese química , Hipóxia , Ligantes , Estrutura Molecular , Oxirredução , Pró-Fármacos/química , Triazóis/síntese química
13.
Curr Pharm Des ; 22(39): 5899-5914, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27291398

RESUMO

Quinones are among the most studied natural and synthetic products in the literature because they have considerable biological potential. These compounds exhibit activity against many microorganisms and are able to eliminate tumor cells through several mechanisms of action. Some of these compounds have become drugs that are used clinically. However, they also have problems with respect to solubility, stability and toxicity. The alternative of using controlled-release systems has been applied to quinones, with good results in some cases, indicating that these formulations may be a strategy for improving the pharmacological profile of this class of compounds.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Naftoquinonas/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/química , Disponibilidade Biológica , Produtos Biológicos/efeitos adversos , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Humanos , Naftoquinonas/efeitos adversos , Naftoquinonas/química , Neoplasias/patologia , Solubilidade
14.
Eur J Med Chem ; 74: 461-76, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24487194

RESUMO

Due to aging and increasingly overweight in human population, the incidence of non-insulin dependent diabetes mellitus (NIDDM or Type 2 DM) is increasing considerably. Therefore, searching for new α-glycosidase inhibitors (GIs) capable of slowing down carbohydrate assimilation by humans is an important strategy towards control of NIDDM. In this report, we disclose the search for new easily accessible synthetic triazoles as anti-diabetic compounds. Two series of non-glycosid triazoles were synthesized (series A and B) and screened against baker's yeast α-glucosidase (MAL12) and porcine pancreatic α-amylase activity (PPA). Of the 60 compounds tested at 500 µM, were considered hits (≥60% inhibition) six triazoles against MAL12 and three against PPA, with the inhibition reaching up to 99.4% on MAL12 and 88.6% on PPA. The IC50 values were calculated for both enzymes and ranged from 54 to 482 µM for MAL12 and 145 to 282 µM for PPA. These results demonstrated the potential activity of simple and non-glycosidic triazoles as an important novel class of GIs for the development of drugs to treat Type 2 DM.


Assuntos
Inibidores Enzimáticos/química , Inibidores de Glicosídeo Hidrolases , Triazóis/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Espectroscopia de Ressonância Magnética , Triazóis/síntese química , Triazóis/uso terapêutico
15.
Phytomedicine ; 20(11): 1007-12, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23746950

RESUMO

ß-Lapachone is a phytochemotherapeutic originally isolated from Lapacho tree whose extract has been used medicinally for centuries. It is well known that NAD(P)H:quinone oxidoreductase (NQO1) activity is the principal determinant of ß-Lapachone cytotoxicity. As NQO1 is overexpressed in most common carcinomas, recent investigations suggest its potential application against cancer. Photodynamic therapy (PDT) is a clinically approved and rapidly developing cancer treatment. PDT involves the administration of photosensitizer (PS) followed by local illumination with visible light of specific wavelength. In the presence of oxygen molecules, the light illumination of PS can lead to a series of photochemical reactions and consequently the generation of cytotoxic reactive oxygen species (ROS). It has been reported that ß-Lapachone synergistically interacts with ionizing radiation, hyperthermia and cisplatin and that the sensitivity of cells to ß-Lapachone is closely related to the activity of NQO1. So, the present study aimed to investigate the feasibility of PDT to increase the anticancer effect of ß-Lapachone by up-regulating NQO1 expression on breast cancer MCF-7c3 cells. NQO1 expression was evaluated by Western blot analysis at different times after PDT using ME-ALA as PS. The cytotoxicity of the photodynamic treatment and ß-Lapachone alone or in combination was determined by MTT assay and the combination index (CI)-isobologram method and the dose reduction index (DRI) analysis were used to assess the effect of drug combinations. Our studies for the first time demonstrated that the expression of NQO1 is induced 24h after photodynamic treatment. The sensitivity of cancer cells to ß-Lapachone treatment increased 24h after PDT and a synergistic inhibitory effect on MCF-7c3 cells was showed. Taken together, these results lead us to conclude that the synergistic interaction between ß-Lapachone and PDT in killing cells was consistent with the up-regulation of NQO1. The combination of ß-Lapachone and PDT is a potentially promising modality for the treatment of cancer.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/uso terapêutico , Fotoquimioterapia , Fitoterapia , Tabebuia/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Luz , Células MCF-7 , Naftoquinonas/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
16.
Org Biomol Chem ; 8(21): 4793-802, 2010 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-20838670

RESUMO

Taking into account the numerous reports in the literature related to pyran naphthoquinones in searching for new pharmacologically promising molecules against different therapeutic targets, this review intends to explore the synthetic methodologies for preparing these bioactive compounds.


Assuntos
Química/métodos , Naftoquinonas/síntese química , Piranos/síntese química
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