RESUMO
BACKGROUND: Chagas disease (CD) is a neglected tropical disease caused by Trypanosoma cruzi. The current drugs used to treat these diseases have limited efficacy and produce severe side effects. 4-aminoquinoline derivatives were shown to be a promising class of inhibitors of cysteine proteases cruzain and TbrCATL. OBJECTIVES: To evaluate the trypanocidal activity of a new series of aminoquinolines as potential inhibitors of cruzain and TbrCATL. METHODS: Three aminoquinolines were synthesised and their in vitro activity was evaluated against cruzain and TbrCATL as well as against amastigotes and trypomastigotes forms of T. cruzi. In silico studies were also carried out to try to understand the experimental results. FINDINGS: Compound 5 showed promising activity against cruzain and TbrCATL, with better performance than E60, the reference drug. Compound 5 inhibited cruzain and TbrCATL at IC50 of 23 µM ±3 and 29 µM ±1, respectively, but this inhibition showed characteristics of promiscuous inhibition by colloidal aggregation. On the other hand, the compound 4 showed to be more promising activity against T. cruzi with IC50 2.57 µM ± 0.03 lower than the reference drug benznidazole 3.8 µM. MAIN CONCLUSIONS: The results of this study can guide new drug development for the treatment of trypanosomiasis.
Assuntos
Aminoquinolinas , Doença de Chagas , Inibidores de Cisteína Proteinase , Tripanossomicidas , Trypanosoma cruzi , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Doença de Chagas/tratamento farmacológico , Aminoquinolinas/farmacologia , Cisteína Endopeptidases , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/antagonistas & inibidoresRESUMO
The continuous increase in the incidence of invasive mycoses, particularly those caused by Candida albicans, is a relevant health issue worldwide due to the lack of effective antifungals and the constant emergence of resistant strains. One of the most promising therapies to treat infections caused by resistant microorganisms is photodynamic inactivation (PDI). The development of novel photosensitizers (PSs) with suitable properties is a key factor to consider when optimizing this therapy. In this work, we designed, synthesized, and characterized four glycoporphyrins functionalized with S-galactose (acetylated and deacetylated) and varying the number of tertiary amino groups as precursors of cationic centers, which can be activated by protonation at physiological pH. The amino and glycosyl groups were introduced to enhance interaction with the microbial cell wall, increase hydrophilicity, and evaluate their combined effect on PS efficiency in photoinactivation. All derivatives presented the characteristic absorption and emission properties of the porphyrin macrocycle. Moreover, the glycoporphyrins were capable of generating singlet oxygen and superoxide anion radical. The photophysical and photodynamic properties were not affected by the different substitution patterns on the porphyrin core. PDI treatments of C. albicans cultures, treated with 5 µM of the PS and irradiated for 30 min, produced cellular inactivation of â¼3.5 log for glycoporphyrins with cationic centers. Furthermore, PDI of C. albicans mediated by glycoporphyrins was potentiated by the addition of KI. Under these conditions, a significant enhancement in cellular death was observed, achieving complete eradication of the treated cell suspensions. Moreover, glycoporphyrins containing pH-activable groups, combined with KI, showed outstanding efficacy against C. albicans pseudohyphae. These in vitro findings underscore the significant impact of substitution patterns on antimicrobial action. To our knowledge, this study marks the first application of glycosylated porphyrin derivatives containing pH-activatable cationic groups in the photoinactivation of C. albicans, paving the way for the development of novel derivatives with potential applications as effective antifungal PSs.
Assuntos
Candida albicans , Fármacos Fotossensibilizantes , Porfirinas , Candida albicans/efeitos dos fármacos , Candida albicans/efeitos da radiação , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Porfirinas/química , Porfirinas/farmacologia , Fotoquimioterapia , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/síntese química , Luz , Oxigênio Singlete/metabolismo , Superóxidos/metabolismo , Superóxidos/química , Concentração de Íons de Hidrogênio , Galactose/química , Galactose/farmacologiaRESUMO
Perillic acid (PA) is a limonene derivative in which the exocyclic methyl is oxidized to a carboxyl group. Although endowed with potential anticancer activity, PA has been much less explored regarding its biological properties than analogous compounds such as perillyl alcohol, perillaldehyde, or limonene itself. PA is usually described in mixture with alcohols and ketones produced in the oxidation of monoterpenes, with relatively few existing reports focusing on the PA molecule. This study provides a comprehensive review of PA, addressing its origin, the processes of obtaining it through organic synthesis and biotransformation, and the pharmacological tests in which it is either the lead compound or reference for in vitro efficacy in experimental models. Although feasible and generally poorly yielded, the synthesis of PA from limonene requires multiple steps and the use of unusual catalysts. The most economical process involves using (-)-ß-pinene epoxide as the starting material, ending up with (-)-PA. On the other hand, some bacteria and yeasts are successful in producing, exclusively or at satisfactory purity level, PA from limonene or a few other monoterpenes, through environmentally friendly approaches. The compiled data revealed that, with few exceptions, most reports on PA bioactivity are related to its ability to interfere with the prenylation process of oncogenic proteins, an essential step for the growth and dissemination of cancer cells. The present survey reveals that there is still a vast field to disclose regarding the obtaining and scaling of PA via the fermentative route, as well as extending prospective studies on its properties and possible pharmacological applications, especially in the preclinical oncology field.
Assuntos
Monoterpenos , Humanos , Monoterpenos/química , Monoterpenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Limoneno/química , Limoneno/farmacologia , CicloexenosRESUMO
In recent years, metallodrugs have been playing an important role, showing to be more efficient in the treatment of several diseases, such as cancer. Indeed, it is important to synthesize novel molecules to be used as more effective agents against cancer. In the present paper, the synthesis of two new molecules belonging to Casiopeínas® is reported. These compounds present a ß2-aminoacidate derivative as the secondary ligand. The novel metal complexes were characterized by high-resolution mass spectrometry, FT-IR, UV-Vis, EPR, effective magnetic moment and cyclic voltammetry measurements, and single crystal X-ray diffraction analysis. Furthermore, these compounds were evaluated in vitro against the cancer lines MCF-7 (breast cancer) and A549 (lung cancer).
Assuntos
Antineoplásicos , Proliferação de Células , Complexos de Coordenação , Cobre , Humanos , Proliferação de Células/efeitos dos fármacos , Células MCF-7 , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Cobre/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Células A549 , Fenantrolinas/química , Fenantrolinas/farmacologia , Fenantrolinas/síntese química , Estrutura Molecular , Cristalografia por Raios X , Nitratos/química , Nitratos/farmacologiaRESUMO
Cancer resistance to chemotherapeutic agents such as cisplatin presents a significant challenge, leading to treatment failure and poor outcomes. Novel metal-based compounds offer a promising strategy to overcome drug resistance and to enhance efficacy. Four Ru(II) complexes with fenamic acid derivatives were synthesized and characterized: [Ru(L)(bipy)(dppp)]PF6, where L represents fenamic acid (HFen, complex 1), mefenamic acid (HMFen, complex 2), tolfenamic acid (HTFen, complex 3), and flufenamic acid (HFFen, complex 4). Their composition was supported by molar conductivity, elemental analysis, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, mass spectrometry, and 31P{1H}, 1H, and 13C nuclear magnetic resonance, with the crystal structure of complex 1 confirmed via X-ray diffraction. Complexes 1-4 exhibited notable cytotoxicity against tested cell lines, particularly A2780 and A2780cisR (cisplatin-resistant ovarian tumors), compared to MDA-MB-231 (breast) and A549 (lung) lines. Mechanistic studies revealed weak DNA interactions through minor grooves or electrostatic binding. Cellular uptake assays showed effective internalization of complexes 1 (3.6%) and 2 (4.5%), correlating with potent IC50 values. These complexes also altered cell morphology, reduced cell density, and inhibited colony formation in the A2780 cells. Staining assays indicated induced cell death and organelle damage, highlighting their potential as promising antitumor agents.
Assuntos
Antineoplásicos , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Ovarianas , Rutênio , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Rutênio/química , Rutênio/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Feminino , DNA/química , Fenamatos/química , Fenamatos/farmacologia , Fenamatos/síntese química , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Linhagem Celular Tumoral , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologiaRESUMO
A series of new tetrasubstituted α-aminophosphonate derivatives with a methylphosphoserine fragment were described. These compounds were synthesized by a three-component (3-CR) "Kabachnik-Fields reaction." The novel α-aminophosphonates were screened for in vivo anti-inflammatory activity through topical and oral administration routes. All compounds decreased TPA-induced ear edema in a dose-dependent fashion. In this test, compounds 2, 5, and 7 showed the same efficacy (≈ 90%) and higher potency than indomethacin and decreased the inflammatory marker neutrophil-to-lymphocyte ratio (NLR). Moreover, oral pretreatment and post-treatment with compounds 2-7 reduced CFA-induced paw edema, as did indomethacin or (S)-naproxen. Based on the promising in vivo anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles in silico. The analysis also revealed that the novel tetrasubstituted α-aminophosphonates did not break Lipinski's rule of five and had drug-likeness and favorable ADME properties for oral and transdermal administration.
Assuntos
Edema , Organofosfonatos , Animais , Organofosfonatos/química , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Organofosfonatos/farmacocinética , Camundongos , Edema/tratamento farmacológico , Edema/induzido quimicamente , Masculino , Administração Oral , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Relação Estrutura-Atividade , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/química , Ratos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismoRESUMO
In the present study, we investigated the potential use of five linear peptides as a potential antigens for the immunodiagnosis of tegumentary leishmaniasis (TL) and canine visceral leishmaniasis (CVL). We used bioinformatics approaches to identify linear B-cell epitopes in five hypothetical proteins from a Leishmania (Leishmania) infantum proteome study. To obtain the peptide sequences of each hypothetical protein, we used the GenBank and SwissProt online databases. These peptides were synthesized and tested, alone or in a cocktail, in enzyme-linked immunosorbent assays (ELISAs) against serum samples from patients with TL and from dogs infected with CVL. Our data shows that for CVL diagnosis, the best results were found with peptides 1 and 5, which showed sensitivity values of 97.30% and 94.54%, and specificity values of 93.83% (pep 1) and 91.63% (pep 5), respectively. For TL, all peptides showed higher sensitivity and specificity when compared with SLALb, with the peptide cocktail obtaining a 99.10% accuracy. This study's outcome suggests that these peptides may constitute a potential tool for a more sensitive and specific serodiagnosis of TL and CVL.
Assuntos
Antígenos de Protozoários , Doenças do Cão , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito B , Leishmania infantum , Leishmaniose Cutânea , Leishmaniose Visceral , Peptídeos , Sensibilidade e Especificidade , Cães , Animais , Doenças do Cão/diagnóstico , Doenças do Cão/parasitologia , Doenças do Cão/imunologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/veterinária , Leishmaniose Visceral/imunologia , Ensaio de Imunoadsorção Enzimática/veterinária , Antígenos de Protozoários/imunologia , Leishmania infantum/imunologia , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/veterinária , Leishmaniose Cutânea/imunologia , Peptídeos/imunologia , Peptídeos/síntese química , Peptídeos/química , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/química , Anticorpos Antiprotozoários/sangue , Proteínas de Protozoários/imunologia , Sequência de AminoácidosRESUMO
The global impact of SARS-CoV-2 has highlighted the urgent need for novel antiviral therapies. This study integrates combinatorial chemistry, molecular docking, and deep learning to design, evaluate and synthesize new pyrazole derivatives as potential inhibitors of the SARS-CoV-2 main protease (Mpro). A library of over 60,000 pyrazole-based structures was generated through scaffold decoration to enhance chemical diversity. Virtual screening employed molecular docking (ChemPLP scoring) and deep learning (DeepPurpose), with consensus ranking to identify top candidates. Binding free energy calculations refined the selection, revealing critical structural features such as tryptamine and N-phenyl fragments for Mpro binding. High-temperature solvent-free amidation allowed the synthesis of a selected derivative. Final compounds demonstrated favorable drug-likeness properties based on Lipinski's and Veber's rules. This work highlights the integration of computational and synthetic strategies to accelerate the discovery of Mpro inhibitors and provides a framework for future antiviral development.
Assuntos
Antivirais , Técnicas de Química Combinatória , Proteases 3C de Coronavírus , Aprendizado Profundo , Desenho de Fármacos , Simulação de Acoplamento Molecular , Pirazóis , SARS-CoV-2 , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
The occurrence of spirocyclic motifs in clinical candidates and approved drugs is on the rise. This is related to the improvement of drug-like properties that can be achieved by introducing this sp3-rich system into bioactive compounds. Given the increasing number of synthetic methodologies and building blocks available, spirocycles are becoming widely accessible to medicinal chemists. From restricting conformation to induce a better fit with the target, to modulation of physicochemical and pharmacokinetic properties, spirocycles are being used to address several challenges in drug discovery. This review covers general aspects of the chemistry of spirocycles, highlighting some key strategies for their preparation. As reported in publications over the past five years, we demonstrate that, beyond the exploration of structure-activity relationships (SAR) in medicinal chemistry, the use of spirocycles is an attractive approach for enhancing properties such as potency, selectivity, physicochemistry, and pharmacokinetics.
Assuntos
Química Farmacêutica , Descoberta de Drogas , Compostos de Espiro , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Compostos de Espiro/síntese química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , AnimaisRESUMO
Zileuton is the only FDA-approved 5-lipoxygenase (5-LOX) inhibitor for asthma treatment, but it produces hepatotoxicity associated with the benzothiophene fragment. Using the concept of organometallic derivatization pioneered by Jaouen and Brocard, we synthesized five new organometallic Zileuton derivatives, maintaining the urea fragment and incorporating ferrocenyl and ruthenocenyl moiety (3a-e). Their biological activity was evaluated against 5-LOX, 15-LOX, COX-1, and COX-2 enzymes. The ferrocenyl and ruthenocenyl N-hydroxyurea complexes coined Ferroleuton (3a) and Ruthenoleuton (3e) showed the highest selective inhibitory activity against 5-LOX, with IC50 values of 0.21 ± 0.12 and 3.49 ± 1.11 µM, respectively. Notably, 3a exhibited superior activity compared to Zileuton (IC50 0.67 ± 0.09 µM), demonstrating the key role of N-hydroxyurea and ferrocenyl fragments in the inhibitory process. Worthy of note, both compounds displayed low cytotoxicity in lung fibroblast healthy cells line (MRC-5) (CC50 of 116.40 and >200 µM, respectively). Enzyme kinetic studies indicated competitive and mixed types of inhibition for 3a and 3e, respectively. Additionally, they demonstrated superior antioxidant capacity compared to Zileuton (DPPH, ABTS, and FRAP assays). Electrochemical and molecular dynamics (MD) studies suggest a chelating-redox deactivation mechanism for 5-LOX. These findings position Ferroleuton (3a) and Ruthenoleuton (3e) as promising candidates for inflammatory disease treatment.
Assuntos
Araquidonato 5-Lipoxigenase , Compostos Ferrosos , Hidroxiureia , Inibidores de Lipoxigenase , Humanos , Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/síntese química , Hidroxiureia/farmacologia , Hidroxiureia/análogos & derivados , Hidroxiureia/química , Compostos Ferrosos/farmacologia , Compostos Ferrosos/química , Compostos Ferrosos/síntese química , Ureia/farmacologia , Ureia/análogos & derivados , Ureia/química , Estrutura Molecular , Metalocenos/química , Metalocenos/farmacologia , Relação Estrutura-Atividade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Inflamação/tratamento farmacológico , Simulação de Acoplamento MolecularRESUMO
The naphthalene ring is a moiety featured by many bioactive agents. Dihydroxynaphthalenes are readily available substances but their use for the synthesis of a series of compounds results in limited chemical diversity due to the similar reactivity of the phenolic hydroxyl groups. Herein, we describe the use of regioselective lipases in acylation and hydrolysis reactions to synthesize 5 different regioisomeric acetoxyhydroxynaphthalenes on a 91-122 mg scale with moderate to good yields (50-78%) from 1,3-, 1,6- and 1,7-dihydroxynaphthalenes and their corresponding diacetates. Reactions were optimised through medium engineering, thus providing information on the impact of different organic solvents on conversion and selectivity. Additionally, computational studies using molecular dynamic simulations were performed and suggested a correlation between the regiopreference displayed by lipase CAL-B in hydrolytic reactions and a distance ≤3.2 Å between the most reactive carbonyl group and the Ser-105 residue on the catalytic site. The herein described enzymatic methods may allow for introducing two different moieties at the naphthalene ring through a protection-deprotection strategy, thus allowing for better exploitation of the chemical space.
Assuntos
Lipase , Naftalenos , Lipase/metabolismo , Lipase/química , Naftalenos/química , Naftalenos/síntese química , Estereoisomerismo , Simulação de Dinâmica Molecular , Hidrólise , Estrutura Molecular , AcilaçãoRESUMO
This paper describes the synthesis of a MbioF (Metal-biomolecule Framework) using glutamic acid and nickel carbonate as precursors. The direct action of glutamic acid (H2Glu) on basic nickel carbonate (NiCO3·2Ni(OH)2·4H2O) initially indicated the formation of a complex, [Ni(HGlu)2], which was then treated in a Teflon-lined stainless steel autoclave at 100 °C for 24 hours, resulting in the compound {[Ni(Glu)(H2O)]·H2O}n, with a yield of 43%. The resolution of the structure of this compound by single-crystal X-ray diffraction indicated that it belongs to the orthorhombic crystal system and space group P212121, with a structure analogous to those of the compounds {[Co(Glu)(H2O)]·H2O}n, {[Cu(Glu)(H2O)]·H2O}n and {[Zn(Glu)(H2O])·H2O}n described in the literature, with a molecular formula of C5H9NO5Ni·H2O, molar mass of 239.8379 g mol-1, parameters a, b and c with values of 7.0577(2) (Å), 10.2307(3) (Å) and 11.5350(4) (Å), and a volume of 837.219 Å3. This compound, which is an intensely green crystalline solid, was characterized by electron (UV-Vis) and vibrational spectroscopy in the Fourier Transform Infrared (FTIR) region, powder X-ray diffractometry (PXRD) and thermogravimetric analysis (TGA/DTA). The in vivo toxicity and in vitro antimicrobial activity of the complex and the Ni-MOF were tested. The two compounds presented no toxicity at a concentration of 5000 µg mL-1, and showed inhibitory activity at 64 µg mL-1 in 24 h and at 128 µg mL-1 in 48 h against the yeast Candida albicans.
Assuntos
Ácido Glutâmico , Níquel , Níquel/química , Ácido Glutâmico/química , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Cristalografia por Raios XRESUMO
6-Fluoro-2-(aryl)quinoline-4-carboxylic acids 1-11 were synthesized via Pfitzinger reactions between 5-fluoroisatin and methyl aryl ketones. The molecules were studied regarding the impact of their substituent patterns (a-e) on their optical and bioactivity properties. All compounds were fluorescent in solution and had significant solvatochromic behavior, measured in tetrahydrofuran, dichloromethane, dimethylsulfoxide, acetonitrile, methanol, and water at different pHs. Compounds emitted in a broad spectral range from ultraviolet to green, with quantum efficiencies, varying from very weak (ex.: <0.5 % for 1a in DMSO and MeOH) to moderate-strong (â¼35 % for 11e in dichloromethane). A biomonitoring of the synthetized compounds reveals antimicrobial and larvicidal (Aedes aegypti mosquitoes) profile. Gram-positive bacterial and fungal species showed greater sensitivity to the 11e, that presented both bactericidal and fungicidal nature. This compound with a methylenedioxy substituent showed favourable interactions with Dehydrosqualene synthase (DQS) and Squalene synthase (SQS), well-validated antimicrobial targets, considering key residues in the complex formation. The molecule also presented a good larvicidal profile, ranking second in terms of significant LC50 values. Thus, 11e has demonstrated an advantage scaffold for future biological tests in other organisms or at the cellular level.
Assuntos
Anti-Infecciosos , Corantes Fluorescentes , Larva , Testes de Sensibilidade Microbiana , Quinolinas , Animais , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Larva/efeitos dos fármacos , Fungos/efeitos dos fármacos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Ácidos Carboxílicos/síntese química , Aedes/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Solventes/química , Espectrometria de Fluorescência , Inseticidas/farmacologia , Inseticidas/síntese química , Inseticidas/químicaRESUMO
Lumefantrine (LMF) is a low-solubility antimalarial drug that cures acute, uncomplicated malaria. It exerts its pharmacological effects against erythrocytic stages of Plasmodium spp. and prevents malaria pathogens from producing nucleic acid and protein, thereby eliminating the parasites. Modifying the structure of a drug through the formation of a pharmaceutical cocrystal or salt presents an avenue through which its physicochemical properties can be optimized. In this work, we report the design/synthesis and solid-state characterization of four new salts and cocrystal-salt forms of LMF; an LMF-ADP salt, monoclinic space group P21/n; an LMF-FUM cocrystal-salt, monoclinic space group P21/c; an LMF-TAR solvate salt, monoclinic space group P21/n; and an LMF-SUC salt, triclinic, space group P1Ì (ADP, dianion of adipic acid; FUM, monoanion of fumaric acid; TAR, dianion of tartaric acid; SUC, dianion of succinic acid). These salts can be obtained by solution as well as by mechanochemical cocrystallization methods. The multicomponent systems gain their stability from hydrogen and partial ionic bonding interactions (N-H···O, O-H···O, N+-H···O-, and O-H+···O-) originating from both the dibutyl ammonium (N+-H) site and the alcohol hydroxyl (-OH) site of LMF toward the carboxylate (-C(O-)âO) functional groups of the coformer anions. SCXRD indicates for LMF-ADP, LMF-TAR, and LMF-SUC complete transfer of all carboxylic acid protons (H+) toward the LMF nitrogen, while for LMF-FUM, one of the protons is transferred (leaving a hydrofumarate monoanion). Using salicylic and acetylsalicylic acids as coformers yielded coamorphous solids. Solid-state characterization using powder X-ray diffraction (XRD) and thermal techniques (DSC and TGA) support and confirm the structures obtained from single-crystal XRD. LMF-ADP and LMF-FUM present superior stability under standard conditions (40 ± 2 °C, 75 ± 5% RH, and 3 months) compared to the amorphous samples and the other two salts. LMF-SUC showed poor thermal stability by DSC/TGA, and powder XRD patterns for LMF-TAR showed substantial change after the 3-month stability test. Finally, the calculated equilibrium solubilities for the cocrystal salts indicate an increase of more than twofold compared to LMF's solubility.
Assuntos
Antimaláricos , Cristalização , Etanolaminas , Fluorenos , Lumefantrina , Sais , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/síntese química , Sais/química , Fluorenos/química , Lumefantrina/química , Etanolaminas/química , Desenho de Fármacos , Solubilidade , Cristalografia por Raios X/métodos , Ligação de HidrogênioRESUMO
In this work, we studied six Ruthenium(II)-diphosphine compounds containing different mercapto ligands (N-S), with general formula [Ru(N-S)(dppm)2]Cl (dppm=1,1-bis(diphenylphosphino)methane). These compounds were characterized by several techniques (NMR [1H, 31P(1H), and 13C], HRMS, IR, UV-Vis and XRD) and their purity confirmed by elemental analysis. DLS experiments revealed low diameters and polydispersity indexes, and positive log P values in n-octanol/PBS indicated their preference for the organic phase. In general, these compounds are stable in different media over 48â h. Cytotoxicity experiments revealed promising IC50 values on A549 breast cancer cells, 0.48â µM and 0.80â µM for [Ru(mtz)(dppm)2]Cl (1) and [Ru(mmi)(dppm)2]Cl (2), respectively (mtz and mmi are 2-mercapto-2-thiazoline and mercapto-1-methylimidazole in their deprotonated form, respectively). Clonogenic and migration experiments indicated their antiproliferative and anti-migratory capacity. ICP-MS results indicated their cellular accumulation in the nucleus, with little amounts in mitochondria. No covalent DNA binding was observed by ICP-MS. JC-1 and cell Mito Stress test confirmed mitochondrial dysfunction, which was verified by mitochondrial membrane potential uncoupling and drastic alterations in the oxygen consumption rate. Taken together, our results provide crucial insights regarding the anticancer potential of ruthenium(II)-phosphine compounds.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias Pulmonares , Mitocôndrias , Fosfinas , Rutênio , Humanos , Rutênio/química , Rutênio/farmacologia , Fosfinas/química , Fosfinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Células A549 , Proliferação de Células/efeitos dos fármacos , Estrutura MolecularRESUMO
Breast cancer is the deadliest cancer among women and its treatment using traditional methods leads the patient to experience adverse effects. However, photodynamic therapy (PDT) is a non-invasive therapy modality that works through a photosensitizing agent, which treating activated by a suitable light source, releases reactive oxygen species capable of treating cancer. Furthermore, recent research indicates that combining PDT and nanoparticles can enhance therapeutic effects. In this way, the synthesis of IONPs (iron oxide nanoparticles) was carried out, and their subsequent coating was done with curcumin (IONPs@curcumin) so that they could act as therapeutic agents against breast cancer. Curcumin solubility tests were carried out to achieve the best results, with ethanol as a solvent, in different concentrations of ethanolic curcumin solution, with the optimal outcome observed at a concentration of 1 mM. Subsequently, the stability analysis was conducted by adjusting the pH of the medium, revealing that at pH 10, the IONPs@curcumin exhibited the best stability and dispersion conditions. Then, cytotoxicity tests of IONPs@curcumin were carried out on the MDA-MB-468 triple-negative breast cancer cell line, under experimental conditions without irradiation and subjected to PDT. The results revealed a viability greater than 70%, as it did not exhibit cytotoxicity for cells in the dark. After 1 h of incubation, the PDT associated with IONPs@curcumin showed 32% of cell viability at a concentration of 30 mg/mL.
Assuntos
Neoplasias da Mama , Curcumina , Nanopartículas Magnéticas de Óxido de Ferro , Fotoquimioterapia , Fármacos Fotossensibilizantes , Curcumina/química , Curcumina/farmacologia , Humanos , Feminino , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Nanopartículas Magnéticas de Óxido de Ferro/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Férricos/química , Compostos Férricos/farmacologiaRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairments and is considered the most prevalent form of dementia. Among the contributing factors to AD lies the hyperphosphorylation of the microtubule-associated protein tau. Phosphorylated tau reduces its affinity for microtubules and triggers other posttranslational modifications that result in its aggregation and assembly into filaments. These structures progressively accumulate within neurons leading to neurodegeneration. While current AD medications often involve undesirable side effects, the exploration of natural products as a potential therapeutic alternative has gained considerable attention. Numerous compounds have shown potential capacity for reducing tau pathology through different mechanisms, such as inhibiting kinases to reduce tau hyperphosphorylation, enhancing phosphatase activity, and blocking fibril formation. Since tau hyperphosphorylation-induced aggregation is pivotal in AD onset, this review aims to elucidate the potential of natural products in modulating this crucial molecular mechanism.
Assuntos
Doença de Alzheimer , Produtos Biológicos , Proteínas tau , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inibidores , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/síntese química , Fosforilação , Animais , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológicoRESUMO
Candida is a commensal fungus of clinical interest that commonly lives in oral cavity and intestine but can become an opportunist microrganism and cause severe infections. A serie of 10 aminochalcones were designed and synthetized to obtain compounds anti-Candida with potent and broad-spectrum activity. The most active compound J34 demonstrated excellent in vitro activity against Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata and Candida krusei with minimum inhibitory concentration between 1.9 and 7.8 µg/mL. The association of aminochalcone J34 with amphotericin B demonstrated synergistic effect against C. albicans, with Fractional Inhibiroty Concentration Index (FICI) value of 0.5. Subinhibitory concentration of J34 inhibited the C. albicans adhesion to human keratinocytes. Treatment with J34 reduced C. albicans biofilm formation, as well as acts on preformed biofilm in concentration-dependent mode. Time-kill curve demonstrated that J34 had fungicidal action after 12 h of treatment. Preliminary mechanism of action study showed J34 interacts with membrane ergosterol but does not act on fungal cell wall of C. albicans. In additon, in vivo studies using Galleria mellonella indicated low toxic effect of chalcone J34 after 72 h of treatment.
Assuntos
Antifúngicos , Biofilmes , Candida , Chalconas , Testes de Sensibilidade Microbiana , Biofilmes/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/síntese química , Chalconas/farmacologia , Chalconas/síntese química , Candida/efeitos dos fármacos , Candida/fisiologia , Animais , Humanos , Anfotericina B/farmacologia , Mariposas/efeitos dos fármacos , Mariposas/microbiologia , Candida albicans/efeitos dos fármacos , Candida albicans/fisiologia , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Queratinócitos/efeitos dos fármacos , Sinergismo FarmacológicoRESUMO
This study presents an innovative approach to creating antibacterial aluminum surfaces by combining the antibacterial properties of silver nanoparticles (Ag NPs) with the nanoarchitecture of anodized aluminum oxide in one step. An Al-Ag alloy containing 10 wt % Ag was synthesized and anodized in 0.3 M oxalic acid. Ag NPs precipitated in the solid state during anodization, resulting in a porous nanocomposite structure. Comprehensive characterization using SEM, TEM, and EDS revealed a 43 µm thick oxide layer with uniformly distributed nanopores of approximately 100 nm in diameter. Ag NPs with diameters ranging from 2 to 14 nm precipitated dispersed on the surface, inside pores, and within the Al2O3 matrix. Antibacterial properties were evaluated against Escherichia coli. The anodized Al-Ag surface demonstrated robust antibacterial activity after short incubation times (up to 1 × 108 CFU/ml after 3 h). The enhanced antibacterial properties are attributed to the optimal size and distribution of Ag NPs and the potential physical bactericidal effect of the nanoporous structure. This strategy for the precipitation of Ag NPs in the solid state could be used to fabricate high-touch surfaces in hospitals.
Assuntos
Antibacterianos , Escherichia coli , Teste de Materiais , Nanopartículas Metálicas , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Prata , Propriedades de Superfície , Prata/química , Prata/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Escherichia coli/efeitos dos fármacos , Nanopartículas Metálicas/química , Alumínio/química , Alumínio/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , EletrodosRESUMO
Schistosomiasis is the infection caused by Schistosoma mansoni and constitutes a worldwide public health problem. The parasitological recommended method and serological methods can be used for the detection of eggs and antibodies, respectively. However, both have limitations, especially in low endemicity areas. Thus, new approaches for the diagnosis of schistosomiasis are essential. In this study, a six-amino acid peptide and derived sequences from SmATPDase1 were synthesized for the evaluation of immunogenicity. SmATPDase1 is included in a protein group in S. mansoni tegument; therefore, its peptides could be potential candidates for diagnostic antigens. In the hypothetical SmATPDase1 three-dimensional structure, peptides are located in a region exposed and accessible to antibody binding. In addition, peptide amino acid sequences are conserved in the most relevant Schistosoma species and have low identity with human NTPDases isoforms. Swiss mice immunization resulted in significant anti-peptide polyclonal antibodies production, which recognized a 63 kDa protein in tegument and adult worm preparations. By immunofluorescence microscopy, polyclonal antibodies also identified this enzyme in cercariae. Sera of infected animals presented high seropositivity in ELISA-peptides, with an area under curve (AUC) greater than 0.96 for all peptides. In mice with low parasite burden, we observed a seropositivity AUC > 0.9. Reactivity in the prepatent period exhibited AUC values greater than 0.94 for all peptides. Anti-P1425 monoclonal antibodies were successfully produced, and mAbs recognized the integral protein in ELISA and Western blots. The data indicate that peptides from SmATPDase1 are potential biomarkers for schistosomiasis, and anti-peptide antibodies are interesting tools for the detection of the infection.