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1.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21264320

RESUMO

BackgroundOur understanding of COVID-19 vaccine immune responses in people living with HIV (PLWH) remains incomplete. MethodsWe measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and ACE2 displacement activities after one and two COVID-19 vaccine doses in 100 adult PLWH and 152 controls. ResultsAll PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Median nadir CD4+ T-cell counts were 280 (IQR 120- 490) cells/mm3, and ranged as low as <10 cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and [~]7% lower ACE2 displacement activity (p=0.037) after one vaccine dose. Following two vaccine doses however, the association between HIV and weaker responses no longer remained. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (as opposed to a heterologous or dual mRNA vaccine regimen) were the most significant correlates of weaker humoral responses. No significant association was observed between the most recent or nadir CD4+ T-cell counts and responses to COVID-19 vaccination in PLWH following two vaccine doses. ConclusionsThese results suggest that PLWH whose viral loads are well-controlled on antiretroviral therapy and whose CD4+ T-cell counts are in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, type of initial vaccine regimen and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed.

2.
Molecules ; 26(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361832

RESUMO

In recent times, researchers have aimed for new strategies to combat cancer by the implementation of nanotechnologies in biomedical applications. This work focuses on developing protein-based nanoparticles loaded with a newly synthesized NIR emitting and absorbing phthalocyanine dye, with photodynamic and photothermal properties. More precisely, we synthesized highly reproducible bovine serum albumin-based nanoparticles (75% particle yield) through a two-step protocol and successfully encapsulated the NIR active photosensitizer agent, achieving a good loading efficiency of 91%. Making use of molecular docking simulations, we confirm that the NIR photosensitizer is well protected within the nanoparticles, docked in site I of the albumin molecule. Encouraging results were obtained for our nanoparticles towards biomedical use, thanks to their negatively charged surface (-13.6 ± 0.5 mV) and hydrodynamic diameter (25.06 ± 0.62 nm), favorable for benefitting from the enhanced permeability and retention effect; moreover, the MTT viability assay upholds the good biocompatibility of our NIR active nanoparticles. Finally, upon irradiation with an NIR 785 nm laser, the dual phototherapeutic effect of our NIR fluorescent nanoparticles was highlighted by their excellent light-to-heat conversion performance (photothermal conversion efficiency 20%) and good photothermal and size stability, supporting their further implementation as fluorescent therapeutic agents in biomedical applications.


Assuntos
Indóis/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Soroalbumina Bovina/química , Proliferação de Células , Feminino , Humanos , Indóis/química , Luz , Simulação de Acoplamento Molecular , Nanopartículas/química , Neoplasias Ovarianas/patologia , Fármacos Fotossensibilizantes/química , Espectroscopia de Luz Próxima ao Infravermelho , Células Tumorais Cultivadas
3.
Rev Prat ; 71(2): e63-e70, 2021 02.
Artigo em Francês | MEDLINE | ID: mdl-34160993
5.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21257732

RESUMO

ImportanceUnderstanding feasibility of rapid testing in congregate living setting provides critical data to reduce the risk of outbreaks in these settings. ObjectiveUse rapid antigen screening to detect SARS-CoV-2 in an asymptomatic group of university students and staff. DesignCross-sectional SettingUniversity of British Columbia, Vancouver, Canada. ParticipantsStudents and staff living or working in congregate housing. InterventionHealth care professional administered rapid antigen test Main Outcomes and measuresUse of BD Veritor rapid antigen testing and asymptomatic participants experiences with rapid testing ResultsA total of 3536 BD Veritor tests were completed in 1141 unique individuals. One third of participants completed between two to four tests and 21% were screened five or more times. The mean number of tests completed per person was three. The mean length of time between those who had more than one test was seven days. There were eight false positives and 25 PCR confirmed COVID-19 positive individuals identified through this work. All individuals reported having no symptoms that they attributed to COVID-19. Almost all (n=22, 88%) COVID-19 positive cases were found in male participants. A total of 86 additional students from multiple different student residences (n=9) were asked to self-isolate while they waited for their COVID-19 diagnostic test results. An average of seven additional students positive for COVID-19 living in congregate housing were identified through contact tracing by finding one positive case. Conclusions and relevanceRapid testing is a relatively inexpensive and operationally easy method of identifying asymptomatic individuals with COVID-19.

7.
Nanotechnology ; 31(31): 315102, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32315999

RESUMO

Nowadays, extensive research is being carried out to find innovative solutions for the development of stable, reproductible, and highly efficient fluorescent contrast agents with the ability of targeting specific cells, which can be further implemented for fluorescent-guided surgery in a real clinical setting. The present study is focused on the development of fluorescent dye-loaded protein nanoparticles (NPs) to overcome the drawbacks of the standard administration of free organic fluorophores, such as cytotoxicity, aqueousinstability, and rapid photo-degradation. Precisely, human serum albumin (HSA) NPs loaded with two different FDA approved dyes, namely indocyanine green (ICG) and fluorescein isothiocyanate (FITC), with a fluorescence response in the near-infrared and visible spectral domains, respectively, have been successfully designed. Even though the diameter of fluorescent HSA NPs is around 30 nm as proven by dynamic light scattering and transmission electron microscopy investigations, they present good loading efficiencies of almost 50% for ICG, and over 30% for FITC and a high particle yield of over 75%. Molecular docking simulations of ICG and FITC within the structure of HSA confirmed that the dyes were loaded inside the NPs, and docked in Site I (subdomain IIA) of the HSA molecule. After the confirmation of their high fluorescence photostability, the NPs were covalently conjugated with folic acid (HSA-FA NPs) in order to bind specifically to the folate receptor alpha (FRα) protein overexpressed on NIH:OVCAR3 ovarian cancer cells. Finally, fluorescence microscopy imaging investigations validate the improved internalization of folate targeted HSA&FITC NPs compared to cells treated with untargeted ones. Furthermore, TEM examinations of the distribution of HSA NPs into the NIH:OVCAR3 cells revealed anincreased number of NP-containing vesicles for the cells treated with HSA-FA NPs, compared to the cells exposed to untargeted HAS NPs, upholding the enhanced cellular uptake through FRα-mediated potocytosis.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Corantes Fluorescentes/química , Ácido Fólico/farmacologia , Neoplasias Ovarianas/metabolismo , Albumina Sérica Humana/química , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Fluoresceína-5-Isotiocianato/química , Ácido Fólico/química , Humanos , Verde de Indocianina/química , Simulação de Acoplamento Molecular , Nanopartículas , Regulação para Cima
8.
Molecules ; 25(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121062

RESUMO

Herein we report the synthesis of two novel series of 1,3-thiazole derivatives having a lipophilic C4-substituent on account of the increasing need for novel and versatile antifungal drugs for the treatment of resistant Candida sp.-based infections. Following their structural characterization, the anti-Candida activity was evaluated in vitro while using the broth microdilution method. Three compounds exhibited lower Minimum Inhibitory Concentration (MIC) values when compared to fluconazole, being used as the reference antifungal drug. An in silico molecular docking study was subsequently carried out in order to gain more insight into the antifungal mechanism of action, while using lanosterol-C14α-demethylase as the target enzyme. Fluorescence microscopy was employed to further investigate the cellular target of the most promising molecule, with the obtained results confirming its damaging effect towards the fungal cell membrane integrity. Finally, the distribution and the pharmacological potential in vivo of the novel thiazole derivatives was investigated through the study of their binding interaction with bovine serum albumin, while using fluorescence spectroscopy.


Assuntos
Antifúngicos , Candida/crescimento & desenvolvimento , Soroalbumina Bovina/química , Tiazóis , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
9.
Molecules ; 24(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683749

RESUMO

 In an effort to improve the antimicrobial activity of norfloxacin, a series of hybrid norfloxacin-thiazolidinedione molecules were synthesized and screened for their direct antimicrobial activity and their anti-biofilm properties. The new hybrids were intended to have a new binding mode to DNA gyrase, that will allow for a more potent antibacterial effect, and for activity against current quinolone-resistant bacterial strains. Moreover, the thiazolidinedione moiety aimed to include additional anti-pathogenicity by preventing biofilm formation. The resulting compounds showed promising direct activity against Gram-negative strains, and anti-biofilm activity against Gram-positive strains. Docking studies and ADMET were also used in order to explain the biological properties and revealed some potential advantages over the parent molecule norfloxacin.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Norfloxacino/análogos & derivados , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Domínio Catalítico , DNA Girase/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento Molecular , Solubilidade , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/farmacologia , Água/química
10.
Molecules ; 24(19)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546673

RESUMO

In the context of there being a limited number of clinically approved drugs for the treatment of Candida sp.-based infections, along with the rapid development of resistance to the existing antifungals, two novel series of 4-phenyl-1,3-thiazole and 2-hydrazinyl-4-phenyl-1,3-thiazole derivatives were synthesized and tested in vitro for their anti-Candida potential. Two compounds (7a and 7e) showed promising inhibitory activity against the pathogenic C. albicans strain, exhibiting substantially lower MIC values (7.81 µg/mL and 3.9 µg/mL, respectively) as compared with the reference drug fluconazole (15.62 µg/mL). Their anti-Candida activity is also supported by molecular docking studies, using the fungal lanosterol C14α-demethylase as the target enzyme. The interaction of the most biologically active synthesized compound 7e with bovine serum albumin was investigated through fluorescence spectroscopy, and the obtained data suggested that this molecule might efficiently bind carrier proteins in vivo in order to reach the target site.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Simulação de Acoplamento Molecular , Soroalbumina Bovina/química , Relação Estrutura-Atividade
11.
Molecules ; 24(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151176

RESUMO

Oxidative stress has been incriminated in the physiopathology of many diseases, such as diabetes, cancer, atherosclerosis, and cardiovascular and neurodegenerative diseases. There is a great interest in developing new antioxidants that could be useful for preventing and treating conditions for which oxidative stress is suggested as the root cause. The thiazolidine-2,4-dione derivatives have been reported to possess various pharmacological activities and the phenol moiety is known as a pharmacophore in many naturally occurring and synthetic antioxidants. Twelve new phenolic derivatives of thiazolidine-2,4-dione were synthesized and physicochemically characterized. The antioxidant capacity of the synthesized compounds was assessed through several in vitro antiradical, electron transfer, and Fe2+ chelation assays. The top polyphenolic compounds 5f and 5l acted as potent antiradical and electron donors, with activity comparable to the reference antioxidants used. The ferrous ion chelation capacity of the newly synthesized compounds was modest. Several quantum descriptors were calculated in order to evaluate their influence on the antioxidant and antiradical properties of the compounds and the chemoselectivity of the radical generation reactions has been evaluated. The correlation with the energetic level of the frontier orbitals partially explained the antioxidant activity, whereas a better correlation was found while evaluating the O-H bond dissociation energy of the phenolic groups.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Antioxidantes/síntese química , Quelantes/síntese química , Quelantes/química , Quelantes/farmacologia , Técnicas de Química Sintética , Transporte de Elétrons , Sequestradores de Radicais Livres/síntese química , Radicais Livres/antagonistas & inibidores , Humanos , Estrutura Molecular , Fenóis/química , Teoria Quântica , Tiazolidinedionas/síntese química
12.
J Enzyme Inhib Med Chem ; 34(1): 898-908, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30938216

RESUMO

The rapid emergence of bacterial resistance to antibiotics currently available for treating infectious diseases requires effective antimicrobial agents with new structural profiles and mechanisms of action. Twenty-three thiazolin-4-one derivatives were evaluated for their antibacterial activity by determining the growth inhibition zone diameter, the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC), against gram-positive and gram-negative bacteria. Compounds 3a-c, 3e-h, 6b-c and 9a-c expressed better MIC values than moxifloxacin, against Staphylococcus aureus. Compounds 3h and 9b displayed similar effect to indolmycin, a tryptophanyl-tRNA ligase inhibitor. Due to their structural analogy to indolmycin, all compounds were subjected to molecular docking on tryptophanyl-tRNA synthetase. Compounds 3a-e, 6a-e, 8 and 9a-e exhibited better binding affinities towards the target enzymes than indolmycin. The antioxidant potential of the compounds was evaluated by four spectrophotometric methods. Thiazolin-4-ones 3e, 6e and 9e presented better antiradical activity than ascorbic acid, trolox and BHT, used as references.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Tiazóis/farmacologia , Triptofano-tRNA Ligase/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Triptofano-tRNA Ligase/metabolismo
13.
Molecules ; 24(1)2019 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-30621322

RESUMO

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the binding poses towards lanosterol 14α-demethylase. An in silico ADMET analysis showed that the compounds possess drug-like properties and represent a biologically active framework that should be further optimized as potential hits.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Hidrazonas/farmacologia , Antifúngicos/síntese química , Desenho de Fármacos , Fluconazol/farmacologia , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
14.
Pak J Pharm Sci ; 31(5(Supplementary)): 2085-2090, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30393216

RESUMO

New imine derivatives, that contain the thiazolyl-phenyl-thiazole scaffold, were synthesized and evaluated as anti-Candida agents. Elemental analysis and FT-IR, MS, 1H-NMR and 13C-NMR spectroscopic methods confirmed the structure of the newly synthesized compounds. The in vitro antifungal activity was investigated using the broth microdilution method against different Candida spp, including C. albicans, C. krusei and C. parapsilosis. All synthesized compounds exhibited good antifungal activity. Compound 4f showed the highest inhibitory effect against all tested Candida strains, being more potent than fluconazole. The results revealed that the new compounds have promising antifungal activity, with MIC values, ranging from 3.9 to 31.25µg/mL and MFC values between 7.81 and 62.5 µg/mL and could be considered for further development as anti-Candida agents.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Candida/fisiologia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Testes de Sensibilidade Microbiana/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
15.
Molecules ; 23(10)2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279343

RESUMO

C. albicans is the most frequently occurring fungal pathogen, and is becoming an increasing public health problem, especially in the context of increased microbial resistance. This opportunistic pathogen is characterized by a versatility explained mainly by its ability to form complex biofilm structures that lead to enhanced virulence and antibiotic resistance. In this context, a review of the known C. albicans biofilm formation inhibitors were performed and a new N-(oxazolylmethyl)-thiazolidinedione scaffold was constructed. 16 new compounds were synthesized and characterized in order to confirm their proposed structures. A general antimicrobial screening against Gram-positive and Gram-negative bacteria, as well as fungi, was performed and revealed that the compounds do not have direct antimicrobial activity. The anti-biofilm activity evaluation confirmed the compounds act as selective inhibitors of C. albicans biofilm formation. In an effort to substantiate this biologic profile, we used in silico investigations which suggest that the compounds could act by binding, and thus obstructing the functions of, the C. albicans Als surface proteins, especially Als1, Als3, Als5 and Als6. Considering the well documented role of Als1 and Als3 in biofilm formation, our new class of compounds that target these proteins could represent a new approach in C. albicans infection prevention and management.


Assuntos
Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Proteínas Fúngicas/antagonistas & inibidores , Tiazolidinedionas/química , Biofilmes/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Adesão Celular/efeitos dos fármacos , Proteínas Fúngicas/química , Humanos , Tiazolidinedionas/síntese química , Tiazolidinedionas/isolamento & purificação
16.
Molecules ; 23(10)2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30248903

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are an important pharmacological class of drugs used for the treatment of inflammatory diseases. They are also characterized by severe side effects, such as gastrointestinal damage, increased cardiovascular risk and renal function abnormalities. In order to synthesize new anti-inflammatory and analgesic compounds with a safer profile of side effects, a series of 2,6-diaryl-imidazo[2,1-b][1,3,4]thiadiazole derivatives 5a⁻l were synthesized and evaluated in vivo for their anti-inflammatory and analgesic activities in carrageenan-induced rat paw edema. Among all compounds, 5c showed better anti-inflammatory activity compared to diclofenac, the standard drug, and compounds 5g, 5i, 5j presented a comparable antinociceptive activity to diclofenac. None of the compounds showed ulcerogenic activity. Molecular docking studies were carried out to investigate the theoretical bond interactions between the compounds and target, the cyclooxygenases (COX-1/COX-2). The compound 5c exhibited a higher inhibition of COX-2 compared to diclofenac.


Assuntos
Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Edema/tratamento farmacológico , Imidazóis/síntese química , Tiadiazóis/síntese química , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Carragenina/efeitos adversos , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Diclofenaco/administração & dosagem , Diclofenaco/uso terapêutico , Edema/induzido quimicamente , Feminino , Imidazóis/administração & dosagem , Imidazóis/química , Imidazóis/farmacologia , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tiadiazóis/administração & dosagem , Tiadiazóis/química , Tiadiazóis/farmacologia
17.
Biomed Chromatogr ; 32(7): e4221, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29485694

RESUMO

The chromatographic behavior of a series of thiazolyl-1,3,4-oxadiazoles with antifungal activity was studied by reverse-phase thin-layer chromatography (RP-TLC). The lipophilicity parameters derived from RP-TLC were correlated with the data derived from liquid-chromatography mass-spectrometry. Good linear relationships were observed between the chromatographic lipophilicity parameters and the theoretical lipophilicity descriptors (logP) generated by various computer software and internet modules. Principal component analysis, applied on the experimental chromatographic lipophilicity indices and the theoretically calculated logP, enabled us to obtain a lipophilicity chart for better vizualization of the similarities and differences of the investigated compounds, which were grouped by k-means clustering in two congeneric classes.


Assuntos
Antifúngicos/química , Oxidiazóis/química , Tiazóis/química , Antifúngicos/análise , Cromatografia de Fase Reversa/métodos , Cromatografia em Camada Delgada/métodos , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas , Oxidiazóis/análise , Análise de Componente Principal , Tiazóis/análise
18.
SLAS Discov ; 23(8): 807-814, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29437525

RESUMO

A series of 12 new thiazolidine-2,4-dione derivatives were obtained by microwave-assisted synthesis. All compounds were physicochemically characterized by quantitative elemental C, H, N, S analysis and spectral data (mass spectrometry [MS], infrared [IR], and nuclear magnetic resonance [NMR]), with the results being in agreement with the expected data. An in vitro screening performed on Candida albicans ATCC 10231 showed their moderate antifungal activity, which was further investigated by determining the minimum inhibitory concentration and minimum fungicidal concentration values for the most active compounds on four strains of Candida. The molecular docking studies, performed against a fungal lanosterol 14α-demethylase, emphasized the importance of different molecular fragments in the compounds' structures for their antifungal activity. The synthesized compounds were subjected to in silico screening for the prediction of their absorption, distribution, metabolism, excretion, and toxicity (ADMET) and molecular properties. The results of the antifungal activity assays, docking study, and ADMET predictions revealed that the synthesized compounds are potential anti- Candida agents that might act by interacting with the fungal lanosterol 14α-demethylase and could be further optimized and developed as antifungal agents.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Técnicas de Química Sintética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana/métodos , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Antifúngicos/síntese química , Barreira Hematoencefálica/metabolismo , Permeabilidade da Membrana Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Absorção Gastrointestinal , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química
19.
Molecules ; 22(11)2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29077016

RESUMO

Sortase A inhibition is a well establish strategy for decreasing bacterial virulence by affecting numerous key processes that control biofilm formation, host cell entry, evasion and suppression of the immune response and acquisition of essential nutrients. A meta-analysis of structures known to act as Sortase A inhibitors provided the starting point for identifying a new potential scaffold. Based on this template a series of new potential Sortase A inhibitors, that contain the 2-phenylthiazole moiety, were synthesized. The physicochemical characterisation confirmed the identity of the proposed structures. Antibacterial activity evaluation showed that the new compounds have a reduced activity against bacterial cell viability. However, the compounds prevent biofilm formation at very low concentrations, especially in the case of E. faecalis. Molecular docking studies performed estimate that this is most likely due to the inhibition of Sortase A. The new compounds could be used as add-on therapies together with known antibacterial agents in order to combat multidrug-resistance enterococcal infections.


Assuntos
Aminoaciltransferases/química , Proteínas de Bactérias/química , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/química , Tiazóis/química , Aminoaciltransferases/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Biofilmes/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia
20.
Molecules ; 21(11)2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27879678

RESUMO

In the context of the dangerous phenomenon of fungal resistance to the available therapies, we present here the chemical synthesis of a new series of thiazolyl-triazole Schiff bases B1-B15, which were in vitro assessed for their anti-Candida potential. Compound B10 was found to be more potent against Candida spp. when compared with the reference drugs Fluconazole and Ketoconazole. A docking study of the newly synthesized Schiff bases was performed, and results showed good binding affinity in the active site of co-crystallized Itraconazole-lanosterol 14α-demethylase isolated from Saccharomyces cerevisiae. An in silico ADMET (absorption, distribution, metabolism, excretion, toxicity) study was done in order to predict some pharmacokinetic and pharmacotoxicological properties. The Schiff bases showed good drug-like properties. The results of in vitro anti-Candida activity, a docking study and ADMET prediction revealed that the newly synthesized compounds have potential anti-Candida activity and evidenced the most active derivative, B10, which can be further optimized as a lead compound.


Assuntos
Candida/efeitos dos fármacos , Bases de Schiff/síntese química , Esterol 14-Desmetilase/metabolismo , Triazóis/síntese química , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Candida/metabolismo , Domínio Catalítico , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Bases de Schiff/química , Bases de Schiff/farmacologia , Esterol 14-Desmetilase/química , Triazóis/química , Triazóis/farmacologia
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