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1.
J Am Chem Soc ; 143(40): 16673-16681, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34605242

RESUMO

Marine plastic pollution is a worldwide challenge making advances in the field of biodegradable polymer materials necessary. Polylactide (PLA) is a promising biodegradable polymer used in various applications; however, it has a very slow seawater degradability. Herein, we present the first library of PLA derivatives with incorporated "breaking points" to vary the speed of degradation in artificial seawater from years to weeks. Inspired by the fast hydrolysis of ribonucleic acid (RNA) by intramolecular transesterification, we installed phosphoester breaking points with similar hydroxyethoxy side groups into the PLA backbone to accelerate chain scission. Sequence-controlled anionic ring-opening copolymerization of lactide and a cyclic phosphate allowed PLA to be prepared with controlled distances of the breaking points along the backbone. This general concept could be translated to other slowly degrading polymers and thereby be able to prevent additional marine pollution in the future.

2.
PLoS One ; 16(9): e0256834, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34499662

RESUMO

The current pandemic outbreak clearly indicated the urgent need for tools allowing fast predictions of bioactivity of a large number of compounds, either available or at least synthesizable. In the computational chemistry toolbox, several such tools are available, with the main ones being docking and structure-activity relationship modeling either by classical linear QSAR or Machine Learning techniques. In this contribution, we focus on the comparison of the results obtained using different docking protocols on the example of the search for bioactivity of compounds containing N-N-C(S)-N scaffold at the S-protein of SARS-CoV-2 virus with ACE2 human receptor interface. Based on over 1800 structures in the training set we have predicted binding properties of the complete set of nearly 600000 structures from the same class using the Machine Learning Random Forest Regressor approach.


Assuntos
Antivirais/farmacologia , Aprendizado de Máquina , Simulação de Dinâmica Molecular , SARS-CoV-2/química , Tioureia/farmacologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Humanos , Ligação Proteica , Tioureia/química
3.
J Enzyme Inhib Med Chem ; 36(1): 1145-1164, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34074198

RESUMO

We report herein anti-proliferation effects of 4-arylthiosemicarbazides, with a cyclopentane substitution at N1 position, on highly virulent RH strain of Toxoplasma gondii. Among them, the highest in vitro anti-Toxoplasma activity was found with the meta-iodo derivative. Further experiments demonstrated inhibitory effects of thiosemicarbazides on tyrosinase (Tyr) activity, and good correlation was found between percentage of Tyr inhibition and IC50Tg. To confirm the concept that thiosemicarbazides are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites, the most potent Tyr inhibitors were tested for their efficacy of T. gondii growth inhibition. All of them significantly reduced the number of tachyzoites in the parasitophorous vacuoles (PVs) compared to untreated cells, as well as inhibited tachyzoites growth by impeding cell division. Collectively, these results indicate that compounds with the thiosemicarbazide scaffold are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites by deregulation of their crucial enzyme tyrosine hydroxylase (TyrH).


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Semicarbazidas/farmacologia , Toxoplasma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Testes de Sensibilidade Parasitária , Semicarbazidas/síntese química , Semicarbazidas/química , Relação Estrutura-Atividade , Toxoplasma/crescimento & desenvolvimento
4.
Cells ; 10(5)2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946881

RESUMO

Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b-12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC50) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b-12b, especially 12b with IC50 of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells.


Assuntos
Antiprotozoários/toxicidade , Tiadiazóis/toxicidade , Toxoplasma/efeitos dos fármacos , Antiprotozoários/síntese química , Linhagem Celular , Proliferação de Células , Humanos , Tiadiazóis/síntese química , Toxoplasma/fisiologia
5.
Dalton Trans ; 50(16): 5557-5573, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33908935

RESUMO

Three half-sandwich organometallic ruthenium(ii) complexes containing purine analogs such as triazolopyrimidines of general formula [(η6-p-cym)Ru(L)Cl2], where p-cym represents p-cymene and L is 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp for 1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for 2) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO for 3), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, 15N), and single-crystal X-ray diffraction (for 1 and 2). All these complexes have been thoroughly screened for their in vitro cytotoxicity against MCF-7 and HeLa cell lines as well as L929 murine fibroblast cells, indicating [(η6-p-cym)Ru(HmtpO)Cl2] (3) as the most active representative against the HeLa cell line and simultaneously being 64-fold less toxic to normal L929 murine fibroblast cells than cisplatin. At the same time, 3 has shown antimetastatic activity comparable to NAMI-A against HeLa cells both after 24 and 48 h of treatment in a wound healing assay. In order to better understand the mechanism of anticancer action and differences in the cytotoxic activity of 1-3, the studies were expanded to determining their lipophilicity, the kinetic stability at pH 6.5-8, the effect on reactive oxygen species (ROS) production in HeLa cells and interactions with significant biomolecules (DNA and albumin) by using molecular docking and circular dichroism (CD) experiments. Furthermore, antiparasitic studies against L. braziliensis, L. infantum and T. cruzi reveal that the newly synthesized complexes 1-3 are very promising candidates which can compete with commercial antiparasitic drugs. Complex 3 in particular, on top of exhibiting a high antiparasitic effect (IC50 < 1 µM against two strains), reaches a selectivity index >1000.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rutênio/química , Células HeLa , Humanos , Simulação de Acoplamento Molecular
6.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918623

RESUMO

Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide (4) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide (7), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis, as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/enzimologia , Semicarbazidas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Antibacterianos/química , Sítios de Ligação , DNA Girase/química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Semicarbazidas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologia
7.
J Phys Chem B ; 125(7): 1874-1880, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33570409

RESUMO

Although weak intermolecular interactions are the essence of most processes of key importance in medicine, industry, environment, and life cycles, their characterization is still not sufficient. Enzymatic dehalogenations that involve chloride anion interaction within a host-guest framework is one of the many examples. Recently published experimental results on host-guest systems provided us with models suitable to assess isotopic consequences of these noncovalent interactions. Herein, we report the influence of environmental and structural variations on chlorine isotope effects. We show that these effects, although small, may obscure mechanistic interpretations, as well as analytical protocols of dehalogenation processes.

8.
Molecules ; 25(20)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053830

RESUMO

Docking of over 160 aminothiourea derivatives at the SARS-CoV-2 S-protein-human ACE2 receptor interface, whose structure became available recently, has been evaluated for its complex stabilizing potency and subsequently subjected to quantitative structure-activity relationship (QSAR) analysis. The structural variety of the studied compounds, that include 3 different forms of the N-N-C(S)-N skeleton and combinations of 13 different substituents alongside the extensive length of the interface, resulted in the failure of the QSAR analysis, since different molecules were binding to different parts of the interface. Subsequently, absorption, distribution, metabolism, and excretion (ADME) analysis on all studied compounds, followed by a toxicity analysis using statistical models for selected compounds, was carried out to evaluate their potential use as lead compounds for drug design. Combined, these studies highlighted two molecules among the studied compounds, i.e., 5-(pyrrol-2-yl)-2-(2-methoxyphenylamino)-1,3,4-thiadiazole and 1-(cyclopentanoyl)-4-(3-iodophenyl)-thiosemicarbazide, as the best candidates for the development of future drugs.


Assuntos
Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Semicarbazidas/química , Glicoproteína da Espícula de Coronavírus/química , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/efeitos dos fármacos , COVID-19 , Infecções por Coronavirus/virologia , Humanos , Modelos Estatísticos , Estrutura Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo
9.
Molecules ; 25(18)2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32962192

RESUMO

During recent years, small molecules containing five-member heterocyclic moieties have become the subject of considerable growing interest for designing new antitumor agents. One of them is 1,3,4-thiadiazole. This study is an attempt to collect the 1,3,4-thiadiazole and its derivatives, which can be considered as potential anticancer agents, reported in the literature in the last ten years.


Assuntos
Antineoplásicos/química , Tiadiazóis/química , Aminas/química , Animais , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dissulfetos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiadiazóis/efeitos adversos
10.
Molecules ; 25(12)2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32560032

RESUMO

Parasitic infections caused by different species of intestinal helminths still poses a threat to public health. There is a need to search for new, effective anthelmintic drugs. A series of novel thiosemicarbazides were synthesized and evaluated for their in vitro anthelmintic activity. The preliminary results showed that the most of synthesized compounds were very active. 4-Phenyl-1-[(1-methyl-4-nitroimidazol-2-yl)carbonyl]thiosemicarbazide and 4-(3-chlorophenyl)-1-[(1-methyl-4-nitroimidazol-2-yl)carbonyl]thiosemicarbazide showed a 100% mortality of nematodes and a high anthelmintic activity in both tested concentrations.


Assuntos
Antinematódeos , Rhabditoidea/crescimento & desenvolvimento , Semicarbazidas , Animais , Antinematódeos/síntese química , Antinematódeos/química , Antinematódeos/farmacologia , Estrutura Molecular , Semicarbazidas/síntese química , Semicarbazidas/química , Semicarbazidas/farmacologia
11.
Molecules ; 25(10)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32422899

RESUMO

Antimicrobial resistance spurred by the overuse and misuse of antibiotics is a major global health concern, and of the Gram positive bacteria, S. aureus is a leading cause of mortality and morbidity. Alternative strategies to treat S. aureus infections, such as combination therapy, are urgently needed. In this study, a checkerboard method was used to evaluate synergistic interactions between nine thiosemicarbazides (4-benzoyl-1-(2,3-dichloro-benzoyl)thiosemicarbazides 1-5 and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides 6-9) and conventional antibiotics against S. aureus ATCC 25923, which were determined as the fractional inhibitory concentration indices (FICIs). For these experiments, amoxicillin, gentamicin, levofloxacin, linezolid, and vancomycin were selected to represent the five antimicrobial classes most commonly used in clinical practice. With one exception of 7-vancomycin combination, none of the forty-five thiosemicarbazide-antibiotic combinations tested had an antagonistic effect, showing promising results with respect to a combination therapy. The synergic effect was observed for the 2-linezolid, 4-levofloxacin, 5-linezolid, 6-gentamicin, 6-linezolid, and 7-levofloxacin combinations. No interactions were seen in combination of the thiosemicarbazide with gentamicin or vancomycin, whereas all combinations with linezolid acted in additive or synergism, except for 6-gentamicin and 7-linezolid. The 4-(4-chlorophenyl)-1-(2-fluorobenzoyl)thiosemicarbazide 6 showed a clear preference for the potency; it affected synergistically in combinations with gentamicin or linezolid and additively in combinations with amoxicillin, levofloxacin, or vancomycin. In further studies, the inhibitory potency of the thiosemicarbazides against S. aureus DNA gyrase and topoisomerase IV was examined to clarify the molecular mechanism involved in their synergistic effect in combination with levofloxacin. The most potent synergist 6 at concentration of 100 µM was able to inhibit ~50% activity of S. aureus DNA gyrase, thereby suggesting that its anti-gyrase activity, although weak, may be a possible factor contributing to its synergism effect in combination with linezolid or gentamycin.


Assuntos
Amoxicilina/farmacologia , Antibacterianos/farmacologia , Gentamicinas/farmacologia , Levofloxacino/farmacologia , Linezolida/farmacologia , Semicarbazidas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologia , Amoxicilina/química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , DNA Girase/genética , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/genética , DNA Topoisomerase IV/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Expressão Gênica , Gentamicinas/química , Humanos , Levofloxacino/química , Linezolida/química , Testes de Sensibilidade Microbiana , Semicarbazidas/química , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Vancomicina/química
12.
Bioorg Chem ; 97: 103676, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32097795

RESUMO

The two series of thiosemicarbazone derivatives with thiazolidine-2,4-dione (TZD) core were designed and synthesized. The antimycobacterial activity of the target compounds was tested against Mycobacterium tuberculosis H37Ra by broth microdilution method with resazurin as an indicator of the metabolic activity of mycobacteria. Conducted studies revealed antimycobacterial activity in the concentration range of 0.031-64 µg/ml for 31 synthesized derivatives with TZD core. The highest antimycobacterial activity (MIC = 0.031-0.125 µg/ml) was demonstrated for the new group of compounds: TZD-based hybrids with 4-unsubstituted thiosemicarbazone substituent. Furthermore, all the tested compounds within this group were characterized by low cytotoxicity. Among tested compounds, two compounds are the most promising potential antimycobacterial agents since they not only show very low MIC values, but also non-toxicity against Vero cells at tested concentration range. High effectiveness and safety of these synthesized compounds makes them promising candidates as antimycobacterial agents.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Animais , Antituberculosos/síntese química , Chlorocebus aethiops , Desenho de Fármacos , Humanos , Tiazolidinedionas/síntese química , Tiossemicarbazonas/síntese química , Tuberculose/tratamento farmacológico , Células Vero
13.
Eur J Med Chem ; 189: 112045, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951961

RESUMO

The two series of thiazolidine-2,4-dione (TZD) based hybrids with halogenbenzohydrazones and pyridinecarbohydrazones substituents were designed and synthesized. Target hydrazones were evaluated for their antimycobacterial activity by broth microdilution method with resazurin as an indicator of the metabolic activity of mycobacteria. Conducted studies revealed antimycobacterial activity in the concentration range of 1-512 µg/ml for 23 synthesized TZD-based derivatives. The highest antimycobacterial activity (MIC = 1 µg/ml) was demonstrated for the new group of compounds: TZD-based derivatives with pyridine-4-carbohydrazone substituent. Furthermore, all the tested compounds within this group were characterized by low cytotoxicity. On the basis of the results obtained, three compounds with the highest SI were selected. High effectiveness and safety of these synthesized derivatives makes them promising candidates as antimycobacterial agents.


Assuntos
Antituberculosos/farmacologia , Hidrazonas/farmacologia , Tiazolidinedionas/farmacologia , Animais , Antituberculosos/síntese química , Chlorocebus aethiops , Desenho de Fármacos , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazolidinedionas/síntese química , Células Vero
14.
Molecules ; 26(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396536

RESUMO

The development of drug-resistant bacteria is currently one of the major challenges in medicine. Therefore, the discovery of novel lead structures for the design of antibacterial drugs is urgently needed. In this structure-activity relationship study, a library of ortho-, meta-, and para-fluorobenzoylthiosemicarbazides, and their cyclic analogues with 1,2,4-triazole scaffold, was created and tested for antibacterial activity against Gram-positive bacteria strains. While all tested 1,2,4-triazoles were devoid of potent activity, the antibacterial response of the thiosemicarbazides was highly dependent on substitution pattern at the N4 aryl position. The optimum activity for these compounds was found for trifluoromethyl derivatives such as 15a, 15b, and 16b, which were active against both the reference strains panel, and pathogenic methicillin-sensitive and methicillin-resistant Staphylococcus aureus clinical isolates at minimal inhibitory concentrations (MICs) ranging from 7.82 to 31.25 µg/mL. Based on the binding affinities obtained from docking, the conclusion can be reached that fluorobenzoylthiosemicarbazides can be considered as potential allosteric d-alanyl-d-alanine ligase inhibitors.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Semicarbazidas/química , Staphylococcus aureus/efeitos dos fármacos , Triazóis/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
15.
J Mol Model ; 25(9): 286, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471757

RESUMO

Due to its importance in chemistry and biology, mechanisms of reactions involving phosphates are of central interest. However, only recently, quantum-chemical modeling of these reactions has become possible. With the advent of DFT calculations on phosphate-containing molecules, we have, therefore, investigated theoretically the mechanism of thiol-thione isomerization of a monothiopyrophosphate, which has been for a long time a subject of controversy. The calculations indicate that the reaction proceeds via concerted intramolecular mechanisms.

16.
Molecules ; 24(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438527

RESUMO

Recent findings on the biological activity of thiazolidin-4-ones and taking into account the lack of effective drugs used in the treatment of toxoplasmosis, their numerous side effects, as well as the problem of drug resistance of parasites prompted us to look for new agents. We designed and synthesized a series of new thiazolidin-4-one derivatives through a two-step reaction between 4-substituted thiosemicarbazides with hydroxybenzaldehydes followed by the treatment with ethyl bromoacetate; maleic anhydride and dimethyl acetylenedicarboxylate afforded target compounds. The thiazolidin-4-one derivatives were used to assess the inhibition of Toxoplasma gondii growth in vitro. All active thiazolidine-4-one derivatives (12 compounds) inhibited T. gondii proliferation in vitro much better than used references drugs both sulfadiazine as well as the synergistic effect of sulfadiazine + trimethoprim (weight ratio 5:1). Most active among them derivatives 94 and 95 showed inhibition of proliferation at about 392-fold better than sulfadiazine and 18-fold better than sulfadiazine with trimethoprim. All active compounds (82-88 and 91-95) against T. gondii represent values from 1.75 to 15.86 (CC30/IC50) lower than no cytotoxic value (CC30).


Assuntos
Antiprotozoários/uso terapêutico , Sulfadiazina/uso terapêutico , Toxoplasma/efeitos dos fármacos , Trimetoprima/uso terapêutico , Animais , Antiprotozoários/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Relação Estrutura-Atividade , Sulfadiazina/química , Tiossemicarbazonas/uso terapêutico , Toxoplasmose
17.
Chem Biodivers ; 16(10): e1900377, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31436917

RESUMO

The series of novel Mannich bases were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative bacterial strains. The results showed that all compounds were less active than the drugs used as reference, but some of them had moderate potency against Staphylococcus epidermidis ATCC 12228 and Bacillus subtilis ATCC 6633. The presence of a phenyl ring in the position 4 of piperazine seems to be necessary for antibacterial activity in this class of compounds.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bases de Mannich/química , Staphylococcus epidermidis/efeitos dos fármacos , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Triazóis/síntese química , Triazóis/química
18.
Pharmaceuticals (Basel) ; 12(2)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022835

RESUMO

In this study, 48 inhibitors were docked to 107 allosteric centers of human immunodeficiency virus 1 (HIV-1) reverse transcriptase from the Protein Data Bank (PDB). Based on the average binding scores, quantitative structure-activity relationship (QSAR) equations were constructed in order to elucidate directions of further development in the design of inhibitors. Such developments, informed by structural data, must have a focus on activity against mutated forms of the enzyme, which are the cause of the emergence of multidrug-resistant viral strains. Docking studies employed the HYDE scoring function. Two types of QSARs have been considered: One based on topological descriptors and the other on structural fragments of the inhibitors. Both methods gave similar results, indicating substructures favoring binding to mutated forms of the enzyme.

19.
Molecules ; 24(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022878

RESUMO

Employing a simple synthetic protocol, a series of highly effective halogen-substituted imidazole-thiosemicarbazides with anti-Toxoplasma gondii effects against the RH tachyzoites, much better than sulfadiazine, were obtained (IC50s 10.30-113.45 µg/mL vs. ~2721.45 µg/mL). The most potent of them, 12, 13, and 15, blocked the in vitro proliferation of T. gondii more potently than trimethoprim (IC50 12.13 µg/mL), as well. The results of lipophilicity studies collectively suggest that logP would be a rate-limiting factor for the anti-Toxoplasma activity of this class of compounds.


Assuntos
Semicarbazidas/síntese química , Relação Estrutura-Atividade , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Animais , Halogênios/química , Humanos , Imidazóis/química , Imidazóis/farmacologia , Semicarbazidas/química , Sulfadiazina/farmacologia , Toxoplasma/patogenicidade , Toxoplasmose/parasitologia
20.
Molecules ; 24(6)2019 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-30884874

RESUMO

Biofilm, naturally formed by microorganisms as integrated surface-bound communities, is one of the reasons for the development of antimicrobial resistance. Haemophilus spp. are common and representative opportunistic Gram-negative rods forming from the upper respiratory tract microbiota. The aim of this paper was to evaluate the influence of thiazolidine-2,4-dionebased azolidine and chlorophenylthiosemicarbazone hybrids against both planktonic and biofilm-forming Haemophilus spp. cells. The in vitro activity against planktonic and biofilm-forming cells of the tested compounds were evaluated by using the broth microdilution method. These activities were detected against reference and clinical strains of Haemophilus spp. on the basis of MICs (minimal inhibitory concentrations) and MBICs (minimal biofilm inhibitory concentrations). In addition, anti-adhesive properties of these compounds were examined. The target compounds showed potential activity against planktonic cells with MIC = 62.5⁻500 mg/L and biofilm-forming cells with MBIC = 62.5⁻1000 mg/L. The observed anti-adhesive properties of the tested compounds were reversible during long-term incubation in a lower concentration of compounds.


Assuntos
Antibacterianos/química , Biofilmes/efeitos dos fármacos , Haemophilus/efeitos dos fármacos , Tiossemicarbazonas/química , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/patogenicidade , Haemophilus/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Plâncton/efeitos dos fármacos , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Tiossemicarbazonas/farmacologia
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