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11.
Lorraine Martins Rocha Orlando Guilherme Curty Lechuga Leonardo da Silva Lara Byanca Silva Ferreira Cynthia Nathalia Pereira Rafaela Corrêa Silva Maurício Silva dos Santos Mirian Claudia S. Pereira 《Molecules (Basel, Switzerland)》2021,26(21)
Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure–activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies. 相似文献
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Kevin J. Weiland Nathalia Münch Wanja Gschwind Daniel Hussinger Marcel Mayor 《Helvetica chimica acta》2019,102(1)
A macrocyclic oligothiophene with an integrated pseudo‐para substituted [2.2]paracyclophane has been achieved. The synthetic sequence relies on alternating steps of halogenation‐ and Suzuki‐coupling conditions. By employing a modified Eglinton reaction under high dilution conditions, the macrocycle is closed and the obtained diacetylene is efficiently transferred to the corresponding thiophene. The molecule is fully characterized and its dynamic racemization is analyzed by variable temperature NMR experiments. The racemization barrier hints with 38 kJ/mol at rapid enantiomerization at room temperature by Mislow’s ‘Euclidian rubber glove’ enantiomerization process. Macrocycle formation results in red‐shifted absorption and emission spectra, hinting at increased conjugation through the oligothiophene versus the trough space conjugation through the [2.2]paracyclophane. 相似文献
14.
Estevo Silveira Grams Alessandro Silva Ramos Mauro Neves Muniz Raoní S. Rambo Marcia Alberton Perell Nathalia Sperotto Laura Calle Gonzlez Lovaine Silva Duarte Luiza Galina Adilio Silva Dadda Guilherme Arrach Gonalves Cristiano Valim Bizarro Luiz Augusto Basso Pablo Machado 《Molecules (Basel, Switzerland)》2022,27(8)
Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment. 相似文献
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da Silva Ronivaldo Rodrigues da Rosa Nathalia Gonsales de Oliveira Lilian Caroline Gonçalves Juliano Maria Aparecida Juliano Luiz Rosa Jose C. Cabral Hamilton 《Applied biochemistry and biotechnology》2019,187(4):1158-1172
Applied Biochemistry and Biotechnology - The fungal genus Pyrenochaetopsis has received particular attention because of its different lifestyles, such as numerous plant pathogenic, saprophytic, and... 相似文献
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Pavel N. D'Yachkov Nina V. Kharchevnikova Zoya I. Zholdakova Nathalia Fjodorova Mariana Novich Marian Vrachko 《International journal of quantum chemistry》2010,110(7):1402-1411
Using an oxenoid model, we investigated dependences of carcinogenic potency of the benzenes C6H5‐X on a nature of substituents X. According to the model, a P450 enzyme breaks a dioxygen molecule and generates the oxens, which readily react with substrates. We suggest that a stability of the intermediate OC6H6‐X with tetrahedrally coordinated C atom relative to the molecule C6H5‐X determines a rate of substrate biotransformation. Using MO LCAO MNDO approach, we calculated the total energies of molecules C6H6‐X and arene oxides OC6H6‐X. A difference ΔEmin of these values determines activation energy of oxidation reaction. The compounds with the low ΔEmin values are noncarcinogenic. Benzene derivatives with high ΔEmin values belong to carcinogenic compounds series. The carcinogenicity of amino‐ and nitro‐substituted benzenes is also determined by N‐oxidation of amino and reduction of the nitro group. As the phenylhydroxylamines XC6H4NHOH and nitrenium ions XC6OH4NH+ are the common metabolites of the nitro‐ and amino‐substituted benzenes and nitrenium ions XC6H4NH+ are the ultimate carcinogens, we use the differences ΔEN = E(XC6H4NH+) ? E(XC6H4NHOH) as the second parameter characterizing the carcinogenic activity of amino‐ and nitro‐substituted benzenes. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 相似文献
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Nathalia I. Larionova Stepan S. Vartanov Nadezhda V. Sorokina Inna P. Gladysheva Sergey D. Varfolomeyev 《Applied biochemistry and biotechnology》1997,62(2-3):175-182
The classical Bowman-Birk soybean proteinase inhibitor was modified by hydroxyethylstarch. The modified inhibitor retained
the capacity for simultaneous binding of trypsin and human leukocyte elastase. The inhibition constants,K
i
, of bovine trypsin,α-chymotrypsin and human leukocyte elastase (HLE) increased not more than 10-, 1.5-, and 20-fold, respectively, on modification
of the inhibitor. The less effective inhibition is presumably due to the steric hindrance brought about by the conjugation
with polysaccharide molecules. The results obtained indicate the pronounced structure differences of the binding regions for
trypsin and chymotrypsin/leukocyte elastase in the modified preparation. 相似文献
18.
Janaína M. Santos Nathalia M. Cury José A. Yunes Jorge A. López 《Natural product research》2019,33(11):1633-1636
Anacardium occidentale leaves are used in folk medicine due its therapeutic properties attributed to phenolic compounds. Therefore, this study was undertaken on its hydroethanolic leaf extract (AoHE) to evaluate cytotoxicity and apoptosis induction on acute lymphoblastic leukaemia cells. Results indicated that AoHE interfered in the cell cycle progression, inducing apoptosis by activation of casp3 at lower concentrations, thence, a promising candidate for the development of new cancer drugs. 相似文献
19.
Fabiana Fuentes-León Andressa Peres de Oliveira Nathalia Quintero-Ruiz Veridiana Munford Gustavo Satoru Kajitani Antônio Coimbra Brum André Passaglia Schuch Pio Colepicolo Angel Sánchez-Lamar Carlos Frederico Martins Menck 《Photochemistry and photobiology》2020,96(6):1215-1220
Sunlight ultraviolet (UV) radiation constitutes an important environmental genotoxic agent that organisms are exposed to, as it can damage DNA directly, generating pyrimidine dimers, and indirectly, generating oxidized bases and single-strand breaks (SSBs). These lesions can lead to mutations, triggering skin and eye disorders, including carcinogenesis and photoaging. Stratospheric ozone layer depletion, particularly in the Antarctic continent, predicts an uncertain scenario of UV incidence on the Earth in the next decades. This research evaluates the DNA damage caused by environmental exposure to late spring sunlight in the Antarctic Peninsula, where the ozone layer hole is more pronounced. These experiments were performed at the Brazilian Comandante Ferraz Antarctic Station, at King’s George Island, South Shetlands Islands. For comparison, tropical regions were also analyzed. Samples of plasmid DNA were exposed to sunlight. Cyclobutane pyrimidine dimers (CPDs), oxidized base damage and SSBs were detected using specific enzymes. In addition, an immunological approach was used to detect CPDs. The results reveal high levels of DNA damage induced by exposure under the Antarctic sunlight, inversely correlated with ozone layer thickness, confirming the high impact of ozone layer depletion on the DNA damaging action of sunlight in Antarctica. 相似文献