دورية أكاديمية
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi.
| العنوان: | Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi. |
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| المؤلفون: | Simões-Silva MR; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., Nefertiti AS; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., De Araújo JS; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., Batista MM; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., Da Silva PB; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., Bahia MT; Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil., Menna-Barreto RS; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., Pavão BP; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., Green J; Department of Chemistry, Georgia State University, Atlanta, Georgia, USA., Farahat AA; Department of Chemistry, Georgia State University, Atlanta, Georgia, USA Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Kumar A; Department of Chemistry, Georgia State University, Atlanta, Georgia, USA., Boykin DW; Department of Chemistry, Georgia State University, Atlanta, Georgia, USA., Soeiro MN; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil soeiro@ioc.fiocruz.br. |
| المصدر: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2016 Jul 22; Vol. 60 (8), pp. 4701-7. Date of Electronic Publication: 2016 Jul 22 (Print Publication: 2016). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Society for Microbiology |
| مواضيع طبية MeSH: | Amidines/*pharmacology , Trypanocidal Agents/*pharmacology , Trypanosoma cruzi/*drug effects, Animals ; Cell Line ; Cell Nucleus/drug effects ; Cell Nucleus/parasitology ; Chagas Disease/drug therapy ; Chagas Disease/parasitology ; Cytoplasm/drug effects ; Cytoplasm/parasitology ; Mammals/parasitology ; Parasitic Sensitivity Tests/methods ; Phenotype |
| مستخلص: | The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono- and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC50] = 0.23 μM; selectivity index = 417), which was 28-fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations < 4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC50 = 0.87 ± 0.05 μM) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles (β-cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD. (Copyright © 2016, American Society for Microbiology. All Rights Reserved.) |
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| معلومات مُعتمدة: | R01 AI064200 United States AI NIAID NIH HHS |
| المشرفين على المادة: | 0 (Amidines) 0 (Trypanocidal Agents) |
| تواريخ الأحداث: | Date Created: 20160525 Date Completed: 20170912 Latest Revision: 20181113 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC4958229 |
| DOI: | 10.1128/AAC.01788-15 |
| PMID: | 27216059 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-6596 |
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| DOI: | 10.1128/AAC.01788-15 |