Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2012 |
| Outros Autores: | , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/15967 |
Resumo: | The Ohio State University. College of Pharmacy. Division of Medicinal Chemistry and Pharmacognosy. Columbus, Ohio, USA. |
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Zhu, XiaohuaLiu, QiangYang, SihyungParman, ToufanGreen, Carol E.Mirsalis, Jon C.Soeiro, Maria de Nazaré CorreiaSouza, Elen Mello deSilva, Cristiane França daBatista, Denise da Gama JaenStephens, Chad E.Banerjee, MoloyFarahat, Abdelbasset A.Munde, ManojWilson, W. DavidBoykin, David W.Wang, Michael ZhuoWerbovetz, Karl A.2016-09-27T14:52:39Z2016-09-27T14:52:39Z2012ZHU, Xiaohua; et al. Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies. Antimicrobial Agents and Chemotherapy, v.56, n.7, p.3690-3699, July 2012.0066-4804https://www.arca.fiocruz.br/handle/icict/1596710.1128/AAC.06404-111098-6596engAmerican Society for MicrobiologyDoença de ChagasLeishmaniose visceralEstudos roxicológicosArylimidamidesArylimidamidesChagas DiseaseVisceral LeishmaniasisToxicology StudiesEvaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studiesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleThe Ohio State University. College of Pharmacy. Division of Medicinal Chemistry and Pharmacognosy. Columbus, Ohio, USA.The University of North Carolina at Chapel Hill. Eshelman School of Pharmacy. Chapel Hill, North Carolina, USA,SRI International. Menlo Park, California, USA.SRI International. Menlo Park, California, USA.SRI International. Menlo Park, California, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Augusta State University. Department of Chemistry and Physics. Augusta, Georgia, USA.Georgia State University. Department of Chemistry. Atlanta, Georgia, USA.Georgia State University. Department of Chemistry. Atlanta, Georgia, USA / Mansoura University. Faculty of Pharmacy. Department of Pharmaceutical Organic Chemistry. Mansoura, Egypt.Georgia State University. Department of Chemistry. Atlanta, Georgia, USA.Georgia State University. Department of Chemistry. Atlanta, Georgia, USA.Georgia State University. Department of Chemistry. Atlanta, Georgia, USAThe University of North Carolina at Chapel Hill. Eshelman School of Pharmacy. Chapel Hill, North Carolina, USA,The Ohio State University. College of Pharmacy. Division of Medicinal Chemistry and Pharmacognosy. Columbus, Ohio, USA.Arylimidamides (AIAs) have shown outstanding in vitro potency against intracellular kinetoplastid parasites, and the AIA 2,5- bis[2-(2-propoxy)-4-(2-pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good in vivo efficacy in rodent models of visceral leishmaniasis (VL) and Chagas’ disease. In an attempt to further increase the solubility and in vivo antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4- (2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murine Trypanosoma cruzi infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/15967/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALelen_souza_etal_IOC_2012.pdfelen_souza_etal_IOC_2012.pdfapplication/pdf891815https://www.arca.fiocruz.br/bitstream/icict/15967/2/elen_souza_etal_IOC_2012.pdf4644ea8f751e8547e0b7b994dd7b28b4MD52TEXTelen_souza_etal_IOC_2012.pdf.txtelen_souza_etal_IOC_2012.pdf.txtExtracted texttext/plain54139https://www.arca.fiocruz.br/bitstream/icict/15967/3/elen_souza_etal_IOC_2012.pdf.txt60e1c71d36f11dbe67e58b17c35b6192MD53icict/159672018-04-02 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| dc.title.pt_BR.fl_str_mv |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies |
| title |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies |
| spellingShingle |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies Zhu, Xiaohua Doença de Chagas Leishmaniose visceral Estudos roxicológicos Arylimidamides Arylimidamides Chagas Disease Visceral Leishmaniasis Toxicology Studies |
| title_short |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies |
| title_full |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies |
| title_fullStr |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies |
| title_full_unstemmed |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies |
| title_sort |
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies |
| author |
Zhu, Xiaohua |
| author_facet |
Zhu, Xiaohua Liu, Qiang Yang, Sihyung Parman, Toufan Green, Carol E. Mirsalis, Jon C. Soeiro, Maria de Nazaré Correia Souza, Elen Mello de Silva, Cristiane França da Batista, Denise da Gama Jaen Stephens, Chad E. Banerjee, Moloy Farahat, Abdelbasset A. Munde, Manoj Wilson, W. David Boykin, David W. Wang, Michael Zhuo Werbovetz, Karl A. |
| author_role |
author |
| author2 |
Liu, Qiang Yang, Sihyung Parman, Toufan Green, Carol E. Mirsalis, Jon C. Soeiro, Maria de Nazaré Correia Souza, Elen Mello de Silva, Cristiane França da Batista, Denise da Gama Jaen Stephens, Chad E. Banerjee, Moloy Farahat, Abdelbasset A. Munde, Manoj Wilson, W. David Boykin, David W. Wang, Michael Zhuo Werbovetz, Karl A. |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Zhu, Xiaohua Liu, Qiang Yang, Sihyung Parman, Toufan Green, Carol E. Mirsalis, Jon C. Soeiro, Maria de Nazaré Correia Souza, Elen Mello de Silva, Cristiane França da Batista, Denise da Gama Jaen Stephens, Chad E. Banerjee, Moloy Farahat, Abdelbasset A. Munde, Manoj Wilson, W. David Boykin, David W. Wang, Michael Zhuo Werbovetz, Karl A. |
| dc.subject.other.pt_BR.fl_str_mv |
Doença de Chagas Leishmaniose visceral Estudos roxicológicos Arylimidamides |
| topic |
Doença de Chagas Leishmaniose visceral Estudos roxicológicos Arylimidamides Arylimidamides Chagas Disease Visceral Leishmaniasis Toxicology Studies |
| dc.subject.en.pt_BR.fl_str_mv |
Arylimidamides Chagas Disease Visceral Leishmaniasis Toxicology Studies |
| description |
The Ohio State University. College of Pharmacy. Division of Medicinal Chemistry and Pharmacognosy. Columbus, Ohio, USA. |
| publishDate |
2012 |
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2012 |
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2016-09-27T14:52:39Z |
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2016-09-27T14:52:39Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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ZHU, Xiaohua; et al. Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies. Antimicrobial Agents and Chemotherapy, v.56, n.7, p.3690-3699, July 2012. |
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https://www.arca.fiocruz.br/handle/icict/15967 |
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0066-4804 |
| dc.identifier.doi.none.fl_str_mv |
10.1128/AAC.06404-11 |
| dc.identifier.eissn.none.fl_str_mv |
1098-6596 |
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ZHU, Xiaohua; et al. Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas’ Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies. Antimicrobial Agents and Chemotherapy, v.56, n.7, p.3690-3699, July 2012. 0066-4804 10.1128/AAC.06404-11 1098-6596 |
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American Society for Microbiology |
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American Society for Microbiology |
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