Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies
| Autor: | Denise da Gama Jaen Batista, Alicia Gómez-Barrio, José Antonio Escario, Vicente J. Arán, Cristiane França da Silva, Maria de Nazaré Correia Soeiro, Raiza Brandão Peres, Gabriel Melo de Oliveira, A. S. G. Nefertiti, José Cumella, Marcos Meuser Batista, Cristina Fonseca-Berzal |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Ministerio de Ciencia, Innovación y Universidades (España) |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Chagas disease 030231 tropical medicine Pharmacology 03 medical and health sciences 0302 clinical medicine In vitro In vivo medicine Chemotherapy Trypanosoma cruzi Amastigote biology 5-nitroindazole biology.organism_classification medicine.disease Acute toxicity 030104 developmental biology Infectious Diseases Benznidazole Toxicity Animal Science and Zoology Parasitology medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1469-8161 0031-1820 2015-6669 |
| Popis: | In previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug. This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness(MINEICO,ref.SAF2015-66690-R), the National Council for Scientific and Technological Development of Brazil (CNPq, ref. 301372/2015-2) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ,ref. E02/2017). The 911120 UCM-CEI Moncloa Research Group‘Epidemiología, Diagnóstico y Terapia Antiparasitaria’and the Spanish Ministry of Science, Innovation and Universities (MICIU, ref.RTI-2018-093940-B-I00) are also acknowledged. M.N.C.S. is a research fellowof CNPq and CNE researcher. |
| Databáze: | OpenAIRE |
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