Evaluation of the anti-Leishmania effect of mesoionic derivatives of 1,3,4 thiadiazolium on L.amazonensis in vitro

Autor: Rosa, Alice dos Santos
Přispěvatelé: Silva, Lucia Helena Pinto da, Rodrigues, Juliany Cola Fernandes, Santos, Eduardo Caio Torres dos
Jazyk: portugalština
Rok vydání: 2020
Předmět:
Zdroj: Biblioteca Digital de Teses e Dissertações da UFRRJ
Universidade Federal Rural do Rio de Janeiro (UFRRJ)
instacron:UFRRJ
Popis: Submitted by Celso Magalhaes (celsomagalhaes@ufrrj.br) on 2022-09-05T12:23:26Z No. of bitstreams: 1 2020 - Alice dos Santos Rosa.pdf: 2142627 bytes, checksum: 7c6e34554a8391000ea88af07e07d806 (MD5) Made available in DSpace on 2022-09-05T12:23:26Z (GMT). No. of bitstreams: 1 2020 - Alice dos Santos Rosa.pdf: 2142627 bytes, checksum: 7c6e34554a8391000ea88af07e07d806 (MD5) Previous issue date: 2020-03-30 CNPq - Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico CAPES - Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior Leishmaniasis is a group of diseases which affect millions of people annually around world mainly in the population in economic vulnerability, for this reason, this disease is part of a group of neglected diseases. Leishmaniasis is caused by protozoa of the Leishmania genus and transmitted to several mammals, including the man and domestic dog, by diptera belonging to the Lutzomyia and Phlebotomus genus. Its clinical manifestations vary according to the species of infected mammal, presenting in humans a broad clinical spectrum, and visceral-cutaneous manifestations in the dog. Drugs used in treatment have high production costs and a high toxicity, presents several side effects. In addition, in endemic countries, resistant strains have been reported. Therefore, the search for new bioactive molecules is necessary. Mesoionic salts are a subclass of the betaine group, widely studied by the pharmaceutical industry since the 1950s, and exhibit extensive biological activity. Our work aims to analyze the cytotoxic effects of three mesoionic compounds, MI-4 Cl (4-phenyl-5- (4-chloro-phenyl) -1,3,4-thiadiazolium-2-phenylamine), MI-3,4 diCl (4-phenyl-5- (3,4-dichloro-phenyl) -1,3,4-thiadiazolium-2-phenylamine) and MI-3,4 diF (4-phenyl-5- (3,4-difluor-phenyl ) -1,3,4-thiadiazolium-2-phenylamine), on Leishmania amazonensis in vitro. To evaluate the anti-promastigote effect, L. amazonensis promastigotes were incubated with different concentrations of mesoionic salts during 72 hours. Our results show that the mesoionic salts MI-3.4 diCl, MI-4Cl and MI-3.4 diF were toxic, with IC50/48 h values of 14.3, 40.1 and 61.8 ?M, respectively. The anti-amastigote effect was evaluated in infected macrophages, and results demonstrate that chlorine compounds have a toxic effect against amastigotes present IC50/24 h of 33 ?M (MI-4Cl) and 43 ?M (MI-3.4diCl). None of the mesoionic compounds tested present host cell toxicity up to the tested concentration of 100 ?M. Nitric oxide (NO) production in macrophages stimulated or not with LPS in the presence of the salts showed that only the MI-3.4 diCl compound reduced 2 times the NO levels. Lipid profile analysis of treated-promastigotes showed no alteration of neutral lipids. Mitochondrial membrane potential evaluation showed that MI-4Cl compound was the only one able to reduce mitochondrial membrane potential by 50%. Therefore, the results suggest that the mesoionic salts MI-4Cl and MI-3,4diCl have a potential anti-Leishmania effect As leishmanioses s?o um conjunto de doen?as que afetam milh?es de pessoas anualmente no mundo, principalmente a popula??o em vulnerabilidade econ?mica, por tal raz?o essa enfermidade faz parte do grupo de doen?as negligenciadas. As leishmanioses s?o causadas pelo protozo?rio do g?nero Leishmania e transmitidas a diversos mam?feros, incluindo o homem e o c?o dom?stico, por d?pteros pertencentes aos g?neros Lutzomyia e Phlebotomus. Suas manifesta??es cl?nicas variam conforme a esp?cie de mam?fero infectado, apresentando em humanos um amplo espectro cl?nico, e no c?o, manifesta??es viscero-cut?neas. Os f?rmacos utilizados no tratamento dessa doen?a possuem elevado custo de produ??o e uma alta toxicidade, gerando diversos efeitos colaterais. Al?m disso, em pa?ses end?micos, t?m ocorrido o aparecimento de cepas resistentes. Por esses motivos, torna-se necess?rio a busca por novas mol?culas bioativas. Os sais mesoi?nicos s?o uma subclasse do grupo beta?na amplamente estudada pela ind?stria farmac?utica desde a d?cada de 50, que exibem extensa atividade biol?gica. Nosso trabalho tem por objetivo analisar os efeitos citot?xicos de tr?s compostos mesoi?nicos, MI-4 Cl (4-fenil-5-(4-cloro-fenil) -1,3,4-tiadiaz?lio-2-fenilamina), MI-3,4 diCl (4-fenil-5-(3,4-dicloro-fenil) -1,3,4-tiadiaz?lio-2-fenilamina) e MI-3,4 diF (4-fenil-5-(3,4-difluor-fenil) -1,3,4-tiadiaz?lio-2-fenilamina), sobre Leishmania amazonensis in vitro. Para avaliar o efeito anti-promastigotas, promastigotas de L.. amazonensis foram incubadas com diferentes concentra??es dos sais mesoi?nicos por at? 72 horas. Nossos resultados demonstram que os sais mesoi?nicos MI-3,4 diCl, MI-4Cl e MI-3,4 diF foram t?xicos, tendo valores de IC50/48 h de 14,3, 40,1 e 61,8 ?M, respectivamente. O efeito anti-amastigota foi avaliado em macr?fagos infectados e nossos resultados demonstram que os compostos clorados possuem efeito t?xico contra as amastigotas com IC50/24 h de 33 ?M (MI-4Cl) e 43 ?M (MI-3,4diCl). Nenhum dos compostos mesoi?nicos testados apresentam toxicidade para c?lula hospedeira at? a concentra??o testada de 100 ?M. A produ??o de ?xido n?trico (NO) em macr?fagos estimulados ou n?o com LPS na presen?a dos sais demonstrou que somente o composto MI-3,4 diCl reduziu os n?veis de NO em at? 2x. A an?lise do perfil lip?dico de promastigotas tratadas com os sais mesoi?nicos n?o mostrou altera??o na composi??o dos lip?dios neutros. A avalia??o do potencial de membrana mitocondrial, mostrou que somente o composto MI-4Cl foi capaz de reduzir o potencial de membrana mitocondrial em 50%. Portanto, os resultados sugerem que os sais mesoi?nicos MI-4Cl e MI-3,4diCl apresentam um potencial efeito anti-Leishmania
Databáze: OpenAIRE
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