ABSTRACT
In the present work, thirty-two hybrid compounds containing cycloalka[b]thiophene and indole moieties (TN5, TN5 1-7, TN6, TN6 1-7, TN7, TN7 1-7, TN8, TN8 1-7) were designed, synthesized and evaluated for their cytotoxic and antileishmanial activity against Leishmania amazonensis promastigotes. More than half of the compounds (18 compounds) exhibited significant antileishmanial activity (IC50 lower than 10.0µg/L), showing better performance than the reference drugs (tri- and penta-valent antimonials). The most active compounds were TN8-7, TN6-1 and TN7 with respective IC50 values of 2.1, 2.3 and 3.2µg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400µg/mL), no compound tested presented human erythrocyte cytotoxicity. Compound TN8-7's effectiveness against a trivalent antimony-resistant culture was demonstrated. It was observed that TN8-7's antileishmanial activity is associated with DNA fragmentation of L. amazonensis promastigotes. Chemometric studies (CPCA, PCA, and PLS) highlight intrinsic solubility/lipophilicity, and compound size and shape as closely related to activity. Our results suggest that hybrid cycloalka[b]thiophene-indole derivatives may be considered as lead compounds for further development of new drugs for the treatment of leishmaniasis.
Subject(s)
Antiprotozoal Agents/pharmacology , Indoles/pharmacology , Leishmania mexicana/drug effects , Thiophenes/pharmacology , Antiprotozoal Agents/chemistry , DNA Fragmentation/drug effects , Drug Discovery , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Leishmania mexicana/genetics , Leishmaniasis, Cutaneous/drug therapy , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
A toxoplasmose é considerada uma doença parasitária fatal em primatas neotropicais. O objetivo deste trabalho foi descrever, através de um estudo retrospectivo, os casos de toxoplasmose em primatas neotropicais. No período de 1999-2009 foram realizados 86 exames anatomopatológicos em primatas e a toxoplasmose foi a enfermidade mais comum (7/86), relatando-se um caso em sagui-do-tufo-preto (Callithrix penicillata) e seis em bugio-ruivo (Alouatta guariba). Dois animais foram encontrados mortos e cinco morreram em poucos dias. Os sinais clínicos mais frequentes foram apatia e anorexia (5/7), distensão abdominal (4/7) e febre (3/7). Na necropsia observou-se esplenomegalia (4/7), hemorragia do trato digestório, linfonodos e bexiga (4/7), pulmões avermelhados (3/7) e hepatomegalia (2/7). No exame histopatológico evidenciou-se hepatite (7/7), esplenite (3/7), miocardite (2/7), enterite (2/7), linfadenite (1/7) e sialite (1/7) necróticas e, pneumonia intersticial (4/7). Em fígado, pulmões, baço, coração, linfonodos e glândula salivar havia taquizoítos de Toxoplasma gondii que foram também detectados pelo exame de imuno-histoquímica anti-T. gondii em fígado, baço e pulmões (5/7). A toxoplasmose pode causar alta mortalidade em colônias de primatas neotropicais e representar mais uma ameaça à conversação dessas espécies em cativeiro. Sendo assim, medidas preventivas devem ser tomadas para evitar a contaminação desses animais.
Toxoplasmosis is considered to be a fatal parasitic disease in New World primates. The objective of this report was to describe, through a retrospective study, the toxoplasmosis cases in New World primates. From 1999 to 2009 eighty-six anatomopathological exams was performed in primates and toxoplasmosis was the most common disease (7/86). One case occurred in Black-Tufted-Marmoset (Callithrix penicillata) and six in Brown-Howler monkeys (Alouatta guariba). Two monkeys were found death and five died within few days. The most common clinical signs were apathy and anorexia (5/7), abdominal distension (4/7) and fever (3/7). The main gross lesions were splenomegaly (4/7), hemorrhage in digestory system, lymph nodes and urinary bladder (4/7), reddish lungs (3/7) and hepatomegaly (2/7). Histopathological findings were necrotizing hepatitis (7/7), splenitis (3/7), myocarditis (2/7), enteritis (2/7), lymphadenitis (1/7) and sialitis (1/7), and interstitial pneumonia (4/7). In the liver, lungs, spleen, heart, lymph nodes and salivary gland there were tachyzoites of Toxoplasma gondii that also detected by immunohistochemistry against T. gondii in liver, spleen and lungs (5/7). Toxoplasmosis can cause high mortality in New World primate colonies and can be a threat to preservation of those species in captivity. Therefore, preventive measures should be taken to avoid the contamination of those animals.
