RESUMO
No vaccines or safe chemotherapy are available for Chagas disease. Pentamidine and related di-cations are DNA minor groove-binders with broad-spectrum anti-protozoal activity. Therefore our aim was to evaluate the in vitro efficacy of di-cationic compounds - DB1645, DB1582, DB1651, DB1646, DB1670 and DB1627 - against bloodstream trypomastigotes (BT) and intracellular forms of Trypanosoma cruzi. Cellular targets of these compounds in treated parasites were also analysed by fluorescence and transmission electron microscopy (TEM). DB1645, DB1582 and DB1651 were the most active against BT showing IC50 values ranging between 0.15 and 6.9 microm. All compounds displayed low toxicity towards mammalian cells and DB1645, DB1582 and DB1651 were also the most effective against intracellular parasites, with IC50 values ranging between 7.3 and 13.3 microm. All compounds localized in parasite nuclei and kDNA (with greater intensity in the latter structure), and DB1582 and DB1651 also concentrated in non-DNA-containing cytoplasmic organelles possibly acidocalcisomes. TEM revealed alterations in mitochondria and kinetoplasts, as well as important disorganization of microtubules. Our data provide further information regarding the activity of this class of compounds upon T. cruzi which should aid future design and synthesis of agents that could be used for Chagas disease therapy.
Assuntos
Amidinas/farmacologia , Antiprotozoários/farmacologia , Núcleo Celular/metabolismo , DNA de Cinetoplasto/metabolismo , Frações Subcelulares/metabolismo , Trypanosoma cruzi/efeitos dos fármacos , Amidinas/química , Animais , Antiprotozoários/química , Doença de Chagas/tratamento farmacológico , Citoplasma/metabolismo , Citoplasma/ultraestrutura , DNA de Cinetoplasto/genética , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Organelas/metabolismo , Testes de Sensibilidade Parasitária/métodos , Trypanosoma cruzi/fisiologia , Trypanosoma cruzi/ultraestruturaRESUMO
Synthesis of bisfunctionalized unsymmetrical 2,2'-bipyridines 8 or their sulfonyl derivatives 12a,b are described. They were prepared via the Diels-Alder reaction of 1-methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (6) with 3,3'-bis(methyl- sulfanyl)-5,5'-bi-1,2,4-triazine (1). The reaction leads to the single cycloaddition product 7 which undergoes Diels-Alder reaction with cyclic enamines 2a,b to give unsymmetrical 2,2'-bipyridine derivatives 8, consisting of the two different heterocyclic units: cycloalkeno[c]pyridine and 2,6-naphthyridine.
