ABSTRACT
In the fight against malaria, chemotherapy using bisacridines may represent an alternative method to overcoming chloroquine-resistance. Eight bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties were linked by polyamines substituted with a side chain, were tested for their in-vivo activity upon mice infected by Plasmodium berghei. Three of the compounds revealed antimalarial activity but no relationship could be deduced from a comparison of in-vitro and in-vivo activities. N-alkylation of the central amino group generated toxicity and, therefore, only compounds N-acylated in this position can be selected as leads.
Subject(s)
Aminoacridines/pharmacology , Antimalarials/pharmacology , Plasmodium berghei/drug effects , Aminoacridines/therapeutic use , Animals , Antimalarials/chemistry , Antimalarials/therapeutic use , Chloroquine/pharmacology , Chloroquine/therapeutic use , Female , Malaria/drug therapy , Malaria/parasitology , MiceABSTRACT
Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of enhanced bulkiness and rigidity on both their activity on strains of Plasmodium falciparum expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward mammalian cells. While cyclization yielded molecules of greater rigidity that were not more active than their linear counterparts, they were characterized by an absence of cytotoxicity. Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for CQ-resistant strains and noncytotoxic.
Subject(s)
Antimalarials/chemical synthesis , Quinolines/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antimalarials/toxicity , Cells, Cultured , Chloroquine/pharmacology , Drug Resistance , Humans , Macrophages, Peritoneal/drug effects , Mice , Plasmodium falciparum/drug effects , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/toxicityABSTRACT
Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 microM upon MRC-5 cells, one displayed IC(50) values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 microM.
