Antileishmanial Activities of Several Classes of Aromatic Dications

Abstract

Aromatic dicationic molecules possess impressive activity against a broad spectrum of microbial pathogens, including Pneumocystis carinii, Cryptosporidium parvum, and Candida albicans. In this work, 58 aromatic cations were examined for inhibitory activity against axenic amastigote-like Leishmania donovani parasites. In general, the most potent of the compounds were substituted diphenyl furan and thiophene dications. 2,5-Bis-(4-amidinophenyl)thiophene was the most active compound. This agent displayed a 50% inhibitory concentration (IC 50 ) of 0.42 ؎ 0.08 M against L. donovani and an in vitro antileishmanial potency 6.2-fold greater than that of the clinical antileishmanial dication pentamidine and was 155-fold more toxic to the parasites than to a mouse macrophage cell line. 2,4-Bis-(4-amidinopheny)furan was twice as active as pentamidine (IC 50 , 1.30 ؎ 0.21 M), while 2,5-bis-(4-amidinopheny)furan and pentamidine were essentially equipotent in our in vitro antileishmanial assay. Carbazoles, dibenzofurans, dibenzothiophenes, and benzimidazoles containing amidine or substituted amidine groups were generally less active than the diphenyl furans and thiophenes. In all cases, aromatic dications possessing strong antileishmanial activity were severalfold more toxic to the parasites than to a cultured mouse macrophage cell line. These structure-activity relationships demonstrate the potent antileishmanial activity of several aromatic dications and provide valuable information for the future design and synthesis of more potent antiparasitic agents.

Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

“…Comparison of the activity of EC with that of other compounds indicates the antileishmanial potential of the natural product tested. This activity seems superior to that observed for the antiulcer agent omeprazole against different leishmanial species (27), similar to that demonstrated for some naphthoquinones and ␥-pyrones (27,28), and inferior to that determined for aphidicolin derivatives, aromatic dications, some tetra-acridine complexes, and an essential oil from the leaves of Croton cajucara (4,15,29,43). The mechanism of killing is still a matter of debate; promastigote damage by EC was irreversible, suggesting fatal metabolic injury.…”

4-Amino Bis-Pyridinium Derivatives as Novel Antileishmanial Agents

“…Miltefosine was purchased from AEterna Zentaris (Frankfurt, Germany). Fluo4-AM, Pluronic F-127, Sytox green, bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC 4 (3)], Mitosox red, and JC-1 were purchased from Invitrogen (Carlsbad, CA). All the chemicals were of the highest quality available.…”

“…Pentamidine is actively transported into Leishmania promastigotes (1) and binds to nuclear and mitochondrial DNA (kinetoplasts), thereby hindering replication and transcription at the mitochondrial level (2). New diamidine and choline derivate dications have been developed recently in order to find new drugs with improved activity against leishmaniasis and lower toxicity (3)(4)(5)(6).…”

Principais métodos de síntese de amidinas

“…Como exemplo, temos a distamicina, extraída a partir de Streptomyces, que apresenta significante atividade antiviral 4 (Esquema 3). Na química medicinal, muitas substâncias contendo este grupo funcional têm apresentado atividade contra vários agentes patogênicos como Giardia lamblia 5 , Leishmania sp [6][7][8][9] , Pneumocystis carinii [10][11][12][13][14] , Candida albicans 15,16 , Cryptococcus neoformans 15,16 , 17 , Trypanosoma sp [18][19][20][21] , Cryptosporidium sp 22 , Acanthamoeba polyphaga 23 e Plasmodium sp 24 . Além disso, o grupo amidina está presente em diversos compostos com atividade antitrombótica [25][26][27][28] .…”