Trypanocidal Activity of Melamine-Based Nitroheterocycles

Abstract

A series of nitroheterocyclic compounds were designed with linkages to melamine or benzamidine groups that are known substrates of the P2 aminopurine and other transporters in African trypanosomes of the brucei group. Several compounds showed in vitro trypanotoxicity with 50% inhibitory concentrations in the submicromolar range. Although most compounds interacted with the P2 transporter, as judged by their ability to inhibit adenosine transport via this carrier, uptake through this route was not necessary for activity since TbAT1-null mutant parasites, deficient in this transporter, retained sensitivity to these drugs. One compound, a melamine-linked nitrofuran, also showed pronounced activity against parasites in mice. Studies into the mode of action of this compound indicated that neither reductive, nor oxidative, stress were related to its trypanocidal activity ruling out a genotoxic effect in T. brucei, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles.

Interaction of Monobenzamidine-Linked Trypanocides with the Trypanosoma brucei P2 Aminopurine Transporter

“…The ability of these compounds to interact with the P2 transporter was assessed using the well-established oil-stop method to measure tritiated adenosine (0.05 M) uptake via that transporter in the presence of a range of concentrations (0.1 mM to 100 nM) of each inhibitor. In general the compounds were found to have high affinities for the P2 transporter (Table 1), of the same magnitude as the transporter's natural substrate adenosine, and generally around an order of magnitude higher than the affinities of a series of novel melamine-carrying compounds (1,14,18,19). This could indicate a structural preference for the benzamidine group in P2 interactions, and, this being the case, future compounds developed as potential P2- selective trypanocides could benefit from carrying a benzamidine residue.…”

Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

“…We previously reported (11,17) that the melamine nitrofuran WSP934 has very potent activity against T. brucei rhodesiense STIB 900, with a 50% effective concentration (EC 50 ) of about 11 nM, which is around the same order as that of melarsoprol (6 nM), a currently licensed drug. For comparison, the EC 50 of nifurtimox is 1.5 M. This compound is a nitrofuran registered for use against Chagas' disease and, in combination with eflornithine, to treat human African trypanosomiasis (2).…”

“…One of these molecules, our initial lead, WSP934 ( Fig. 1) (compound 3a in Stewart et al [17]), was found to be curative of a rodent model of HAT (11,12,17).…”

“…This led to some very potent molecules. We have described the design process and data in previous publications (11,12,17). One of these molecules, our initial lead, WSP934 ( Fig.…”

Quimioterapia da doença de Chagas: estado da arte e perspectivas no desenvolvimento de novos fármacos

“…73 A estratégia empregada neste trabalho envolveu o acoplamento do grupo melamina (fração de reconhecimento estrutural P2) a nitro-heterocíclicos, levando em consideração alguns requerimentos importantes para a absorção através do transportador P2, incluindo um grupo amidino, um anel aromático e um heteroátomo eletronegativo. Entre as características estruturais marcantes do composto líder da série (53), 74 pode-se destacar a presença de um grupo nitro, um fragmento triazina contendo o sistema amidínico, dois aneis aromáticos, heteroátomos e a presença da função hidrazona na fusão dos fragmentos de triazina e do anel contendo o grupo nitro, como pode ser observado na Figura 13.…”