Abstract
Sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors targeting the α-class enzyme from the protozoan pathogen Trypanosoma cruzi, responsible of Chagas disease, were recently reported. Although many such derivatives showed low nanomolar activity in vitro, they were inefficient anti-T. cruzi agents in vivo. Here, we show that by formulating such sulfonamides as nanoemulsions in clove (Eugenia caryophyllus) oil, highly efficient anti-protozoan effects are observed against two different strains of T. cruzi. These effects are probably due to an enhanced permeation of the enzyme inhibitor through the nanoemulsion formulation, interfering in this way with the life cycle of the pathogen either by inhibiting pH regulation or carboxylating reactions in which bicarbonate/CO2 are involved. This type of formulation of sulfonamides with T. cruzi CA inhibitory effects may lead to novel therapeutic approaches against this orphan disease.
Highlights
Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in regions of Central and South America
RAW 264.7 macrophages were obtained from the National Institute of Metrology, Quality and Technology (Instituto Nacional de Metrologia, Qualidade e Tecnologia, INMETRO) and maintained in Dulbecco’s modified Eagle’s medium (DMEM) medium supplemented with 10% Fetal bovine serum (FBS) at 37 C in a 5% controlled CO2 atmosphere
The evaluation of NEs antiprotozoal activity was performed by successive microdilutions in 96 well plates (1.8 Â 106 parasites/well) NEs in the PHBIL medium supplemented with 10% FBS in the following concentrations: 128, 64, 32, 16, 8, 4, 2, and 1 lM
Summary
Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in regions of Central and South America. Some heterocyclic thiols[20] and hydroxamates[26,27] did show in vivo efficacy as anti-T. cruzi agents (and they acted as efficient in vitro TcCA inhibitors)[24–28], and we considered that this might be due to the lack of permeability of the sulfonamides through the biological membranes of the protozoan. This is the reason why we decided to investigate the formulation of such sulfonamides, highly effective as TcCA inhibitors in NEs, in order to enhance their bioavailability and penetrability through membranes. We report that sulfonamide TcCA inhibitors formulated as NEs in clove oil, potently inhibit the growth of T. cruzi ex vivo, showing a potential as a novel class of antitrypanosomal drugs
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