Antileishmanial activity of sulphonamide nanoemulsions targeting theβ-carbonic anhydrase fromLeishmaniaspecies

Abstract

The β-carbonic anhydrase (CA, EC 4.2.1.1) from Leishmania spp. (LdcCA) is effectively inhibited by aromatic/heterocyclic sulphonamides, in the low nanomolar range, but no in vitro antileishmanial activity was detected for such compounds. We formulated some of these sulphonamides as nanoemulsions (NEs) in clove oil, and tested them in vitro against Leishmania infantum MHOM/BR/1974/PP75 and Leishmania amazonensis IFLA/BR/1967/PH8 strains. Interesting inhibitory concentrations IC50 were observed for some of the sulphonamides NEs, with IC50 as low as 3.90 µM (NE-3F) and 2.24 µM (NE-5B) for L. amazonensis and 3.47 µM (NE-5B) for L. infantum. Some of the investigated NEs displayed toxicity for macrophages beyond the parasites. For the same nonoemulsions, a selective index (SI) greater than for Amphotericin B. Haemolytic assay using human red blood cells indicate that the NEs were less cytotoxic than amphotericin B, a widely used antifungal agent. NEs demonstrated to be an excellent strategy for increasing the penetration of these hydrophilic drugs through membranes, with a huge increase of efficacy over the sulphonamide CA inhibitor (CAI) alone.

Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome

“…Inhibitors such as chalcones that block the activity of these trypanosomatid enzymes may be effective in treatment of leishmaniasis [29]. β-carbonic anhydrase [30], acid phosphatases [31], uracil DNA glycosylase [32] and Type 2 NADH dehydrogenase [33] are other potential therapeutic targets that are being explored. NLR (NOD-Like Receptor) family member NOD2 has also been implicated as an essential therapeutic target [34].…”

“…Recently, antileishmanial activity of sulphonamide nanoemulsions have been reported that target the leishmanial β-carbonic anhydrase [30]. Linalool-loaded gold nanoparticles have also been found to exhibit therapeutic effectiveness against Leishmania [49].…”

Cloning, Characterization and Anion Inhibition Studies of a β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica

“…The physiological relevance of β-CAs in many organisms, including protozoans belonging to the Amoebozoas, is yet to be discovered. However, in Leishmania spp., a β-class CA enzyme (LdcCA) was recently shown to be a potential drug target [19,20,21]. Indeed, the inhibition of protozoan β-CAs with sulfonamides, formulated as nanoemulsions, had a profound effect on the survival and growth of L. amazonensis and L. infantum , two species which provoke serious disease in the tropical and subtropical countries [21].…”

Sulfonamide Inhibition Studies of a New β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica

“…Recently, we have shown that the inhibition of the α- or β-CAs from the pathogenic protozoans Trypanosoma cruzi [28] or Leishmania spp. [29] has a potent anti-protozoan effect, with the possibility to inhibit the growth of the pathogen. Considering that the genome of E. histolytica has been published [30], we decided to investigate in detail whether the β-CA present in this pathogenic protozoan may have a similar role to the enzymes investigated earlier in other pathogenic protozoans [28,29].…”

“…[29] has a potent anti-protozoan effect, with the possibility to inhibit the growth of the pathogen. Considering that the genome of E. histolytica has been published [30], we decided to investigate in detail whether the β-CA present in this pathogenic protozoan may have a similar role to the enzymes investigated earlier in other pathogenic protozoans [28,29]. Here we report an investigation of the catalytic activity and the sulfonamide/sulfamate inhibition profile of the recombinant enzyme belonging to the β-class, identified in the genome of the pathogenic protozoan E. histolytica , denominated EhiCA.…”