Rodrigo L. O. R. Cunha

A novel organotellurium compound (RT-01) as a new antileishmanial agent.

Leishmaniasis is a neglected disease and endemic in developing countries. A lack of adequate and definitive chemotherapeutic agents to fight against this infection has led to the investigation of numerous compounds. The aim of this study was to investigate the effect of RT-01, an organotellurane compound presenting biological activities, in 2 experimental systems against Leishmania amazonensis. The in vitro system consisted of promastigotes and amastigotes forms of the parasite, and the in vivo system consisted of L. amazonensis infected BALB/c mice, an extremely susceptible mouse strain. The compound proved to be toxic against promastigotes and amastigotes. The study also showed that treatment with RT-01 produces an effect similar to that treatment with the reference antimonial drug, Glucantime, in L. amazonensis infected mice. The best results were obtained following RT-01 intralesional administration (720 microg/kg/day); mice showed significant delay in the development of cutaneous lesions and decreased numbers of parasites obtained from the lesions. Significant differences in tissue pathology consisted mainly of no expressive accumulation of inflammatory cells and well-preserved structures in the skin tissue of RT-01-treated mice compared with expressive infiltration of infected cells replacing the skin tissue in lesions of untreated mice. These findings highlight the fact that the apparent potency of organotellurane compounds, together with their relatively simple structure, may represent a new avenue for the development of novel drugs to combat parasitic diseases.

In Vitro and In Vivo Activity of an Organic Tellurium Compound on Leishmania (Leishmania) chagasi

Tellurium compounds have shown several biological properties and recently the leishmanicidal effect of one organotellurane was demonstrated. These findings led us to test the effect of the organotellurium compound RF07 on Leishmania (Leishmania) chagasi, the agent of visceral leishmaniasis in Latin America. In vitro assays were performed in L. (L.) chagasi-infected bone marrow derived macrophages treated with different concentrations of RF07. In in vivo experiments Golden hamsters were infected with L. (L.) chagasi and injected intraperitoneally with RF07 whereas control animals received either Glucantime or PBS. The effect of RF07 on cathepsin B activity of L. (L.) chagasi amastigotes was assayed spectrofluorometrically using fluorogenic substrates. The main findings were: 1) RF07 showed significant leishmanicidal activity against intracellular parasites at submicromolar concentrations (IC50 of 529.7±26.5 nM), and the drug displayed 10-fold less toxicity to macrophages (CC50 of 5,426±272.8 nM); 2) kinetics assays showed an increasing leishmanicidal action of RF07 at longer periods of treatment; 3) one month after intraperitoneal injection of RF07 L. (L.) chagasi-infected hamsters showed a reduction of 99.6% of parasite burden when compared to controls that received PBS; 4) RF07 inhibited the cathepsin B activity of L. (L.) chagasi amastigotes. The present results demonstrated that the tellurium compound RF07 is able to destroy L. (L.) chagasi in vitro and in vivo at concentrations that are non toxic to the host. We believe these findings support further study of the potential of RF07 as a possible alternative for the chemotherapy of visceral leishmaniasis.

Irreversible inhibition of human cathepsins B, L, S and K by hypervalent tellurium compounds.

Abstract The inhibition of human cysteine cathepsins B, L, S and K was evaluated by a set of hypervalent tellurium compounds (telluranes) comprising both organic and inorganic derivatives. All telluranes studied showed a time- and concentration-dependent irreversible inhibition of the cathepsins, and their second-order inactivation rate constants were determined. The organic derivatives were potent inhibitors of the cathepsins and clear specificities were detected, which were parallel to their known substrate specificities. In all cases, the activity of the tellurane-inhibited cathepsins was recovered by treatment of the inactivated enzymes with reducing agents. The maximum stoichiometry of the reaction between cysteine residues and telluranes were also determined. The presented data indicate that it is possible to design organic compounds with a tellurium(IV) moiety as a novel warhead that covalently modifies the catalytic cysteine, and which also form strong interactions with subsites of cathepsins B, L, S and K, resulting in more specific inhibition.

Natural Products from Garcinia brasiliensis as Leishmania Protease Inhibitors

The infections by protozoans of the genus Leishmania are a major worldwide health problem, with high endemicity in developing countries. The drugs of choice for the treatment of leishmaniasis are the pentavalent antimonials, which cause renal and cardiac toxicity. As part of a search for new drugs against leishmaniasis, we evaluated the in vitro Leishmania protease inhibition activity of extracts (hexanic, ethyl-acetate, and ethanolic) and fukugetin, a bioflavonoid purified from the ethyl-acetate extract of the pericarp of the fruit of Garcinia brasiliensis, a tree native to Brazilian forests. The isolated compound was characterized by using spectral analyses with nuclear magnetic resonance, mass spectroscopy, ultraviolet, and infrared techniques. The ethyl-acetate extract and the compound fukugetin showed significant activity as inhibitors of Leishmanias proteases, with mean (±SD) IC(50) (50% inhibition concentration of protease activity) values of 15.0±1.3 μg/mL and 3.2±0.5 μM/mL, respectively, characterizing a bioguided assay. In addition, this isolated compound showed no activity against promastigote and amastigote forms of L. (L.) amazonensis and mammalian cells. These results suggest that fukugetin is a potent protease inhibitor of L. (L.) amazonensis and does not cause toxicity in mammalian or Leishmania cells in vitro. This study provides new perspectives on the development of novel drugs that have leishmanicidal activity obtained from natural products and that target the parasites proteases.

Benzyl­triethyl­ammonium 2,2,2,4-tetra­chloro-2,5-di­hydro-1,2λ5-oxatellurole

The geometry around the Te atom in the anion in C13H22N+·C3H3Cl4OTe− is distorted pseudo-octahedral with three Cl atoms and the O atom forming the equatorial plane, and the C atom lying opposite the tellurium lone pair. Distances and angles are: Te—O 2.0120 (18), Te—C 2.072 (2), Te—Cl 2.5239 (7), 2.5283 (7) and 2.5577 (7) A; O—Te—C 81.61 (9), O—Te—Cl 90.69 (6), 90.99 (6) and 168.13 (5), C—Te—Cl 87.13 (8), 86.64 (8) and 86.59 (8), and Cl—Te—Cl 87.02 (2), 90.00 (3) and 173.24 (3)°. The anions are arranged in an infinite zigzag chain parallel to the a axis through a secondary Te⋯Cl bond [3.8391 (8) A].

Acetonyldichloro[(Z)-2-chloro-1-methyl-2-phenylethenyl]tellurium(IV)

The primary geometry about the Te IV atom in the title compound, C 12 H 13 Cl 3 OTe or [TeCl 2 (C 9 H 8 Cl)(C 3 H 5 O)], is a pseudo-trigonal-bipyramidal arrangement with the lone pair of electrons and the C atoms occupying the equatorial positions, and the Cl atoms occupying the axial positions. There are three secondary interactions, two intramolecular [Te…O 2.926(4) and Te…Cl 3.180(1) A] and one intermolecular [Te…Cl 3.659(1) A], which link the molecules. Significant distances and angles are: Te-Cl 2.4870(13) and 2.5096(12), Te-C 2.119(4) and 2.122(4) A, Cl-Te-Cl 171.78(5), Cl-Te-C 88.07(11), 87.68(15), 86.28(11) and 87.17(15), and C-Te-C 97.59(17)°.

Effects of trichlorotelluro-dypnones on mitochondrial bioenergetics and their relationship to the reactivity with protein thiols.

The effect of four trichlorotelluro-dypnones, named compounds 1, 2, 3, and 4, on the bioenergetics of isolated rat liver mitochondria (RLM) and cells was investigated. In a dose-dependent manner, the studied organotelluranes promoted Ca(2+)-dependent mitochondrial swelling inhibited by cyclosporine A and were associated with a decrease of the total mitochondrial protein thiol content. These effects characterize the opening of the classical mitochondrial permeability transition pore. Despite the reactivity with mitochondrial protein thiol groups, these compounds did not promote significant glutathione depletion. In the absence of Ca(2+), the organotelluranes promoted mitochondrial loss of ΔΨ in RLM concomitant with respiratory control decrease due to an increase of the state 4 respiration rate. In these conditions, mitochondrial swelling was absent, and thiol content was higher than that in the presence of Ca(2+). The differentiated effects observed in the presence and absence of Ca(2+) are probably related to the effects of that ion on membrane structure, with repercussions for the exposure of specific reactive protein thiol groups. In smooth muscle cells, these compounds promoted the loss of mitochondrial ΔΨ and apoptosis. The loss of ΔΨ was not preceded by a decrease of cell viability that is consistent with mitochondria as the primary targets for the action of these organotelluranes.

Acetonyldichloro[(Z)-2-chloro-2-phenylvinyl]tellurium(IV), helical chains of metal complexes.

The primary geometry about the Te(IV) atom in the title compound, [TeCl2(C8H6Cl)(C3H5O)] or C11H11Cl3OTe, is a pseudo-trigonal-bipyramidal arrangement, with two Cl atoms in apical positions, and the lone pair of electrons and C atoms in the equatorial plane. The Te(IV) atom is involved in three secondary interactions, two intramolecular [Te...O = 2.842 (3) A and Te.Cl3 = 3.209 (1) A] and one intermolecular [Te...Cl = 3.637 (1) A], the latter giving rise to a helical chain. These helices are linked by C-H...O interchain interactions.

Dichloro[(E)-2-chloro-1-(2-hydroxyprop-2-yl)vinyl](4-methoxyphenyl)tellurium(IV)

The geometry around the Te IV atom in the title compound, C 12 H 15 Cl 3 O 2 Te or [TeCl 2 (C 5 H 8 ClO)(C 7 H 7 O)], is pseudo-trigonal bipyramidal, with the Cl atoms in the apical positions and the Te lone pair occupying the fifth position in the equatorial plane. By including the intermolecular secondary Te...Cl contact [3.485 (1) A] trans to the Te-C vinyl bond, the structure may be regarded as pseudo-octahedral. The molecules are associated via an O-H...Cl hydrogen bond to form centrosymmetric dimeric units, which in turn are arranged in an infinite zigzag chain along the b axis through the secondary Te...Cl bond. Distances and angles are: Te-Cl 2.4820(8) and 2.5600(8), Te-C 2.124(3) and 2.129 (3) A; Cl-Te-Cl 173.24(3), Cl-Te-C 92.42 (8), 92.86 (8), 87.06 (8) and 88.03 (8), and C-Te-C 98.02 (12)°.