Yannick Estevez

In vitro and in vivo anti-Leishmania activity of polysubstituted synthetic chalcones

The in vitro screening of 43 polysubstituted chalcones against Leishmania amazonensis axenic amastigotes, led to the evaluation of 9 of them in a macrophage-infected model with the two other most infectious Leishmania species prevalent in Peru (L. braziliensis and L. peruviana). The five most active and selective chalcones were studied in vivo, resulting on the identification of two chalcones with high reduction parasite burden percentages.

Trypanoside, anti-tuberculosis, leishmanicidal, and cytotoxic activities of tetrahydrobenzothienopyrimidines.

The synthesis of 2-(5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)hydrazone-derivatives (BTPs) and their in vitro evaluation against Trypanosoma cruzi trypomastigotes, Mycobacterium tuberculosis, Leishmania amazonensis axenic amastigotes, and six human cancer cell lines is described. The in vivo activity of the most active and least toxic compounds against T. cruzi and L. amazonensis was also studied. BTPs constitute a new family of drug leads with potential activity against infectious diseases. Due to their drug-like properties, this series of compounds can potentially serve as templates for future drug-optimization and drug-development efforts for use as therapeutic agents in developing countries.

Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Pyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9 μM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells. Furthermore, insilico studies showed that both series respected Lipinskis rules and that they confirmed a linear correlation between trypanocidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.

Anti-Leishmanial Lindenane Sesquiterpenes from Hedyosmum angustifolium

The aim of this work is the isolation of anti-leishmanial compounds from the ethyl acetate extracts of the bark of HEDYOSMUM ANGUSTIFOLIUM. We have successfully isolated and characterized five sesquiterpenes: one new compound (oxyonoseriolide, 1), one compound isolated for the first time from a natural source (hedyosmone, 2), and three known sesquiterpenes (onoseriolide, 3; chloranthalactone A, 4; and spathulenol, 5) that had not been previously isolated from H. ANGUSTIFOLIUM. The biological activities of 1- 5 showed that onoseriolide ( 3) was the most active compound against axenic amastigotes from LEISHMANIA AMAZONENSIS and L. INFANTUM. Moreover, it was still active on the intramacrophagic amastigotes of L. INFANTUM. The isolated compounds have also been tested on PLASMODIUM FALCIPARUM and against various mammalian cell lines.

Anti-infective and cytotoxic compounds present in Blepharodon nitidum.

A pharmacological screening of the ethanol extract and fractions of Blepharodon nitidum led to the isolation of fourteen compounds, two of which, 24-hydroperoxycycloart-25-en-3beta-ol and 25-hydroperoxycycloart-23-en-3beta-ol, exhibited in vitro anti- Mycobacterium tuberculosis and antileishmanial activities, as well as significant cytotoxic activity against a panel of human tumor cell lines.

Leishmania (Viannia) peruviana (MHOM/PE/LCA08): comparison of THP-1 cell and murine macrophage susceptibility to axenic amastigotes for the screening of leishmanicidal compounds.

This study, undertaken to compare the susceptibility of THP-1 cells and murine peritoneal macrophages to Leishmania peruviana amastigotes, obtained THP-1 infection with 10 parasites/cell compared to 2 parasites/murine macrophage. The parasite burden was maximal at 72 h post-infection (h.p.i.) for THP-1 cells, while it was still increasing at 120 h.p.i. for murine macrophages. Since in both cases the infection with L. peruviana affected cell viability, we recommend evaluating any leishmanicidal activity at 72 h.p.i. Amphotericin B reduced Leishmania infection by 50% at concentrations of 0.1 microM in THP-1 and murine macrophages at 72 h.p.i. Our results demonstrate that amastigotes of L. peruviana can infect THP-1 cells and murine macrophages and indicate the suitability of this model to screen compounds for leishmanicidal activity.