New amides derived from sclareolide as anticholinesterase agents.

A series of 25 amides (15 new) derived from (3aR)-(+)-sclareolide were prepared and subjected to Ellman's assay to determine their efficacies as inhibitors for AChE or BuChE. Five amides (9, 13, 14, 15 and 17) caused inhibition of one of the enzymes greater than 60%; thereby those that inhibited BuChE were more active than positive control galantamine, and they showed better Ki values (1.07 to 8.49). In general, it was found that molecules holding a meta-substituted phenyl group showed a higher percentage of enzymatic inhibition. Molecular modelling calculations indicated the putative interactions of compounds with the amino acids residues of both enzymes AChE and BuChE. The cytotoxicity of compounds 9, 13, 14, 15 and 17 was evaluated against a non-malignant murine embryonic fibroblast cell line (NIH 3T3). Of special note is compound 15, as it presented the second-best Ki value for BuChE (1.71), was not cytotoxic (EC50 > 30 µM). Compound 15 also does not violate Lipinski rules, and showed permeability in the blood brain barrier, indicating that it can be considered a lead for the development of new drugs to treat Alzheimer's disease.

Tetroxanes as New Agents against Leishmania amazonensis.

Leishmaniasis is a neglected disease, caused by a parasite of Leishmania genus and widespread in the tropical and subtropical areas of the world. Currents drugs are limited due to their toxicity and parasite resistance. Therefore, the discovery of new treatment, more effective and less toxic, is urgent. In this study, we report the synthesis of six gem-dihydroperoxides (2a-2f), with yields ranging from 10 % to 90 %, utilizing a new methodology. The dihydroperoxides were converted into ten tetroxanes (3a-3j), among which six (3b, 3c, 3d, 3g, 3h and 3j) showed activity against intracellular amastigotes of Leishmania amazonensis. The cytotoxicity of all compounds was also evaluated against canine macrophages (DH82), human hepatoma (HepG2) and monkey renal cells (BGM). Most compounds were more active and less toxic than potassium antimonyl tartrate trihydrate, used as positive control. Amongst all tetroxanes, 3b (IC50 =0.64 µm) was the most active, being more selective than positive control in relation to DH82, HepG2 and BGM cells. In summary, the results revealed a hit compound for the development of new drugs to treat leishmaniasis.

Synthesis and evaluation of the anti parasitic activity of aromatic nitro compounds.

A series of nitroaromatic compounds was synthesized and evaluated as potential antileishmanial and trypanocidal agents. Five compounds exerted significant anti-leishmanial activity in vitro against promastigotes forms of Leishmania (L.) amazonensis, with IC(50) in the range of 23-59 µmol L(-1), but none were active against amastigotes intracellular forms of Trypanosoma cruzi. In vitro cytotoxicity on the proliferation of human peripheral blood mononuclear cells (PBMC) stimulated with phytohemaglutinin (PHA) was also evaluated. Two compounds, 6 and 7, were found to present a promising anti-leishmanial activity with IC(50) values of 59.5 and 50.6 µM, respectively, without affecting the lymphocyte proliferation in PBMCs (selectivity index of 16.1 and 21.7, respectively), indicating low toxicity to human cells.