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Four gold(I) complexes conceived as anticancer agents were synthesized by reacting [Au(PEt 3 )Cl] and [Au(PPh 3 )Cl] with ligands derived from δ-d-gluconolactone. The ligands' structure was designed to combine desired biological properties previously reported for each group. Ligands were synthesized from δ-d-gluconolactone via ketal protection and hydrazide formation followed by cyclization with CS 2 to produce the novel oxadiazolidine-2-thione 7 and 8. Increasing of the ligands' lipophilicity via ketal protection proved useful since all four gold(I) complexes showed anticancer and antileishmanial properties. The IC 50 values are at low micromolar range, varying from 2 to 3 μm for the most active compounds. The free D-gluconate 1,3,4 oxadiazole-derived ligands were neither toxic nor presented anticancer or antileishmanial properties. Triethylphosphine-derived compounds 9 and 10 were more selective against B16-F10 melanoma cell line. Although similar in vitro antileishmanial activity was observed for the gold(I) precursors themselves and their derived complexes, the latter were three times less toxic for human THP-1 macrophage cell line; this result is attributed to an isomeric variation of the D-gluconate ligand and the oxadiazole portion, which was one of the key concepts behind this work. These findings should encourage further research on gold(I) complexes to develop novel compounds with potential application in cancer and leishmaniasis chemotherapy., (© 2020 John Wiley & Sons A/S.)

The drugs currently used to treat leishmaniases have limitations concerning cost, efficacy, and safety, making the search for new therapeutic approaches urgent. We found that the gold(I)-derived complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC 50 values ranging from 0.5 to 5.5 μM. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC 50 values ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced reactive oxygen species (ROS) production and decreased mitochondrial respiration after 2 h of exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing L. braziliensis or L. amazonensis and treated orally with 12.5 mg/kg/day of AdT Et ( 3 ) or AdO Et ( 4 ) presented reduced lesion size and parasite burden, as revealed by bioimaging. The combination of ( 3 ) and miltefosine allowed for a 50% reduction in miltefosine treatment time. Complexes 3 and 4 presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with a potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites.

We report the synthesis of a series of diaminated terpenoids containing, as side-chain of the diamine core, the "head-to-tail" prenyl derivatives, with amino amino spacers of variable length. In vitro biological activity of these compounds was evaluated against Mycobacterium tuberculosis and Leishmania amazonensis, and the structure-activity relationships are discussed. Different biological results were observed depending on the terpenic side-chain length. The best results were obtained for trans,trans-farnesol derivatives. Moreover, these results demonstrated that the stereochemistry of the double bond could play an important role in determining antitubercular and antileishmanial activities of these compounds., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Polyamine biosynthesis and inhibition in parasites have been an attractive chemotherapeutic approach in the design of novel antiparasitic drugs. We study in this work the effect of N-dodecyl-1,2-ethylenediamine (NDDE) on the morphology and replication of Leishmania using macrophages cultured from the peritoneal exudate of mice infected in vitro with three species of Leishmania: Leishmania (Leishmania) amazonensis, Leishmania (Viannia) brasiliensis and Leishmania (Leishmania) chagasi. The results showed that NDDE inhibited Leishmania amastigotes multiplication into inflammatory peritoneal cells in concentrations which were not toxic to mammalian cells (0.5-1μg/mL). An intracellular disorganization of the promastigote forms was observed by transmission electron microscopy after 3 to 24h of treatment with 1μg/mL NDDE, suggesting that this compound affects the viability of the parasite by an autophagy pathway., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Ten N-monoalkylated diamines were synthesized and evaluated for in vitro activities against Trichomonas vaginalis and Giardia lamblia. Several compounds displayed a good inhibition of parasite growth, with MIC less or equal to 20μg/mL. N-hexadecil-1,4-butanediamine was found to be the most active compound in vitro against T. vaginalis with MIC of 2.5μg/mL, twice more active in comparison to the reference drug metronidazole (MTZ). Seven of the studied compounds showed a better anti-G. lamblia activity than MTZ., (Copyright © 2010. Published by Elsevier SAS.)

We report in this work the preparation and the in vitro antileishmanial activity of a series of long chains N-monoalkylated diamines and two pyridinediamine derivatives. Several compounds, tested for their in vitro antiproliferative activity against Leishmania amazonensis and Leishmania chagasi, displayed a good inhibition of parasite growth, with IC(50) below 10 microM. Compounds 10 (N-dodecyl-1,2-ethanediamine), 15 (N-decyl-1,3-propanediamine) and 20 (N-dodecyl-1,4-butanediamine) were 7.3, 2.6 and 3.6 times, respectively, more active than the reference drug amphotericin B against L. chagasi promastigote forms.