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Published year: 20184
Pharmacokinetics and disposition of miltefosine in healthy mice and hamsters experimentally infected with Leishmania infantum.

Abstract (Expand)

Miltefosine is the only currently available oral drug for treatment of leishmaniasis. However, information on the pharmacokinetics (PK) of miltefosine is relatively scarce in animals. PK parameters and … disposition of the molecule was determined in healthy NMRI mice and Syrian hamsters infected and treated with different miltefosine doses and regimens. Long half-life of the molecule was confirmed and differential pattern of accumulation of the drug was observed in analyzed organs in mice and hamster. Long treatment schedules produced miltefosine levels over IC50 value against L. infantum intracellular amastigotes for at least 24days in spleen and liver of infected hamsters. The observed differential pattern of organ accumulation of the drug in mice and hamster supports the relevance of both species for translational research on chemotherapy of leishmaniasis.

Authors: M. D. Jimenez-Anton, E. Garcia-Calvo, C. Gutierrez, M. D. Escribano, N. Kayali, J. L. Luque-Garcia, A. I. Olias-Molero, M. J. Corral, M. P. Costi, J. J. Torrado, J. M. Alunda

Date Published: 30th Aug 2018

Publication Type: Journal

Development of a Focused Library of Triazole-Linked Privileged-Structure-Based Conjugates Leading to the Discovery of Novel Phenotypic Hits against Protozoan Parasitic Infections.

Abstract (Expand)

Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy … of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phen othiazine (7) and 10-(3-(1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-ph enothiazine (12) showed respective IC50 values of 1.8 and 1.9 mug mL(-1) against T. cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.

Authors: E. Uliassi, L. Piazzi, F. Belluti, A. Mazzanti, M. Kaiser, R. Brun, C. B. Moraes, L. H. Freitas-Junior, S. Gul, M. Kuzikov, B. Ellinger, C. Borsari, M. P. Costi, M. L. Bolognesi

Date Published: 6th Apr 2018

Publication Type: Journal

Aryl thiosemicarbazones for the treatment of trypanosomatidic infections.

Abstract (Expand)

Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of … interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50=2.31muM, LiEC50=6.14muM, TcEC50=1.31muM) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti-parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6-fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.

Authors: P. Linciano, C. B. Moraes, L. M. Alcantara, C. H. Franco, B. Pascoalino, L. H. Freitas-Junior, S. Macedo, N. Santarem, A. Cordeiro-da-Silva, S. Gul, G. Witt, M. Kuzikov, B. Ellinger, S. Ferrari, R. Luciani, A. Quotadamo, L. Costantino, M. P. Costi

Date Published: 25th Feb 2018

Publication Type: Journal

Scaffolds and Biological Targets Avenue to Fight Against Drug Resistance in Leishmaniasis

Abstract

Not specified

Authors: Chiara Borsari, Antonio Quotadamo, Stefania Ferrari, Alberto Venturelli, Anabela Cordeiro-da-Silva, Nuno Santarem, Maria Paola Costi

Date Published: 2018

Publication Type: InBook

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