Antileishmanial activity of polycyclic derivatives.

33 polycyclic derivatives have been studied and tested on Leishmania donovani and L. major promastigotes. Their antileishmanial activity was assessed in vitro and an assay of their cytotoxicity was realized on human myelomonocytic cell line. The reference molecules used in the assays were amphotericin B and pentamidine. Among the compounds tested, 29 possess an antileishmanial activity; 25 of those were more active against L. donovani than amphotericin B, and nine were as effective as amphotericin B against L. major. Many synthesized derivatives were more active against L. donovani than against L. major. The cytotoxicity studies have shown that among the thirty-three derivatives tested, 12 molecules have an IC50 towards THP-1 cells about equal than that reference drugs, the 21 other derivatives are much less toxic. A 3D QSAR study was undertaken and has permitted to predict activity against L. donovani and L. major and to highlight critical area to optimize activity against the two species.

In vitro effects of isoprinosine and a dipeptide methyl ester on Echinococcus multilocularis protoscoleces.

A protoscoleces/vesicles in vitro maintenance test with assessment of viability by eosin exclusion was used to evaluate the quantitative and qualitative activities of isoprinosine, its active component inosine and the dipeptide methylester L-Phe-Phe-OMe on isolated protoscoleces of Echinococcus multilocularis for 24 and 48 h. Isoprinosine and inosine showed dose- and time-dependent activity, the latter displaying a more rapid effect than the former. A high activity was shown with L-Phe-Phe-OMe, when compared to praziquantel. Ultrastructural alterations were much more striking with L-Phe-Phe-OMe, with an effect similar to that of praziquantel, whereas the chemotherapeutic activity of inosine and isoprinosine appeared to be directed against a metabolic target, with a lethal effect not immediately visible at the ultrastructural level. Thus, the previously reported in vivo activities of these drugs result largely from a direct effect on the parasite.

Synthesis and antiproliferative activity of [2-(phthaloylamino)alkyl]triphenyl phosphonium derivatives against K562 cell line.

Given the reported cytotoxicity of phthaloylaminoethyltriphenylphosphonium bromide 2a in the P-388 cell line, we have developed new [2-(phthaloylamino)alkyl]phosphonium derivatives 2b-e and evaluated their cytotoxic activity. These compounds have been synthetized from N,N-phthaloylaminoalcohols and triphenylphosphonium hydrobromide via a one-pot reaction. 2a was found inactive in the K562 cell line, but 2c-e exhibited a cytotoxic activity with IC50 values about 1 microM.

Quinonic derivatives active against a virulent strain of Toxoplasma gondii. Synthesis of 2-methylfuro[2,3-g]- and [3,2-g]isoquinolinetriones.

2-methylfuro[2,3-g]isoquinoline-4,7,9-trione (4) and 2-methylfuro[3,2-g]isoquinoline-4,6,9-trione (5) were prepared regiospecifically from 2-azadiene 9 and bromobenzofuran-4,7-diones 1 or 11. The activity of these two compounds and some other quinonic derivatives was evaluated in vitro against a virulent strain of Toxoplasma gondii. Compounds 4 and 7 were found to be as active as pyrimethamine.

Phenylalanine derivatives active against Toxoplasma gondii brain cysts in mice.

The action of phenylalanine derivatives against a cyst forming strain of Toxoplasma gondii was tested in vitro and in vivo in mice. These compounds were Phe-Phe-OMe (dipeptide methyl ester) 1 and its cyclized product, 3,6-dibenzyl-2,5-dioxopiperazine 2, Boc-L-Phe 3, L-Phe-OMe 4, Boc-L-Phe-L-Phe-OMe 5. After a 48 hr incubation in vitro, the compounds 3 and 5 induced a higher inhibition than the control molecule, pyrimethamine. In the in vivo studies, the compound 3 induced a 77% decrease in the number of cerebral cysts, comparable to pyrimethamine. Compounds 1, 5 and 4 induced a decrease of about 63% in the cyst number. A size reduction and an alteration of the wall of treated cysts were often noted. In a histological study, a reduction in cyst size without either inflammation or intervention of the nevroglial cells was observed. The present study provides evidence on the efficacy of phenylalanine derivatives and especially Boc-Phe 3, against T.gondii brain cysts in mice.

Increases in the effects of albendazole on Echinococcus multilocularis metacestodes by the dipeptide methyl ester (Phe-Phe-OMe).

Three months after infection with Echinococcus multilocularis, Mongolian gerbils were given either the dipeptide methyl ester (Phe-Phe-OMe) or a combination of Phe-Phe-OMe plus albendazole to treat alveolar echinococcosis. Each drug was given orally at the daily dose of 50 mg/kg of body weight following various administration regimens. Histologic and ultrastructural studies of parasites recovered from infected gerbil tissues showed that the dipeptide methyl ester increases the effect of albendazole.

Substitution of peptide bond 53-54 of HEL(52-61) with an ethylene bond rather than reduced peptide bond is tolerated by an MHC-II restricted T cell.

To probe the interactions between major histocompatibility class-II molecules and the amide bonds of the antigenic peptide main chain, we synthesized ethylenic and reduced analogues of HEL(52-61), an immunogenic peptide for murine major histocompatibility class-II IA k restricted T-cell clones. The synthesis of the corresponding ethylenic analogue of HEL(52-61) in position 53-54 was performed by coupling the Fmoc-protected tripeptide Asp-Tyr-psi [E, CH = CH]Gly with HEL(55-61). Biological tests showed that the ethylenic peptide was presented by major histocompatibility class-II IA kappa molecule and recognized by HEL(52-61)-specific T-cell clones. The corresponding reduced peptide of HEL(52-61) at position 53-54 neither stimulated T-cell clones nor competed with the natural peptide. These results show that, while reduced pseudopeptides might not be appropriate, ethylenic pseudopeptides may be used as probes to dissect the role of hydrogen bonding between the peptide main chain and MHC residues and also help in the design of more stable immunogenic peptides.

Critical residue combinations dictate peptide presentation by MHC class II molecules.

Peptides encompassing the core hen egg lysozyme HEL(52-61) peptide elongated or not and substituted or not with natural and unnatural amino acids were used to find a peptide motif for binding to the major histocompatibility complex (MHC) class II I-Ak. Using a T-cell recognition functional assay, nine out of 10 positions were found to be somehow involved in the I-Ak binding, and six out of 10 residues were involved in T-cell recognition. The deleterious effect of single substitutions could be rescued by changing peptide length and/or sequence. Thus, efficient binding to MHC class II molecules requires not only few anchoring residues correctly interspaced, but a complex, nonrandom combination of residues with appropriate orientation of the peptide backbone and some crucial side chains.

Anthelmintic activity of some 3-substituted phenyl-1-alkyl or phenyl propenones and propenamides.

In a search for new anthelmintic compounds, a,beta-unsaturated ketones and amides were synthetized. Their anthelmintic activity was tested against two gastrointestinal worms, a nematode Syphacia obvelata and a cestode Hymenolepis nana. Structure-activity relationships are discussed.

In vivo morphological damage induced by a new benzimidazole prodrug in Echinococcus multilocularis metacestodes.

Benzimidazoles are the most widely used compounds in chemotherapy of alveolar hydatid disease (AHD), but long-term administration is required to reach detectable plasma levels. N-Methoxycarbonyl N'-2-nitro 4-trifluoromethyl phenyl thiourea (2) was prepared as a potential prodrug of (5-trifluoromethyl-1H-benzimidazole-2-yl)-carbamic acid methyl ester. Biological effects of 2 were evaluated in gerbils (Meriones unguiculatus) against the causative agent of AHD, Echinococcus multilocularis metacestodes, through a transmission electron microscopy study. Significant morphological damage of tegument and protoscolices occurred after an 18-day treatment. The treatment of AHD by using the prodrug form of the benzimidazole deserves further study.