Synthesis and antiprotozoal activity of original porphyrin precursors and derivatives

• Published in: European journal of medicinal chemistry 2013-09, Vol.67, p.158-165
• Main Authors: Abada, Zahra, Cojean, Sandrine, Pomel, Sébastien, Ferrié, Laurent, Akagah, Bernardin, Lormier, Anh Tuan, Loiseau, Philippe M., Figadère, Bruno
• Format: Article
• Language: English
• Subjects: Anti-malaric; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Dose-Response Relationship, Drug; Leishmania donovani - drug effects; Leishmanicid; Metal complexes; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium - drug effects; Porphyrins - chemical synthesis; Porphyrins - chemistry; Porphyrins - pharmacology; Structure-Activity Relationship; Trypanocid; Trypanosoma brucei brucei - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.06.002

Importance of heme in African trypanosomes, Leishmania sp. and Plasmodium sp. metabolisms justifies considering the potential of porphyrins and their precursors and derivatives as potential antiparasitic agents by interfering with heme metabolism. Consequently, twenty-four porphyrin precursors and derivatives were evaluated against Leishmania donovani, Trypanosoma brucei and Plasmodium sp. The best active compound against Trypanosoma brucei brucei was a new porphyrin derivative; compound 4i, with a MEC value of 6.25 μM justifying further in vivo evaluation. Whereas these compounds were not active against intramacrophage amastigotes of L. donovani, another new porphyrin derivative, compound 4f was active in vitro against Plasmodium falciparum at 20 nM and a slight delay of mice survival was observed on the Plasmodium berghei/Swiss mice model at 50 μmol/kg/day × 4. Pharmacomodulations should be further developed relying on a better knowledge on the porphyrin behaviour into the parasites comparatively to host cells. [Display omitted] •New dipyrrinato-metallates and 5,15-diarylporphyrins have been prepared in good yields.•These compounds have showed in vitro activity against African trypanosomes, Leishmania sp. and Plasmodium sp.•A porphyrin delayed the mice survival of Plasmodium berghei infected mice in in vivo assays.•The mechanism can be rationalized by invoking heme metabolism.