Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds

The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2011-11, Vol.46 (11), p.5379-5386
Main Authors: Olmo, Esther del, Barboza, Bianca, Chiaradia, Louise D., Moreno, Alicia, Carrero-Lérida, Juana, González-Pacanowska, Dolores, Muñoz, Victoria, López-Pérez, José L., Giménez, Alberto, Benito, Agustín, Martínez, Antonio R., Ruiz-Pérez, Luis M., San Feliciano, Arturo
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalarials - chemistry
Antimalarials - pharmacology
Antimalarials - therapeutic use
Antimalarials - toxicity
Antiparasitic agents
Benzene - chemistry
Biological and medical sciences
Cell Line
Imidazoisoindoles
Imidazoles - chemistry
Imidazoles - pharmacology
Imidazoles - therapeutic use
Imidazoles - toxicity
In vitro assays
In vivo assays
Inhibitory Concentration 50
Isoindoles - chemical synthesis
Isoindoles - chemistry
Isoindoles - pharmacology
Isoindoles - therapeutic use
Isoindoles - toxicity
Male
Medical sciences
Mice
Mouse model
Parasitemia - drug therapy
Pharmacology. Drug treatments
Plasmodium berghei
Plasmodium berghei - drug effects
Plasmodium berghei - pathogenicity
Plasmodium falciparum
Plasmodium falciparum - drug effects
Structure–activity relationship
Synthesis
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Summary:The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC50 values as low as 60 nM and a certain efficacy in vivo by reducing parasitemia in Plasmodium berghei mouse models. Benzyl and β-naphthylmethyl derivatives of imidazo[2,1-a]isoindol-5-ol with potent in vitro antiplasmodial effects (IC50 = 60 nM) and promising antimalarial efficacy in vivo (87% inhibition of parasitemia) are described. [Display omitted] ▸ 29 imidazoisoindoles, imidazobenzimidazoles and isoindolinones synthesized. ▸ IC50 values against 3D7 Plasmodium falciparum ranged between 60 nM and >35 mM. ▸ 7 imidazoisoindoles assayed on mice infected with Plasmodium berghei. ▸ Up to 87% parasitemia inhibition on the 5th day, after 4 daily i.p. 25 mg/kg/day.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2011.08.043