The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum) and in vivo (against Plasmodium berghei). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's chloroquine resistance transporter (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice. © 2012 American Chemical Society.
Gemma, S., Camodeca, C., Brindisi, M., Brogi, S., Gagan, K., Kunjir, S.A., et al. (2012). Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents. JOURNAL OF MEDICINAL CHEMISTRY, 55(23), 10387-10404 [10.1021/jm300831b].
Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents
GEMMA, SANDRA;CAMODECA, CATERINA;KUNJIR, SANIL ASHOK;LAMPONI, STEFANIA;SAVINI, LUISA;FIORINI, ISABELLA;VALOTI, MASSIMO;CAMPIANI, GIUSEPPE;BUTINI, STEFANIA
2012-01-01
Abstract
The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum) and in vivo (against Plasmodium berghei). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's chloroquine resistance transporter (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice. © 2012 American Chemical Society.File | Dimensione | Formato | |
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https://hdl.handle.net/11365/42678
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