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. bergheiinfected mice.

Mimicking the intramolecular hydrogen bond : synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents / S. Gemma, C. Camodeca, M. Brindisi, S. Brogi , G. Kukreja, S. Kunjir, E. Gabellieri, L. Lucantoni, A. Habluetzel, D. Taramelli, N. Basilico, R. Gualdani, F. Tadini-Buoninsegni, G. Bartolommei, M.R. Moncelli, R.E. Martin, R.L. Summers, S. Lamponi, L. Savini, I. Fiorini, M. Valoti, E. Novellino, G. Campiani, S. Butini. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 55:23(2012 Dec 13), pp. 10387-10404.

Mimicking the intramolecular hydrogen bond : synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents

D. Taramelli;N. Basilico;
2012

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. bergheiinfected mice.
Settore MED/04 - Patologia Generale
13-dic-2012
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/220085
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