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XB-ART-46219
J Med Chem 2012 Dec 13;5523:10387-404. doi: 10.1021/jm300831b.
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Mimicking the intramolecular hydrogen bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents.

Gemma S , Camodeca C , Brindisi M , Brogi S , Kukreja G , Kunjir S , Gabellieri E , Lucantoni L , Habluetzel A , Taramelli D , Basilico N , Gualdani R , Tadini-Buoninsegni F , Bartolommei G , Moncelli MR , Martin RE , Summers RL , Lamponi S , Savini L , Fiorini I , Valoti M , Novellino E , Campiani G , Butini S .


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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.

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