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Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents
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posted on 2012-12-13, 00:00 authored by Sandra Gemma, Caterina Camodeca, Margherita Brindisi, Simone Brogi, Gagan Kukreja, Sanil Kunjir, Emanuele Gabellieri, Leonardo Lucantoni, Annette Habluetzel, Donatella Taramelli, Nicoletta Basilico, Roberta Gualdani, Francesco Tadini-Buoninsegni, Gianluca Bartolommei, Maria Rosa Moncelli, Rowena E. Martin, Robert L. Summers, Stefania Lamponi, Luisa Savini, Isabella Fiorini, Massimo Valoti, Ettore Novellino, Giuseppe Campiani, Stefania ButiniThe
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.