Mimicking the intramolecular hydrogen bond : synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents
Articolo
Data di Pubblicazione:
2012
Citazione:
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.
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.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
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
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