Mimicking the intramolecular hydrogen bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents.
(2012) Journal of Medicinal Chemistry — Vol. 55, n° 23, p. 10387-10404 (2012)
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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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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, M. R., Martin, R. E., Summers, R. L., Lamponi, S., Savini, L., 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. https://doi.org/10.1021/jm300831b (Original work published 2012)