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

Gemma, Sandra Camodeca, Caterina Brindisi, Margherita Brogi, Simone Kukreja, Gagan Kunjir, Sanil Gabellieri, Emanuele Lucantoni, Leonardo Habluetzel, Annette Taramelli, Donatella Basilico, Nicoletta Gualdani, Roberta [UCL] Tadini-Buoninsegni, Francesco Bartolommei, Gianluca Moncelli, Maria Rosa Martin, Rowena E Summers, Robert L Lamponi, Stefania Savini, Luisa Fiorini, Isabella Valoti, Massimo Novellino, Ettore Campiani, Giuseppe Butini, Stefania et al.[show all]

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.