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

  • J Med Chem. 2012 Dec 13;55(23):10387-404. doi: 10.1021/jm300831b.
Sandra Gemma  1 ,  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 Butini
Affiliations
  • 1. European Research Centre for Drug Discovery and Development (NatSynDrugs), Dipartimento di Neuroscienze, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
PMID: 23145816 DOI: 10.1021/jm300831b
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. berghei -infected mice.