Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents

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• 作者：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 Butini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10387-10404
• 全文大小：746K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

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鈥檚 鈥渃hloroquine resistance transporter鈥?(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.