Journal article

Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity

Paul R Gilson, Cyrus Tan, Kate E Jarman, Kym N Lowes, Joan M Curtis, William Nguyen, Adrian E Di Rago, Hayley E Bullen, Boris Prinz, Sandra Duffy, Jonathan B Baell, Craig A Hutton, Helene Jousset Subroux, Brendan S Crabb, Vicky M Avery, Alan F Cowman, Brad E Sleebs



Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess poten..

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Awarded by National Health and Medical Research Council of Australia

Awarded by Australian Research Council

Funding Acknowledgements

This work was funded by the National Health and Medical Research Council of Australia (Program Grant APP1092789), the Australian Cancer Research Foundation, Brian Little Bequest, Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. A.F.C. is a Howard Hughes International Scholar and an Australia Fellow of the NHMRC. We thank and acknowledge the Australian Red Cross Blood Bank for the provision of fresh red blood cells, without which this research could not have been performed. This work was supported by the Australian Research Council (LP120200557 to V.M.A.). We thank Associate Professor Guillaume Lessene, Dr. Andrew Powell, and Professor Susan Charman for their helpful discussions, and Halina M. Pietrzak for technical assistance.