Optimization of 2-Anilino 4-amino substituted Quinazolines into potent antimalarial agents with oral in vivo activity

Gilson, PR; Tan, C; Jarman, KE; Lowes, KN; Curtis, JM; Nguyen, W; Di Rago, AE; Bullen, HE; Prinz, B; Duffy, S; Baell, JB; Hutton, CA; Jousset Subroux, H; Crabb, BS; Avery, VM; Cowman, AF; Sleebs, BE

Author(s): Gilson, PR; Tan, C; Jarman, KE; Lowes, KN; Curtis, JM; Nguyen, W; Di Rago, AE; Bullen, HE; Prinz, B; Duffy, S; Baell, JB; Hutton, CA; Jousset Subroux, H; Crabb, BS; Avery, VM; Cowman, AF; Sleebs, BE;
Details: Publication Year 2017-02-09,Volume 60,Issue #3,Page 1171-1188
Journal Title: J Med Chem
Publication Type: Journal Article
Abstract: 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 potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.
Publisher: ACS
Research Division(s): Structural Biology; Systems Biology And Personalised Medicine; Infection And Immunity; Chemical Biology
PubMed ID: 28080063
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.6b01673
NHMRC Grants: NHMRC/1092789,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-04-06 09:27:46

Last Modified: 2017-04-07 03:39:57