Evaluation of 4-Amino 2-Anilinoquinazolines against Plasmodium and Other Apicomplexan Parasites In Vitro and in a P. falciparum Humanized NOD- scid IL2Rγ null Mouse Model of Malaria

• Published in: Antimicrobial agents and chemotherapy Vol. 63; no. 3
• Main Authors: Gilson, Paul R, Nguyen, William, Poole, William A, Teixeira, Jose E, Thompson, Jennifer K, Guo, Kaiyuan, Stewart, Rebecca J, Ashton, Trent D, White, Karen L, Sanz, Laura M, Gamo, Francisco-Javier, Charman, Susan A, Wittlin, Sergio, Duffy, James, Tonkin, Christopher J, Tham, Wai-Hong, Crabb, Brendan S, Cooke, Brian M, Huston, Christopher D, Cowman, Alan F, Sleebs, Brad E
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.03.2019
• Subjects: Aniline Compounds; Aniline Compounds - pharmacology; Animals; Antimalarials - pharmacology; Antiparasitic Agents; Antiparasitic Agents - pharmacology; Babesia bovis; Babesia bovis - drug effects; Cell Line; Chloroquine - pharmacology; Cryptosporidium parvum; Cryptosporidium parvum - drug effects; Disease Models, Animal; Experimental Therapeutics; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Parasitic Sensitivity Tests; Plasmodium falciparum; Plasmodium falciparum - drug effects; Quinazolines; Quinazolines - pharmacology; Rats; Rats, Sprague-Dawley; Toxoplasma; Toxoplasma - drug effects; Plasmodium; Plasmodium falciparum; quinazoline; antimalarial agents; drug metabolism; pharmacokinetics; apicomplexan parasites
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01804-18

A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, , was evaluated for activity against other human parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic , suggesting that they could also be effective against the closely related , another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites , , and were less sensitive to the 2-anilinoquinazoline series with a 50% effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non- parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine and when tested in rodents displayed a half-life that contributed to the compound's capacity to clear blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving efficacy and addressing adverse risk.