4‑Aminoquinoline Antimalarials Containing a Benzyl­methyl­pyridyl­methyl­amine Group Are Active against Drug Resistant Plasmodium falciparum and Exhibit Oral Activity in Mice

• Published in: Journal of medicinal chemistry 2017-12, Vol.60 (24), p.10245-10256
• Main Authors: Joshi, Mukesh C, Okombo, John, Nsumiwa, Samkele, Ndove, Jeffrey, Taylor, Dale, Wiesner, Lubbe, Hunter, Roger, Chibale, Kelly, Egan, Timothy J
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01537

Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethyl­amine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness. These compounds exhibited significantly improved solubility and decreased lipophilicity and were potent against chloroquine-sensitive (NF54) and -resistant (Dd2 and 7G8) P. falciparum strains with 5/6 having IC50 < 100 nM against the NF54 strain. All inhibited both β-hematin (synthetic hemozoin) formation and hemozoin formation in the parasite. Parasitemia was reduced by over 90% in P. berghei infected mice in 3/6 derivatives following oral dosing at 4 × 30 mg/kg, with microsomal metabolic stability data suggesting that this could be attributed to highly active metabolites.