4-Aminoquinoline Antimalarials Containing a Benzylmethylpyridylmethylamine Group Are Active against Drug Resistant Plasmodium falciparum and Exhibit Oral Activity in Mice.
Mukesh C JoshiJohn OkomboSamkele NsumiwaJeffrey NdoveDale TaylorLubbe WiesnerRoger HunterKelly ChibaleTimothy J EganPublished in: Journal of medicinal chemistry (2017)
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.
Keyphrases
- plasmodium falciparum
- drug resistant
- multidrug resistant
- acinetobacter baumannii
- signaling pathway
- high fat diet induced
- lps induced
- oxidative stress
- nuclear factor
- escherichia coli
- pi k akt
- ms ms
- photodynamic therapy
- electronic health record
- type diabetes
- metabolic syndrome
- molecular docking
- immune response
- cystic fibrosis
- skeletal muscle
- structure activity relationship
- toxoplasma gondii