Synthesis and evaluation of naphthyridine compounds as antimalarial agents.
Primaquine is the drug of choice for the radical cure of Plasmodium vivax malaria, but possesses serious side effects. In this study novel primaquine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. In vitro and in vivo studies found that synthesized compounds were less toxic than the parent compound primaquine, while preserving the desired antimalarial activity. Some of these compounds possess a therapeutic index over 10 times superior to that of the commonly used antimalarial drug chloroquine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.
Zhu
Shuren
S
Radix Pharmaceuticals Inc., 880 College Parkway, Rockville, MD 20850, USA. shuren.zhu@gmail.com
Zhang
Quan
Q
Gudise
Chandrashekar
C
Meng
Li
L
Wei
Lai
L
Smith
Erika
E
Kong
Yuliang
Y
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy*; D015394:Molecular Structure; D051189:Murinae; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D021261:Parasitic Sensitivity Tests; D010961:Plasmodium / Q000187:drug effects; D011319:Primaquine / Q000031:analogs & derivatives* / Q000737:chemistry; D023382:Toxicity Tests, Acute
D000962:Antimalarials; D009287:Naphthyridines; D011319:Primaquine