[Benzo[c][2,7]naphthyridine-5-yl-amines and benzo[h][1,6]naphthyridine-5-yl-amines--potential antimalarials].
The chloroimine 1a reacted with the novaldiamine-base to yield the 5-(2-methylpyrrolidinyl)-derivative 3. The 5-chloro-benzonaphthyridines 1 and 9 reacted with secondary aliphatic amines to give the amidines 5-8 and 10, while the aromatic amidines 11-14 were obtained with primary aromatic amines. Mixtures of the phenol Mannich bases 15 and 16 of the isoquine type were isolated from the aminomethylation of 13b. The amodiaquine analogues 19 and 20 were obtained from the reaction of 1b and 9a with 4-amino-2-piperidinomethyl-phenol dihydrochloride. The structure of the compounds 5a (potassium salt), 6b, 10a, 11e and 18 was proven by X-ray crystal analysis. Compounds 3, 6a-e, 7, 10a, 11a, 16, 19 and 20 were tested for in vitro antimalarial activity using a chloroquine-sensitive and -resistant Plasmodium falciparum strain. The highest activity against the sensitive strain was shown by the amodiaquine analogoue 20 with an IC50 value of 160 nM. The mixture of the isoquine derivatives 15a and 16a possessed the highest activity against the resistant strain with an IC50 value of 1100 nM.
Görlitzer
K
K
Institut für Pharmazeutische Chemie, Beethovenstrasse 55, D-38106 Braunschweig, Germany. k.goerlitzer@tu-bs.de
Bode
M
M
Jones
P G
PG
Jomaa
H
H
Wiesner
J
J
D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet
D000588:Amines; D000962:Antimalarials; D007202:Indicators and Reagents; D009287:Naphthyridines