Antitrypanosomal activity of 1,2-dihydroquinolin-6-ols and their ester derivatives.
The current chemotherapy for second stage human African trypanosomiasis is unsatisfactory. A synthetic optimization study based on the lead antitrypanosomal compound 1,2-dihydro-2,2,4-trimethylquinolin-6-yl 3,5-dimethoxybenzoate (TDR20364, 1a) was undertaken in an attempt to discover new trypanocides with potent in vivo activity. While 6-ether derivatives were less active than the lead compound, several N1-substituted derivatives displayed nanomolar IC(50) values against T. b. rhodesiense STIB900 in vitro, with selectivity indexes up to >18000. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate (10a) displayed an IC(50) value of 0.014 microM against these parasites and a selectivity index of 1700. Intraperitoneal administration of 10a at 50 (mg/kg)/day for 4 days caused a promising prolongation of lifespan in T. b. brucei STIB795-infected mice (>14 days vs 7.75 days for untreated controls). Reactive oxygen species were produced when T. b. brucei were exposed to 10a in vitro, implicating oxidative stress in the trypanocidal mode of action of these 1,2-dihydroquinoline derivatives.
Fotie
Jean
J
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
Kaiser
Marcel
M
Delfín
Dawn A
DA
Manley
Joshua
J
Reid
Carolyn S
CS
Paris
Jean-Marc
JM
Wenzler
Tanja
T
Maes
Louis
L
Mahasenan
Kiran V
KV
Li
Chenglong
C
Werbovetz
Karl A
KA
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004952:Esters / Q000737:chemistry*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D032446:Myoblasts / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
D000085:Acetates; D004952:Esters; D011804:Quinolines; D017382:Reactive Oxygen Species; D014344:Trypanocidal Agents