Activity and structure relationship of acridine derivatives against African trypanosomes.
48 newly synthesized acridine derivatives of different classes were screened for antitrypanosomal activity. They showed a dose dependent effect on Trypanosoma rhodesiense and T. brucei bloodstream forms measured by the inhibition of esterase activity in a fluorescence based in vitro assay. After analysis of the IC50 and MIC values of the investigated acridines it was obvious that no new compound reached the level of the trypanocidal drugs in use (50 ng/ml). Most of the derivatives had IC50 values in the range of 1 to 10 micrograms/ml. 9 derivatives from different classes of acridines were in vitro active below 1 microgram/ml. Correlations between structure and effect on trypanosomes have been elucidated by comparing the IC50 and MIC values of these compounds, in the course of which no significant differences in the drug susceptibility between T. brucei und T. rhodesiense was noticed. The dialkylaminoalkyl derivatives among the group of the 9-thioacridines were slightly more potent than the mono-alkylated ones. 1,2,3,4-tetrahydro-9-thioacridines showed the influence of higher substituted side chains on the trypanocidal activity in the same way as 9-thioacridines. The corresponding ketones of 9-thioacridines confirmed the tendency of increasing toxicity due to the derivatisation of the dialkylaminoalkyl side chain. Within the series of the 9-aminoacridines the elongation of the side chain did not markedly change the activity, however the IC50 values are generally low between 0.13 and 1.2 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
Obexer
W
W
Swiss Tropical Institute, Basel.
Schmid
C
C
Barbe
J
J
Galy
J P
JP
Brun
R
R
D000166:Acridines / Q000737:chemistry / Q000633:toxicity*; D000609:Aminoacridines / Q000633:toxicity*; D000818:Animals; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000633:toxicity*; D014346:Trypanosoma brucei brucei / Q000302:isolation & purification*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*
D000166:Acridines; D000609:Aminoacridines; D014344:Trypanocidal Agents