Methoden zur Evaluation von Zytotoxizit¨at und Struktur ... - OPUS

Kapitel 7
Summary
The purpose of this investigation was the search for new potential drugs for treat-
ment of trypanosomal and bacterial infections. According to trypanosomiasis, this stu-
dy aimed at screening large compound libraries for their antitrypanosomal activity
and analyzing structure activity relationships. In the field of bacterial infections the
development of new screening methods was of main interest.
In the first part of this thesis (Section 4.1) the AlamarBlue assay was established.
The assay showed great potential for the determination of drug sensitivities of Afri-
can trypanosomes in vitro and was suitable for high-throughput-screening of different
compound classes. At first the series of naphthylisoquinolin alkaloids (NIQs) having
a C,C-biaryl-axis (Section 4.1.4.1.1) were tested against Trypanosoma brucei brucei. The
most active compounds of this NIQ-class were Dioncophyllin A (ED50=3.4±1.7 µM),
B (ED50=2.6±0.4 µM), and C (ED50=4.2±2.3 µM), and the dimeric Ancistrogriffithin A
(ED50=0.85±0.05 µM). Their ED50 values were in the same range of inhibition concen-
tration as Nifurtimox (ED50=3.4±0.4 µM). Michellamin B which consists of two iden-
tical naphthylisoquinoline portions including six free hydroxy functions was inactive.
Thus, for good antitrypanosomal potency, the number of phenolic hydroxy functions
has to be limited to one or two. Under these circumstances even some naphthalene-free
tetrahydroisoquinolines were active to some extent. Ancistrocladinium B, a represen-
tative of the novel-type N,C coupled NIQ alkaloid with hetero-biaryl-axis exhibited si-
gnificantly higher antitrypanosomal activities (ED50= 0.35±0.02 µM) (Section 4.1.4.1.2).
Investigations of this novel-type alkaloid showed an increase in efficiency when going
from phenyl to anthracen substituted isoquinolines which is probably evoked by the
increase in the lipophilic character of the compounds. The influence of the hydroxy-
group on the potency was also verified for fluoroquinolones by structure-activity rela-
tionship (Section 4.1.4.2). Thus, for potent compounds the Lipinski’s criterion [161] for
drug-like compounds was met as well.
Further aim of this thesis was to find alternative and adjunct methods to the broth
microdilution test according to DIN 58940-8 [2], which is conventionally used for the
179