TITLE:
Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors
AUTHORS:
Abiodun S. Oyedele, Toluwase H. Fatoki, Esha Dalvie, Neil Osheroff, Cosmas O. Okoro
KEYWORDS:
Cancers, 9-Aminoacridone, Anticancer, Topoisomerase II, Pharmacokinetics, Molecular Docking, Etoposide
JOURNAL NAME:
Open Journal of Medicinal Chemistry,
Vol.13 No.2,
June
30,
2023
ABSTRACT: Cancer is a leading cause of death globally,
claiming about 9.6 million lives and approximately 420 million new cases of
cancer will be diagnosed in the world by the year 2025. The aim of this study
was to synthesize and computationally evaluate pharmacological potential of some
derivatives of 9-amino-3-phenylacridone, as topoisomerase II (Topo II)
inhibitors. In this study, 10
derivatives of 3-phenyl-9-aminoacridone were chemically synthesized and
characterized, and the potential pharmacological indications of these compounds
were computationally predicted by methods such as ADMET prediction, molecular
target prediction and molecular docking. The results showed that two
derivatives (58e and 58j) were non-permeant of blood-brain barrier, and this property was found similar to that of
amsacrine and etoposide. The results of molecular docking of the ten
derivatives of 3-phenyl-9-aminoacridone that were synthesized in this
work showed that the synthetic compounds (58a-j) and the standard drugs have
overall best binding affinities for human acetylcholine esterase than
butyrylcholinesterase, and overall best binding affinities for human topo IIα than human
topo IIβ. Overall,
the results of this study suggest that the synthetic compounds 58a, 58c, 58f,
58g, and 58i could probably inhibit topo IIα by catalytic inhibition as seen with amsacrine, but only 58b and 58e possessed
DNA non-intercalation properties as seen with etoposide, serving as topo II
poison. In conclusion, this study showed that 3-phenyl-9-aminoacridone
derivatives are potential inhibitor of topo IIα/β both by catalytic inhibition and
poison as non-intercalator of DNA.