Thiosemicarbazone-acridine hybrids are prominent inhibitors of topoisomerases II. This study reports the design, synthesis, and antiproliferative evaluation of eighteen new acridine–thiosemicarbazone derivatives as possible inhibitors of topoisomerase IIα. In general, compounds showed moderate to low cytotoxicity in the first screening performed on three cell lines, with emphasis on the DT-3OCH3 series, in which five of the six compounds have been active. Further studies against resistant leukemic cells indicated an interesting profile for derivatives DT-3OCH3-H (IC50 = 8.83 µM) and DT-3OCH3-3OH (IC50 = 10.69 µM) in the resistant cell Lucena-1, with relative resistance (RR) index of 0.11 and 0.10, respectively. A cytotoxicity assay on Vero cells showed low toxicity for most of the antileukemic compounds, with only DT-3OCH3-3OH derivative indicating a highlighted reduction in cell viability at a concentration of 61.25 µM. Five compounds were selected for topoisomerase IIα inhibition and all presented enzyme inhibition activity. Also, Topo IIα-DNA docking and molecular dynamics studies indicated that better scores were obtained for compounds interacting with residues Arg487 and Asp463, presenting electron donor groups on the acridine nucleus, as well as the presence of the hydroxyl substituents in the benzylidene. Finally, two selected compounds had their in vitro gastrointestinal absorption profile evaluated in Caco-2 cells, indicating good membrane permeation, with an apparent permeability coefficient greater than 10 × 10-6 cm/s for both.
Full Text Finder