Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives

Abstract

In this study, we report the synthesis of twenty new acridine–thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC50 = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 104 M−1; Ksv = 2.6 × 103 M−1). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC50 between 11.45 and 17.32 µM.

Identification of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies

“…Our study screened 28 acridine compounds already reported in the literature with regards to the inhibition of fungal chitinolytic activity [17,[26][27][28]. All compounds showed percentual inhibition above 80 at concentrations of 100 to 6.25 µg/ml.…”

“…All compounds showed percentual inhibition above 80 at concentrations of 100 to 6.25 µg/ml. Cytotoxicity studies demonstrated that none of acridine derivatives are cytotoxic to human red blood cells up to the highest concentration studied (> 400 µg/mL) [17,27,28].…”

“…Inhibition of T. harziaunum chitinolytic activity by acridine compounds tested corroborates with in silico ndings, where the IC 50 for compound 5 was of 0.07 µg, 0.58 µg for compound 7 and 0.233 µg for compound 9. Although compound 5 was observed to have the best activity, solubility in aqueous solution is a known issue for acridine compounds [27,28].…”

“…In our research group, a total of 28 acridine derivatives were selected from a recent publication, with 3 classes of acridine derivatives (Fig. 4): spiro-acridine [26, 28], thiosemicarbazone-acridine [27] and thiophene-acridine [17]. All names, structures and references are presented in Supplementary Table S4.…”

“…Recently, our research group identi ed antileishmanial and antitumoral activity for acridine and spiroacridine derivatives [17,[26][27][28], which have been shown to be potential drug candidates. However, the few therapeutic applications reported in the literature make us wonder about the best activity performance of these compounds against a target.…”