Planejamento, síntese e prospecção biológica das atividades anticâncer e anticolinesterásica de novos derivados acridínicos

Abstract

Diseases considered multifactorial such as Cancer and Alzheimer's Disease (AD) have high mortality rates and few effective treatments. In this work, we report the design, synthesis, and biological prospecting of fifty new acridines derivatives designed from two specific pharmacodynamic explorations: the inhibition of topoisomerase IIα, when directed to antiproliferative compounds; and cholinesterase inhibition, when AD was proposed. The first two chapters report the pharmacological exploration of thirty-eight derivatives, from the hybridization of acridine nuclei and aromatic fragments derived from thiosemicarbazone, as the proposal for better pharmacodynamic adjustment to the target enzyme. In general, the highest activity was found for a monosubstituted acridine derivative DT-3OCH3-H (IC50 = 8.83 µM) against K562-Lucena 1 cells (resistant leukemic cells). Some more active derivatives were selected and showed interesting Topoisomerase IIα inhibition compared to amsacrine at 100 µM, with emphasis on the acridine–thiosemicarbazone derivative DL-08 (79%). Additionally, compounds selected for non-clinical toxicity testing did not show relevant signs of toxicity at the 2000 mg/kg dose in mice. The third chapter starts with an anticholinesterase screening of the derivatives of the first chapter. Compounds from the unsubstituted acridine (CL) series showed the best activity profile, with emphasis on the derivative (acetylcholinesterase, AChE = 2.47 μM; butyrylcholinesterase, BChE = 0.71 μM). From these results, twelve new derivatives were proposed and synthesized aiming at changes in the benzylidene subunit, as well as the incorporation of additional biological activities, for example, antioxidant. Modification of the acridine subunit by tetrahydroacridine from tacrine has also been proposed. The inhibitory results indicated reproducibility in the profile against BChE, with emphasis on the activity for CL-DiTerc (AChE = 10.53 μM; BChE = 1.15 μM). The replacement of acridine by tacrine tetrahydroacridine (TA-H) led to a reduction in the inhibition potency (AChE = 13.60 μM; BChE = 5.38 μM). Enzymatic kinetics identified distinct inhibition modes between TA-H (mixed inhibition in AChE and BChE) and the acridine derivative CL-01 (non-competitive inhibition in AChE and mixed in BChE). Theoretical studies reproduced the profile identified in the kinetics, suggesting that in AChE the interactions of the CL derivatives are concentrated in the peripheral region and the channel, not being identified as direct interactions with the catalytic residues, distinctly from that found for TA-H. Additionally, studies indicated an antioxidant profile for CL-DiTerc (DPPH EC50 = 47.01 μM), as well as some evaluated compounds indicated the ability to complex metal ions (Zn2+, Cu2+, Fe3+ and Al3+), indicating that these compounds have multitarget activities.