Mode of action of p-quinone derivatives with trypanocidal activity studied by experimental and in silico models

Abstract

Quinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis. The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC₅₀₌38 μM), proved to be similarly or even more potent (EC₅₀ = 0.5-5.5 μM) than the clinical drug nifurtimox (EC₅₀ = 5.3 μM). Three furanequinones and one thiazolequinone displayed a higher selectivity than nifurtimox. Two of these selective hits resulted potent inhibitors of T. cruzi proliferation (EC₅₀₌0.8-1.1 μM) but proved inactive against Leishmania infantum amastigotes. Most of the p-quinones induced a rapid and marked intracellular oxidation in T. b. brucei. DFT calculations on the oxidized quinone (Q), semiquinone (Q^•-) and hydroquinone (QH₂) suggest that all quinones have negative ΔG for the formation of Q^•-. Qualitative and quantitative structure-activity relationship analyses in two or three dimensions of different electronic and biophysical descriptors of quinones and their corresponding bioactivities (killing potency and oxidative capacity) were performed. Charge distribution over the quinone ring carbons of Q and Q^.- and the frontier orbitals energies of SUMO (Q^.-) and LUMO (Q) correlate with their oxidative and trypanocidal activity. QSAR analysis also highlighted that both bromine substitution in the p-quinone ring and a bulky phenyl group attached to the furane and thiazole rings (which generates a negative charge due to the π electron system polarized by the nearby heteroatoms) are favorable for activity. By combining experimental and in silico procedures, this study disclosed important information about p-quinones that may help to rationally tune their electronic properties and biological activities.

Keywords: Genetically-encoded redox biosensor; Leishmania; QSAR; Redox cycling; Thiol-redox balance; Trypanosoma; p-Quinones.