Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites

Abstract

3-Benzylmenadiones are potent antimalarial agents that are thought to act through their 3-benzoylmenadione metabolites as redox cyclers of two essential targets: the NADPH-dependent glutathione reductases (GRs) of Plasmodium-parasitized erythrocytes and methemoglobin. Their physicochemical properties were characterized in a coupled assay using both targets and modeled with QSPR predictive tools built in house. The substitution pattern of the west/east aromatic parts that controls the oxidant character of the electrophore was highlighted and accurately predicted by QSPR models. The effects centered on the benz(o)yl chain, induced by drug bioactivation, markedly influenced the oxidant character of the reduced species through a large anodic shift of the redox potentials that correlated with the redox cycling of both targets in the coupled assay. Our approach demonstrates that the antimalarial activity of 3-benz(o)ylmenadiones results from a subtle interplay between bioactivation, fine-tuned redox properties, and interactions with crucial targets of P. falciparum. Plasmodione and its analogues give emphasis to redox polypharmacology, which constitutes an innovative approach to antimalarial therapy.

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

“…Thus, in addition to the new artemisinin component, we need to examine with particular care the combination partners, and if these are likely to affect quiescent ring stage parasites so as to "protect" the artemisinin. We proposed use of the new artemisinin, which we term an oxidant drug by virtue of its ability to irreversibly oxidize reduced flavin cofactors, in combination with a redox (or "pro-oxidant") drug such as a phenothiazine, e.g., methylene blue (MB), phenoxazine, naphthoquinone (Sidorov et al, 2016), quinone-imine, redox metal chelating agent (Parkinson et al, 2019), or other (Kubota and Gorton, 1999;Dharmaraja, 2017), with a third drug with a different mode of action (Coertzen et al, 2018). MB oxidizes reduced flavin cofactors of flavin disulfide reductases just as does the artemisinin (Haynes et al, 2011(Haynes et al, , 2012.…”

A Mild and Versatile Friedel–Crafts Methodology for the Diversity‐Oriented Synthesis of Redox‐Active 3‐Benzoylmenadiones with Tunable Redox Potentials

“…Photo‐Friedel–Crafts acylation of NQs with a large stoichiometric excess of aromatic aldehydes provided the 2‐benzoyl‐dihydronaphthalene derivatives (Scheme ) . Previous work to synthesize 3‐benzoylmenadione derivatives 1 was based on the formation of a carbanion after i) bromination of the reduced and protected form of menadione, that is, the 1,4‐dimethoxy‐2‐methylnaphthalene, ii) halogen/metal exchange, followed by iii) addition of benzoyl chloride to give 2‐benzoyl‐3‐methyl‐1,4‐dimethoxynaphthalene derivatives 2 , and finally, iv) oxidative demethylation by cerium ammonium nitrate (CAN, Scheme ) …”

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

“…Efficient synthetic methodologies have been established (4,5) and will allow preparation of a large array of diverse benzylmenadiones for further structureactivity relationship investigations. Already developed chemoinformatic tools are available for predicting the redox potentials of polysubstituted menadiones (6,7). Application of these tools to the polysubstituted benz(o)ylmenadiones will be instrumental in predicting their oxidant character and other molecular descriptors in order to guide synthetic efforts toward analogues with desired properties (7).…”

“…Already developed chemoinformatic tools are available for predicting the redox potentials of polysubstituted menadiones (6,7). Application of these tools to the polysubstituted benz(o)ylmenadiones will be instrumental in predicting their oxidant character and other molecular descriptors in order to guide synthetic efforts toward analogues with desired properties (7).…”

“…The synthesis of plasmodione is achieved in only one step from cheap commercially available starting materials, and its low-molecular-weight structure provides a large chemical space for optimization by derivatization (3). Its structure served as a starting point for development of chemical optimization strategies aimed at generating benzylmenadione derivatives with superior pharmacokinetic or pharmacodynamic properties (4)(5)(6)(7).…”