The therapeutic potential of metal-based antimalarial agents: Implications for the mechanism of action

Abstract

Despite recent encouraging advances against the disease, malaria remains a major public health problem affecting almost half a billion people and killing almost a million per annum. Due to a short arsenal of efficient antimalarial agents and the frequent appearance of resistance to the drugs in current use, which consequently reduce our means to treat patients, there is a very urgent and continuous need to develop new compounds. This perspective outlines a unique strategy for that purpose through the development of metal-based antimalarial agents. The examples presented here illustrate an attractive alternative to classical drugs.

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…Intriguingly, the size of the ring with a carbonyl group in these derivatives had an appreciable impact on R isomers, increasing their activity, but had almost no effect on S isomers (55). Using organometallic moieties such as ferrocenyl (already present in anticancer, antibacterial, and antimalarial drugs [56][57][58]) Fc-PZQ derivatives (types A and B, Fig. 4) displayed anthelmintic activity in the micromolar range but were considerably less active than PZQ1 (59).…”

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

“…[13][14][15][16][17][18][19][20][21][22][23][24][25][26] This strategy was found very successful with ferroquine (FQ), a ferrocenyl analogue of the antimalarial drug chloroquine (CQ), as FQ is active on CQ-resistant Plasmodium falciparum strains. Furthermore, intensive chemical biology studies have recently allowed unveiling additional modes of action for FQ compared to the parent drug in FQ, which were attributed to the presence of the organometallic unit.…”

“…Furthermore, intensive chemical biology studies have recently allowed unveiling additional modes of action for FQ compared to the parent drug in FQ, which were attributed to the presence of the organometallic unit. 19,27 It is anticipated that these additional modes of action will help prolonging the period of resistance development. Of note, Sánchez-Delgado and co-workers reported the preparation of ruthenium half-sandwich analogues of CQ which were found to be highly potent and to overcome the CQ resistance.…”

Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity

“…Cell growth was followed every day by measuring the absorbance of the culture at 600 nm. Before inoculation, the medium was supplemented 10 with the indicated amount of the studied complexes from a freshly prepared stock solution in DMSO. The activity of the co-ligand tmp was also determined.…”

“…This strategy has led to the identification of some prospective metal-based drugs against highly prevalent parasitic illnesses, such as Chagas disease, malaria, leishmaniasis and amoebiasis [6][7][8][9][10]. The biological relevance of vanadium has led to increasing research on the potential medicinal uses of its compounds [11] and many vanadium-based prospective drugs have A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 4 been proposed towards the treatment of several types of diseases.…”