Recent Advances in the Biological Investigation of Organometallic Platinum-Group Metal (Ir, Ru, Rh, Os, Pd, Pt) Complexes as Antimalarial Agents

Abstract

In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria.

Keywords: Plasmodium falciparum; bioorganometallic chemistry; malaria; mechanism of action; platinum-group metals.

Figure 1

Chemical structures of chloroquine (1), the first antimalarial iridium-chloroquine complexes (2–4), and early examples of non-quinoline organoiridium complexes (5–6) [21,22,23].

Figure 2

Chemical structures of N^N- and N^O-coordinated IrCp* complexes and their corresponding IC₅₀ values [24,25].

Figure 3

1,3,5-triaza-phosphaadamantane (PTA)-derived IrCp* complexes featuring the chloroquine scaffold [26].

Figure 4

Neutral C^N-chelating half-sandwich Ir(III)Cp* complexes and monodentate N-coordinated analogues, with in vitro antimalarial activity targeting hemozoin inhibition and the NAD⁺/NADH cycle, by intracellular catalysis [29].

Figure 5

Chemical structures of IrCp* complexes based on the sulfadoxine scaffold and their corresponding IC₅₀ values [30].

Figure 6

Chemical structures of antimalarial 2-phenylbenzimidazole ligands (24a–d) and their corresponding IrCp* complexes (25a–d) as well as neutral and cationic quinolinyl-benzimidazole hybrids (26–27) [31,32].

Figure 7

Ruthenium complexes based on the chloroquine scaffold [38,39,40,41,42].

Figure 8

Chemical structures of tamoxifen (32), a tamoxifen-like compound (36), and its ruthenocenyl derivatives (33–35) [44].

Figure 9

Quinoline-based Ru(II)(p-cymene) complexes, containing salicylaldimine (37) and imidazolemethylamine (38 and 39) derivatives [45].

Figure 10

Chemical structures of Ru(II)-based thiosemicarbazone (TSC) (40–43) and aminoquinoline (44–45) complexes, possessing inhibitory activity against NF54 and Dd2 P. falciparum strain [46,47,48,49].

Figure 11

Chemical structures of highly potent antimalarial ruthenocene-quinoline-trioxane hybrids assembled from chemical motifs of chloroquine and artemisinin [54].

Figure 12

Antiplasmodial N^N- and S^N-chelated [Ru(III)Cl]Cp* complexes of 4-arylaminoquinoline scaffold N^N-coordinated pyrazoline congeners [55,56].

Figure 13

Quinolinyl ruthenium(II)-arene PTAs (RAPTAs) 52–53 and 2-phenylbenzimidazole Ru(II)(p-cymene) complexes 54a–d with antimalarial activity [26,31].

Figure 14

Bimetallic organometallic azines with antiplasmodial activity [23,60,61].

Figure 15

Antiplasmodial Rh(III) complexes based on chemical scaffolds of known antimalarial drugs, chloroquine (59–62) and sulfadoxine (63–64) [24,25,30].

Figure 16

Rhodium(II) complexes of silyl ferrocenyl and 3,4-dichlorophenyl TSC, benzimidazole, and chloroquine-benzimidazole hybrid scaffold [31,32,46].

Figure 17

Polyamine quinolinyl Rh(I)COD complexes showing inhibitory activity towards sensitive and resistant P. falciparum parasites [64].

Figure 18

Chemical structures of Os(II/III) RAPTA analogues with anticancer activity [72].

Figure 19

Quinolinyl Os(II) complexes possessing antiplasmodial activity against sensitive and resistant P. falciparum strains [45].

Figure 20

Next generation platinum(II) complexes approved for cancer treatment [73,74,75].

Figure 21

Inorganic (80–81) and organometallic (83–84) platinum complexes with antimalarial activity [20,79,80].

Figure 22

Chemical structures of antiplasmodial cyclopalladated TSC complexes [88].

Figure 23

Antiplasmodial mono- and dinuclear cyclopalladated complexes and their organosilane derivatives [89,90].

Figure 24

DNA binding affinity of Ru(III)Cp* complexes reported by Patel et al. [55,56]. (A) Scatter chart of DNA binding constants of the complexes plotted against their respective antiplasmodial activities. (B) UV/vis DNA titration curve of complex 49c. Adapted from [55,56].

Figure 25

Monitoring of NAD⁺ conversion to NADH using a modified Plasmodium lactate dehydrogenase (pLDH) protocol. Adapted from [29,116].