Cyclopalladated organosilane–tethered thiosemicarbazones: novel strategies for improving antiplasmodial activity

Abstract

Two series of ferrocenyl- and aryl-derived cyclopalladated organosilane thiosemicarbazone complexes were synthesised via C-H bond activation. Selected compounds were evaluated for in vitro antiplasmodial activity against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the human malaria parasite Plasmodium falciparum. Cyclopalladation of the thiosemicarbazones resulted in antiplasmodial activities in the low micromolar range.

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

“…Consequently, there have been various studies on the biological activity of palladium complexes since Graham and Williams proposed the investigation of palladium complexes as anti-infective agents and promising anticancer alternatives to platinum in their pioneering studies [85]. Like in cancer, palladium complexes in malaria research have been explored in the literature with a fair representation of cyclopalladated organometallic variants [86][87][88][89][90][91].…”

“…Expansion of the bisphosphino bridge with a bulky three-benzene linker for the binuclear complex 90 did not enhance the antiplasmodial effects of the resulting compound. The next campaign sought to further augment the activity of mononuclear cyclopalladated TSCs by introducing a lipophilic organosilane motif into the backbone TSC structure of the complexes in an attempt to increase their chances of crossing cellular membranes and potentially retain them in the active site of the targeted malaria parasite (DV) ( Figure 23) [90]. As previously discussed, the strategy of incorporating organosilane motifs into drug molecules is touted for enhancing their lipophilicity and imparting beneficial therapeutic properties such as enhanced tissue penetration and cell permeability.…”

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

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…Adams et al., exploited the metal co‐ordinating properties of thiosemicarbazones in order to develop a series of cyclopalladated complexes (e. g., 67 ), which in several instances displayed mid‐nanomolar anti‐plasmodial activity, against chloroquine‐sensitive and ‐resistant strains. While these compounds were found to be relatively cytotoxic to CHO cells, they do represent an interesting new class of anti‐plasmodial scaffold . A series of related compounds were found to have encouraging selective activity against metronidazole‐resistant Trichomonas vaginalis …”

Synthesis, Antioxidant Activity, Acetylcholinesterase Inhibition and Quantum Studies of Thiosemicarbazones

“…23 Furthermore, thiosemicarbazones have been proposed to inhibit cysteine proteases, which are essential to several functions of the malaria parasite. 32 Based on these observations, the aim of this study was to synthesize a series of thiosemicarbazones, four of which had not been reported in the literature before, as potential therapeutic agents for the treatment of AD. The compounds were assayed to investigate their ability to inhibit acetylcholinesterase (AChE), and two in vitro antioxidants tests were performed, evaluating the thiosemicarbazones' nitric oxide (NO) scavenging activity and hydrogen peroxide (H 2 O 2 ) scavenging activity.…”