Effect of a bis-thiazolium compound on the biosynthesis of Plasmodium falciparum phospholipids

Abstract

In the eukaryotic cell, phospholipids can be biosynthesized by two pathways, one from choline and the other one from ethanolamine. The functional effectiveness of each pathway depends on the type of the cell. Thiazolium designed-drugs have shown, under in vivo conditions, antiplasmodial and antimalarial activities with inhibition of the phospholipids biosynthesis. This study aimed to discover the pathways involved in the biosynthesis of phospholipids in Plasmodium and deduce the biochemical steps inhibited by T4, a bis-thiazolium bromide drug. We compared the uptake of radiolabeled precursors and their selective incorporation in the phospholipids of cultured Plasmodium-infected and -uninfected erythrocytes which revealed that phosphatidylcholine of Plasmodium is synthesized both from choline and ethanolamine (4.7 vs 1.9 nmol/10 10 cells.h -1). T4 has no effect on the biosynthesis of phosphatidylethanolamine but T4 inhibited, in a selective way, the in vitro uptake of choline. However no enzymes in the biosynthesis of phospholipids seem to be inhibited by T4 but rather an inhibition of choline entry into the parasite.

High-affinity host–guest complex of cucurbit[7]uril with a bis(thiazolium) salt

“…4 Bis(thiazolium) salts are able to inhibit phosphatidylcholine biosynthesis in Plasmodium and to block parasite proliferation in the low nanomolar range. 5 On the other hand, thiazolium salts have been studied for more than four decades as models of carbon acids, 6 and for their applications as N-heterocyclic carbene (NHC) precursors leading to the synthesis of novel compounds with applications in various elds including medicine. 7 Labile nucleophilic NHCs may be formed by the deprotonation of the C(2)-proton of the thiazolium cations, and the NHC formation oen brings the issue of thiamine and thiazolium-based drug stability to the forefront.…”

“…10 These high binding affinities, in combination with their high selectivity, provide them with superior binding behaviour to that exhibited by cyclodextrins and calixarenes. Due to the small cavity size of CB [5] and exible nature of the cavity of CB [10], the CB [6], CB [7] and CB [8] hosts have received the greatest attention as supramolecular hosts and as drug delivery vehicles. 11,12 Compared with CB [6] and CB [8], the CB [7] host has received the most attention due to its good solubility and strong complexation with a diverse range of cationic and organometallic drugs.…”