Choline analogues in malaria chemotherapy

Abstract

Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches.

Fig. (1)

Schematic representation of phospholipid metabolic pathways in P. falciparum See [9] for details. Metabolites: CL, cardiolipin; DAG, diacylglycerol; CDP~, cytidine-diphospho-; FA, fatty acids; Glu, glucose; G-3-P, glycerol 3-phosphate; Ino, myoinositol ; P~, phospho; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate; PI, phosphatidylinositol; PI-3P, PI 3-phosphate; PI-4P, PI 4-phosphate; PI-4-5P₂, PI 4,5-bisphosphate; PS, phosphatidylserine. Enzymes: CDS, Cytidine diphosphate-DAG synthase; CK, Cho kinase; CCT, CTP:P~Cho cytidylyltransferase; CLS, CL Synthase; EK, Etn kinase; ECT, CTP:P~#x007E;Etn cytidylyltransferase; CEPT, Cho/Etn-phosphotransferase; INS, Ino 1-phosphate synthase; PAP2, PA phosphatase; PGPS, PGP synthase ; PGPPase, PGP phosphatase ; PEMT, PE N-methyltransferase; PIS, PI synthase; PI3-k, PI 3-kinase; PI4-k, PI 4-kinase; PI-4P5-k, PI 4-P 5-kinase; PLC–δ, phospholipase C_δ; PLMT, phosphatidyl-N-methylethanolamine N-methyltransferase; PMME, phosphatidyl-N-methylethanolamine; PMT, P~Etn Nmethyltransferase; PSD, PS decarboxylase; PSS, PS synthase CDP-DAG dependent; SD, Ser decarboxylase.

Fig. (2)

Generic structures of the studied derivatives (PA, SA, TA & QA).

Fig. (3)

Proposed pharmacophore description (M. Bianciotto, published with permission).

Fig. (4)

Effect of G25 on [³H]choline, [³H]ethanolamine and [³H] hypoxanthine incorporation into PC, PE and nucleic acids (NA) of P. falciparum-infected erythrocytes. Infected red blood cells (RBC, 3.4% hematocrit, 10% parasitemia, Nigerian strain) were incubated for 4 h at 37°C in the absence or presence of the studied compound (G25) as well as in the presence of 1.5 µCi of [³H]choline (●, at 10 µM), 0.8 µCi of [³H]ethanolamine (■ at 2 µM) or 1 µCi of [³H] hypoxanthine (Δ, trace amounts).

Fig. (5)

Generic structures of the studied mono- and bis(thiazolium) derivatives, vitamin B1 and lead compound G25 in the bis(QA) series.

Scheme 1.

Generic structures and synthetic approach of the studied bis(QA) derivatives.

Scheme 4.

Neutral prodrug approach to optimize the oral bioavailability of bis-thiazolium T3 and 4

Scheme 5.

Proposed modifications in the dodecyl linker.