Disulfide Prodrugs of Albitiazolium (T3/SAR97276): Synthesis and Biological Activities

Abstract

We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.

4,4′-Azopyridine as an easily prepared and recyclable oxidant for synthesis of symmetrical disulfides from thiols or alkyl halides(tosylates)/thiourea

“…[1][2][3][4][5][6][7][8] Owing to the increasing importance of the disulfides (disulfanes) in chemistry [9][10][11][12][13][14] and biology, [15][16][17] synthetic approaches for their preparation have been extensively studied. [18][19][20][21][22] According to the literature, disulfides can be obtained directly from *Corresponding author.…”

Recent advances in malaria drug discovery

“…Data are reported for artemisinin, 29 artesunate, 29,30 lumefantrine, 31,32 piperaquine, 31,33 sulfadoxine, 34 pyrimethamine, 35,36 and chloroquine. 29,37,38 …”

“…98,101 This indicates a 2–3-fold improvement in mouse oral bioavailability; the rat bioavailability is 15%. 100 In spite of numerous efforts made in the last few years, 37,102–105 the bioavailability of these bis-cations has not been improved yet.…”

Antimalaria Drug Development & Pipeline

“…An important property of albitiazolium is that it accumulates irreversibly in the Plasmodium up to 1000-fold. Albitiazolium inhibits parasite growth and halts disease progression in mice without recrudescence [16]. DSM265 (Phase I) inhibits Pf DHODH (Dihydroo rotate dehydrogenase (DHODH) is the enzyme which catalyzes the rate-limiting step of the de novo pyrimidine biosynthetic pathway) selectively over its human counterpart.…”