Disulfide Prodrugs of Albitiazolium (T3/SAR97276): Synthesis and Biological Activities Sergio A. Caldarelli, †,⊥ Matthieu Hamel, †,⊥ Jean-Fre ́ de ́ ric Duckert, † Mahama Ouattara, † Miche ̀ le Calas, † Marjorie Maynadier, ‡ Sharon Wein, ‡ Christian Pe ́ rigaud, † Alain Pellet, § Henri J. Vial,* ,‡ and Suzanne Peyrottes* ,† † Institut des Biomole ́ cules Max Mousseron (IBMM), UMR 5247 CNRS-UM1&2, Universite ́ Montpellier 2, cc 1705, place E. Bataillon, 34095 Montpellier, France ‡ Dynamique des Interactions Membranaires Normales et Pathologiques (DIMNP), UMR 5235 CNRS-UM2, Universite ́ Montpellier 2, cc 107, place E. Bataillon, 34095 Montpellier, France § Sanofi Research & Development, 195 route d’Espagne, BP 13669, 31036 Toulouse, France *S Supporting Information 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. ■ INTRODUCTION Malaria is the most prevalent parasite disease, causing each year 250 million cases and 800 000 deaths, mostly in African children, and 80% of these cases are located in sub-Saharan Africa. 1,2 Among the key interventions for controlling this disease, the arsenal of antimalarial drugs is critical, but the current choice of drugs is limited. 3 The discovery and development of the artemisinin derivatives in China have provided a new class of highly effective antimalarials now used as artemisinin-based combination therapy (ACTs) to overcome the chemoresistance problem. However, artemisinin-resistant parasites recently reported in Asia could seriously undermine global malaria control. 4,5 Plasmodium falciparum, the most pathogenic human malaria parasite, is becoming pharmacor- esistant to conventional as well as newly discovered drugs; thus, the need for new antimalarial strategies involving novel targets is as crucial as ever. 6 Thus, various research groups are developing a new family of derivatives differing in their mechanisms of action. 3,7 A decade ago, some of us contributed to this challenge with a novel class of choline analogues. The structure of these potent antimalarials is based on a long lipophilic chain incorporating two thiazolium cationic heads. 8−12 One lead compound, namely albitiazolium bromide (T3/SAR97276, compound 1, Figure 1) shows high efficacy in vitro against P. falciparum and in vivo against P. vinckei in mouse and primate malaria models 8,10,11 and has fulfilled multiple criteria required for its development. Available in a single-step synthesis from commercial reactants, its preparation is therefore adapted for large-scale and low-cost production. Potency and specificity of these antiphospholipid effectors are likely due to their unique property to accumulate in a nonreversible way inside the intraerythrocytic parasite. 11,13,14 The efficiency of albitiazolium comes from its dual mechanism of action that involves, on one hand, the inhibition of the de novo phosphatidylcholine biosynthesis 11 and, on the other hand, an interaction with the ferriprotoporphyrin IX (FPIX) which leads to heme detoxification. 13 Currently, albitiazolium is undergoing phase II clinical trials to treat severe malaria by parenteral administration due to its poor oral bioavailability. Most of the infections by malaria parasites occur in tropical or subtropical countries where the medical care systems are not always available. Consequently, the way of administration of albitiazolium limits its therapeutic use to the treatment of severe malaria and highlights the need for an oral form to treat uncomplicated malaria on a large scale. Owing to the presence of two cationic charges, bis-thiazolium derivatives have greater difficulty crossing biological barriers, especially the intestinal epithelium. Thus, we devoted our recent efforts to the design of S-acyl prodrug approaches to temporally mask the cationic charges, and it was anticipated that the resulting lipophilic albitiazolium prodrugs would then be able to cross the intestinal epithelium by passive diffusion. 11,15 So far, the best absolute bioavailability obtained for a thioester-type prodrug was 15% in rat, 16 and this modest improvement was attributed to the early conversion of the Received: January 17, 2012 Published: May 16, 2012 Article pubs.acs.org/jmc © 2012 American Chemical Society 4619 dx.doi.org/10.1021/jm3000328 | J. Med. Chem. 2012, 55, 4619−4628