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.
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Article Synopsis
- Chemotherapy is a common yet problematic cancer treatment due to issues like poor drug solubility, stability, and drug resistance that lead to limited effectiveness and severe side effects.
- Researchers are exploring innovative combinations of therapies, focusing on targeted therapy, prodrug design, and drug delivery to create improved treatments, such as a self-assembled camptothecin (CPT) prodrug known as CPT-SS-FFEYp-Biotin.
- This prodrug enhances the therapeutic effects on tumor cells while minimizing harm to normal cells, demonstrating greater efficacy and safety, and suggesting potential for developing more prodrugs for effective cancer treatments in the future.
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