Synthesis of the Enantiomers of Thioridazine

Abstract

Thioridazine, a well-known antipsychotic drug, has shown promising effects on several bacterial strains (including Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus). Suppressive effects towards selected cancer cell-lines have also been reported. However, due to adverse effects, the compound is no longer in use for the primary indication. More recent research has demonstrated that these side effects are limited to one of the two enantiomers, (+)-thioridazine. The question arises to whether the beneficial effects of thioridazine are limited to one enantiomer, or if (-)-thioridazine can prove itself to be useful in its pure enantiomeric state. The published procedures on the synthesis of the optically pure enantiomers of thioridazine were found to be unsatisfactory, either due to low optical purity, high cost, or problems scaling up. Herein, we have used an auxiliarybased strategy for the total synthesis of both enantiomers in high optical purity and good overall yield. The strategy can easily be scaled up. Both enantiomers were tested against several bacteria. Comparison of the racemic mixture, (-)-thioridazine and its (+)-antipode revealed that they have the same antimicrobial effects. Thus, the non-toxic enantiomer, (-)-thioridazine, can prove useful in this role and should be investigated further.

The Aryl Sulfide Synthesis via Sulfide Transfer

“…Especially, the MeS functional group needs to be introduced in the initial step. Here, MeS group was successfully introduced into the compound in the last step with MTBT as a “MeS” shuttle in a decent yield (70 %) as shown in Scheme 5a, providing a new synthetic route for 3 z , which may reduce the cost of the medicine [30–31] …”

“…Here, MeS group was successfully introduced into the compound in the last step with MTBT as a "MeS" shuttle in a decent yield (70 %) as shown in Scheme 5a, providing a new synthetic route for 3 z, which may reduce the cost of the medicine. [30][31] Sulfides and bromide groups have orthogonal chemical reactivities. [32] The former ones were usually functionalized in classic Liebeskind-Srogl reaction, which tolerated most crosscoupling reaction conditions when using aryl bromides as electrophiles.…”

A Double-Edged Sword: Thioxanthenes Act on Both the Mind and the Microbiome

“…This underlines the importance of having good procedures for the synthesis of the optically pure enantiomers, something that has been found to be unsatisfactory for the drug thioridazine. Antonsen S. has used an auxiliary-based strategy for the total synthesis of both enantiomers in high optical purity [ 118 ]. Ongoing studies have shown that the antimicrobial effects of these two enantiomers are similar [ 118 ], but further investigations are needed to determine whether the side effects are caused by one or both enantiomers.…”

“…Antonsen S. has used an auxiliary-based strategy for the total synthesis of both enantiomers in high optical purity [ 118 ]. Ongoing studies have shown that the antimicrobial effects of these two enantiomers are similar [ 118 ], but further investigations are needed to determine whether the side effects are caused by one or both enantiomers. In situations where the side effects are caused by only one enantiomer, pure-enantiomeric non-antibiotic drugs will open up the possibility for better treatments of resistant bacterial infections.…”