Novel Organic Salts Based on Mefloquine: Synthesis, Solubility, Permeability, and In Vitro Activity against Mycobacterium tuberculosis

Abstract

The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).

Ionic Liquids: New Forms of Active Pharmaceutical Ingredients with Unique, Tunable Properties

“…When an API-IL is prepared, the first important question is whether the API-IL retains (or even improves) its biological activity. This has been studied in vitro on numerous API-ILs with antibacterial ions in their structure. ,,,− For example, when the acidic antibiotic ampicillin was paired with hexadecyl­pyridinium, the API-IL was significantly more active against both Gram-positive and Gram-negative bacteria, compared to the parent compounds, sodium ampicillinate or hexadecylpyridinium chloride . The same API-IL exhibited higher antitumor activity than sodium ampicillinate .…”

“…It is important to note, however, that the prepared antibacterial compounds, have been named “Organic Salts and Ionic Liquids” (“OSILs”) − and even “Organic salts” with the term “ionic liquids” listed as a keyword in a few literature examples, in order to also include high­(er) melting organic salts. We would like to warn the reader against this practice because (1) high­(er) melting organic salts have their own designation in the field as “a group of uniform materials based on organic salts” (GUMBOS), (2) it is the intentional development of liquid forms of APIs with targeted melting points below body temperature that allows for elimination of a growing number of problems associated with solid dosage forms of pharmaceuticals, and (3) listing “ionic liquids” as a keyword for a research paper that only deals with higher-melting solids results in erroneous databases searches.…”