Abstract
Ionic liquids derived from classical antimalarials are emerging as a new approach towards the cost-effective rescuing of those drugs. Herein, we disclose novel surface-active ionic liquids derived from chloroquine and natural fatty acids whose antimalarial activity in vitro was found to be superior to that of the parent drug. The most potent ionic liquid was the laurate salt of chloroquine, which presented IC50 values of 4 and 110 nM against a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum, respectively, corresponding to an 11- and 6-fold increase in potency as compared to the reference chloroquine bisphosphate salt against the same strains. This unprecedented report opens new perspectives in both the fields of malaria chemotherapy and of surface-active ionic liquids derived from active pharmaceutical ingredients.
Highlights
Ionic liquids (ILs) are gaining prominence as chemical entities of interest in medicinal chemistry, as well as pharmaceutical science and technology [1,2,3,4]
All compounds were analyzed by simultaneous thermogravimetric analysis (STA), as given in detail in the SM, to assess their thermal stability, an important issue for active pharmaceutical ingredients (APIs) typically employed in
Available CQ phosphate salt was first converted into the free amine form 1a, which reacted with fatty acids 2a–e via an acid-base neutralization previously reported by us [11], to afford 3a–e (Scheme 1)
Summary
Ionic liquids (ILs) are gaining prominence as chemical entities of interest in medicinal chemistry, as well as pharmaceutical science and technology [1,2,3,4]. The development of ILs derived from APIs (API-ILs) is an appealing strategy towards the rescuing of drugs that are falling into disuse due to these and other detrimental traits With this idea in mind, and following our previous promising findings on cinnamic acid conjugates of classical antimalarial drugs [7,8,9,10], we applied the API-IL concept onto such drugs, by disclosing room temperature ionic liquids (RTILs) derived from primaquine (PQ) and cinnamic acids as triple-stage antimalarial hits [11]. The most remarkable property of these RTILs was their increased activity against blood-stage malaria parasites, on which PQ has a practically negligible action [12]. We hypothesized that the combination of a blood schizonticide like chloroquine (CQ) with amphiphilic natural fatty acids might deliver new organic salts (Scheme 1) in the form of RTILs with enhanced blood-stage activity, possibly suitable for
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