Primaquine-based ionic liquids as a novel class of antimalarial hits

Abstract

a Descriptors values estimated with molecular operating environment (MOE) soware. 28This journal is

Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs

“…Compounds 20 and 21 were all produced in quantitative yield by acid-base titration of a methanolic solution of the antimalarial drug with a methanolic solution of the CA, and were all liquids at room temperature, hence, classifiable as room-temperature ionic liquids (RTIL). Complete transfer of the acidic proton from the CA building block to the antimalarial aminoquinoline was confirmed by proton nuclear magnetic resonance ( 1 H-NMR) [92]. the mouse bone marrow-derived macrophages [81].…”

“…Compounds 20 and 21 were all produced in quantitative yield by acid-base titration of a methanolic solution of the antimalarial drug with a methanolic solution of the CA, and were all liquids at room temperature, hence, classifiable as room-temperature ionic liquids (RTIL). Complete transfer of the acidic proton from the CA building block to the antimalarial aminoquinoline was confirmed by proton nuclear magnetic resonance ( 1 H-NMR) [92]. Remarkably, the primaquine-derived RTIL 21 were found not only to preserve or even slightly improve the in vitro activity of the parent antimalarial against liver-stage P. berghei parasites and stage V gametocytes of P. falciparum, but also to cause a 4-fold increase in activity against the blood-stage (0.94 < IC 50 < 3.4 µM and 0.69 < IC 50 < 1.4 µM for 3D7 and Dd2 strains, respectively), as compared to primaquine (IC 50 = 6.1 and 4.7 µM, for 3D7 and Dd2 strains, respectively) [92].…”

“…Based on this, Ferraz et al have investigated the therapeutic potential of new API-IL produced by an acid-base combination of CA with the basic antimalarials chloroquine and primaquine (compounds 20 and 21, Figure 9). In other words, compounds 20 and 21 can be regarded as ionic surrogates of the antimalarial drug-CA covalent (amide) conjugates 8 ( Figure 2) and 9 (Figure 3), respectively [85,[92][93][94]. Compounds 20 and 21 were all produced in quantitative yield by acid-base titration of a methanolic solution of the antimalarial drug with a methanolic solution of the CA, and were all liquids at room temperature, hence, classifiable as room-temperature ionic liquids (RTIL).…”

“…Indeed, we have very recently observed that, while chloroquine-CA covalent conjugates 8 are highly toxic for bone marrow-derived macrophages (BMM), their RTIL counterparts 20 are not, which might be related to the fact that the former, but not the latter, tend to crystallize in BMM cell cultures ( Figure 10) [97]. Remarkably, the primaquine-derived RTIL 21 were found not only to preserve or even slightly improve the in vitro activity of the parent antimalarial against liver-stage P. berghei parasites and stage V gametocytes of P. falciparum, but also to cause a 4-fold increase in activity against the bloodstage (0.94 < IC50 < 3.4 μM and 0.69 < IC50 < 1.4 μM for 3D7 and Dd2 strains, respectively), as compared to primaquine (IC50 = 6.1 and 4.7 μM, for 3D7 and Dd2 strains, respectively) [92]. The same authors have later hypothesized that such an increase might be due to a better interaction of the RTIL with the membranes of PiRBC, based on biophysical studies using model membranes [93].…”

Antiproliferative Organic Salts Derived from Betulinic Acid: Disclosure of an Ionic Liquid Selective Against Lung and Liver Cancer Cells

“…1, 59,60 As such, we have been successfully employing this method for the synthesis of ILs and organic salts derived from different API. 1, 28 The target organic salts derived from BA and the antimalarial drugs [ Figure 3a) were thus synthesized by the neutralization method, as previously reported, 28 whereby each of the basic antimalarials was reacted with an equimolar amount of BA. 1, 28 For the chemical synthesis of [P 6,6,6,14 ][BA] (Figure 3b), the commercially available chloride salt [P 6,6,6,14 ][Cl] was converted into the hydroxide, using an Amberlyst anion exchange resin (A26-OH), prior to the neutralization reaction with BA.…”