The Antimalarial Ferroquine: Role of the Metal and Intramolecular Hydrogen Bond in Activity and Resistance

Abstract

Inhibition of hemozoin biocrystallization is considered the main mechanism of action of 4-aminoquinoline antimalarials including chloroquine (CQ) but cannot fully explain the activity of ferroquine (FQ) which has been related to redox properties and intramolecular hydrogen bonding. Analogues of FQ, methylferroquine (Me-FQ), ruthenoquine (RQ), and methylruthenoquine (Me-RQ), were prepared. Combination of physicochemical and molecular modeling methods showed that FQ and RQ favor intramolecular hydrogen bonding between the 4-aminoquinoline NH group and the terminal amino group in the absence of water, suggesting that this structure may enhance its passage through the membrane. This was further supported by the use of Me-FQ and Me-RQ where the intramolecular hydrogen bond cannot be formed. Docking studies suggest that FQ can interact specifically with the {0,0,1} and {1,0,0} faces of hemozoin, blocking crystal growth. With respect to the structure-activity relationship, the antimalarial activity on 15 different P. falciparum strains showed that the activity of FQ and RQ were correlated with each other but not with CQ, confirming lack of cross resistance. Conversely, Me-FQ and Me-RQ showed significant cross-resistance with CQ. Mutations or copy number of pfcrt, pfmrp, pfmdr1, pfmdr2, or pfnhe-1 did not exhibit significant correlations with the IC(50) of FQ or RQ. We next showed that FQ and Me-FQ were able to generate hydroxyl radicals, whereas RQ and me-RQ did not. Ultrastructural studies revealed that FQ and Me-FQ but not RQ or Me-RQ break down the parasite digestive vacuole membrane, which could be related to the ability of the former to generate hydroxyl radicals.

In vitro antiplasmodial effect of ethanolic extracts of coastal medicinal plants along Palk Strait against Plasmodium falciparum

“…The mechanism of action might be due to the inhibition of P. falciparum merozoites invasion into the erythrocytes and disruption of P. falciparum rosettes by the carbohydrates [31][32][33] ; inhibition of P. falciparum fatty acid biosynthesis [34] , inhibition of hemozoin biocrystallization by the alkaloids and inhibition of protein synthesis by triterpenoids [35,36] . It is concluded from the present study that ethanolic extracts from A. indica and J. glandulifera displayed in vitro antiplasmodial activity and warrant further investigation of these plants as potential sources of antiplasmodial agents.…”

Platinum(II) and palladium(II) complexes with (N,N′) and (C,N,N′)− ligands derived from pyrazole as anticancer and antimalarial agents: Synthesis, characterization and in vitro activities

“…As our interests lie also in the area of antiparasitic drugs [42,43] and since a few Pt(II) [44] and Pd(II) based complexes [45] with antimalarial activity (in the micromolar range) have been reported, we also tested the potential of the free ligands (1a-1c) and the complexes 2a-5c against the chloroquine-susceptible strain (3D7) and the chloroquine-resistant strain (W2) of Plasmodium falciparum.…”

The Phenolic Compound from <i>Kalanchoe blossfeldiana</i> (Crassulaceae) Leaf and Its Antiplasmodial Activity against <i>Plasmodium falciparum</i> 3D7

“…From the point of ethnopharmacology, Kalanchoe plants are used as traditional medicines to cure headache, cough, chest pain, ulcer and skin diseases. They cure fever, fix the irregular menstruation, heal wound, hypertension and are utilized, not only in Indonesia but also almost sure [6][7][8][9][10][11][12][13][14][15][16] everywhere in the world [3][4]. Traditional medicines are potential sources for new drugs.…”

“…Biological activity is related to the presence of active groups of Kalanchoe plants [11] (Fig. 1), like ortho acetate and α-phyrone in bufadienolide [6][7][8][9][10][11][12], hydroxyl in phenolic compounds [13][14][15] and amine in alkaloid compounds [16] . The relevance of a functional group of secondary metabolites and their activity are very interesting to study, especially phenolic compounds which are the largest secondary metabolite in Kalanchoe [5].…”