Hemozoin Biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors

Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine‐Resistant Plasmodium falciparum

“…[2] Still, the major mechanism of action of 1 is quite well understood-it is believed to block the biocrystallization of heme, the main process through which Plasmodia eliminate toxic heme after it is released from parasite digestion of host erythrocyte hemoglobin. [3] A recent rational approach of antimalarial drug design characterized as "covalent bitherapy" involves linking two molecules with individual intrinsic activity to create a single agent, thus packaging dual activity into a single hybrid molecule. [4,5] In this regard, we have synthesized twelve novel compounds (7) with the heteroaromatic core of 1, 4-amino-7-chloroquinoline, linked to differently substituted cinnamoyl groups (CIN) through a flexible aminobutyl spacer (Scheme 1 a).…”

“…[4,5] In this regard, we have synthesized twelve novel compounds (7) with the heteroaromatic core of 1, 4-amino-7-chloroquinoline, linked to differently substituted cinnamoyl groups (CIN) through a flexible aminobutyl spacer (Scheme 1 a). Compound design rationale was based on 1) relevance of 6 for inhibition of heme biocrystallization, and consequently, of the development of erythrocytic malaria parasites; [3] and 2) previous reports on cinnamic acid derivatives with promising antimalarial properties. [6][7][8] Moreover, we have recently demonstrated that 1) a spacer between the chloroquinoline and cinnamoyl moieties is required for antiplasmodial activity, as conjugates 5, bearing a dipeptide spacer between those moieties were active, whereas their counterparts 4 lacking such spacer were not; and 2) the higher the lipophilicity of conjugates 5, the higher the antiplasmodial activity.…”

From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy

“…As is the case for most antimicrobial drugs, resistant strains of the target organism eventually developed. However, since the mechanism of the drug (inhibition of hemozoin biocrystallization) involves a host-derived drug target (which cannot be modified by the malarial parasite), it took over 20 years for resistant forms of malaria to develop (Hempelmann 2007). For those 20 years, Andersag's drug saved countless lives and it continues to be an effective antimalarial treatment nearly 80 years later.…”

Existing drugs and their application in drug discovery targeting cancer stem cells

“…This process occurs in an acidic organelle vacuole. Chloroquine, as a weak base, is accumulated in a vacuole and prevent biocrystallization of heme, thus causing heme toxicity to the parasite (Hempelmann 2007). In addition to antimalaria activity, chloroquine has the potential effects on other diseases, such as rheumatoid arthritis (Augustijns et al 1992), lupus erythematosus (Meinao et al 1996) and cancer (Solomon and Lee 2009).…”