Malaria remains one of the most devastating infectious diseases globally, imposing an enormous burden on public health, economic development, and human wellbeing, particularly in tropical and subtropical regions of the world. According to the World Health Organization, there were an estimated 247 million malaria cases worldwide in 2021, resulting in approximately 619,000 deaths, with the African continent bearing the disproportionate burden of over 95% of cases and deaths. Plasmodium falciparum, the most virulent of the human malaria parasites, is responsible for the vast majority of severe malaria cases and malaria-related deaths, particularly among children under five years of age and pregnant women. Over the past two decades, the global malaria control effort has achieved remarkable progress, driven by the widespread deployment of insecticide-treated bed nets, indoor residual spraying, prompt diagnosis and effective treatment with artemisinin-based combination therapies (ACTs), and, more recently, the introduction of the first malaria vaccine.
These interventions have saved millions of lives and have reduced malaria morbidity and mortality in many endemic regions. However, this progress is now threatened by the emergence and spread of antimalarial drug resistance, particularly resistance to artemisinin, the cornerstone of ACTs. Artemisinin resistance was first detected in western Cambodia in 2008 and has since spread across the Greater Mekong Subregion, with focal areas of resistance also reported in Africa in recent years. The potential for artemisinin resistance to become established in Africa, where the malaria burden is highest and healthcare systems are often fragile, represents an urgent global public health emergency that could reverse decades of progress in malaria control and lead to a dramatic resurgence in malaria morbidity and mortality. This looming crisis underscores the critical and immediate need for the discovery and development of novel antimalarial drugs with innovative mechanisms of action that are not affected by existing resistance mechanisms and that can be deployed as part of new combination therapies to sustain the global malaria elimination effort. The hemozoin detoxification pathway represents one of the most validated and attractive targets for antimalarial drug development, as it is a process that is absolutely essential for parasite survival within infected erythrocytes and that has no equivalent in human cells, providing an excellent therapeutic index. During the intraerythrocytic stage of its life cycle, Plasmodium falciparum invades red blood cells and digests massive quantities of host hemoglobin to obtain amino acids for its own protein synthesis and growth.
Hemoglobin digestion occurs within the parasite's digestive vacuole, an acidic lysosome-like organelle, and releases large quantities of free heme (ferriprotoporphyrin IX), which is highly toxic to the parasite due to its ability to generate reactive oxygen species, disrupt membrane integrity, and inhibit essential enzymatic processes. To protect itself from this toxic byproduct, the parasite has evolved a sophisticated detoxification mechanism in which free heme molecules are sequestered into an insoluble, crystalline pigment called hemozoin (also known as malaria pigment), through a process of biomineralization that occurs within the digestive vacuole. Hemozoin formation is mediated by a combination of mechanisms, including catalysis by histidine-rich protein 2 (HRP2) and HRP3, lipid-mediated nucleation, and spontaneous crystallization at the acidic pH of the digestive vacuole.
The critical importance of this pathway for parasite survival is demonstrated by the mechanism of action of chloroquine, one of the most successful antimalarial drugs in history, which accumulates in the parasite's digestive vacuole and binds to free heme, preventing its incorporation into hemozoin and thereby causing the accumulation of toxic heme that kills the parasite. Other quinoline antimalarials, including amodiaquine, piperaquine, and mefloquine, share a similar mechanism of hemozoin inhibition, and the clinical success of these drugs validates the hemozoin detoxification pathway as a highly effective drug target. However, the widespread emergence of resistance to chloroquine and other quinolines, mediated primarily by mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) that reduce drug accumulation in the digestive vacuole, has limited the utility of these drugs in many regions, highlighting the need for novel chemical scaffolds that can target the hemozoin pathway while evading existing resistance mechanisms.
This perspective article proposes an innovative and mechanistically grounded hypothesis for a new class of hemozoin inhibitors based on chlorophyll derivatives, specifically chlorin e6 and related compounds, which could act as tetrapyrrole mimics that disrupt hemozoin formation in Plasmodium falciparum. The rationale for this approach is based on the striking structural and functional similarities between heme, the natural substrate for hemozoin formation, and chlorophyll derivatives, both of which possess a tetrapyrrole macrocyclic structure, a planar aromatic ring system, and a central metal ion (iron in heme, magnesium in chlorophyll, or no metal in certain chlorophyll derivatives).

DOI
10.1007/s11684-026-1214-2