Hexahydroquinoline molecules attacking malaria parasites.

Malaria Breakthrough: New Drugs on the Horizon?

Lena Voss in Health & Wellness November 2025 • 4 min read.

"Scientists identify potent antimalarial compounds that not only combat the disease but also block its transmission, offering hope for eradication."

Malaria continues to pose a significant global health challenge, disproportionately affecting sub-Saharan Africa. The relentless parasite Plasmodium falciparum is behind this disease, creating the need for effective treatment. Although efforts using artemisinin-based combination therapies and vector control measures have reduced morbidity and mortality, malaria remains persistent.

One promising strategy to accelerate malaria elimination is developing combination therapies that include transmission-blocking agents. These drugs target gametocytes, the parasite's sexual forms, which are responsible for infecting mosquitoes and continuing the transmission cycle. While primaquine is the only current drug with potent activity against mature gametocytes, its toxicity limits its use, driving the search for safer alternatives.

Now, researchers have pinpointed a new class of compounds that showcases dual activity, both treating the disease and preventing its spread. The article highlights the identification and characterization of hexahydroquinolines (HHQs), antimalarial candidates demonstrating potent blood-stage and transmission-blocking activity. This discovery can influence future malaria treatment.

Hexahydroquinolines: A Dual-Action Antimalarial

Hexahydroquinoline molecules attacking malaria parasites.

Hexahydroquinolines (HHQs) have emerged as promising antimalarial candidates, exhibiting nanomolar potency against both pathogenic and transmissible forms of Plasmodium falciparum. A recent study screened a library of compounds for activity against gametocytes, identifying HHQs as potent inhibitors. Further investigation revealed that these compounds not only kill the parasites responsible for causing malaria but also block the parasite's ability to infect mosquitoes, disrupting the transmission cycle.

In vitro assays demonstrated that HHQs effectively inhibit male gamete formation and reduce oocyst infection in Anopheles mosquitoes. In vivo studies in mice further confirmed the ability of HHQs to suppress blood-stage parasite proliferation. This dual-action approach is significant because it addresses both the treatment of infected individuals and the prevention of further spread, potentially accelerating malaria elimination efforts.

Dual-Action: Treats malaria and blocks transmission.
Potent Inhibitors: Nanomolar potency against parasite forms.
In Vitro Success: Effective in inhibiting gamete formation.
In Vivo Efficacy: Suppresses parasite proliferation in mice.

Further studies unveiled that resistance to HHQs is mediated by mutations in PfMDR1, a digestive vacuole membrane-spanning transporter. Interestingly, parasites resistant to HHQs showed increased susceptibility to several first-line antimalarial drugs, including lumefantrine. This suggests that HHQs have a different mechanism of action than other antimalarials, offering an opportunity to combine drugs with opposing selective pressures to combat multidrug-resistant malaria.

The Path Forward

The discovery of HHQs represents a significant step forward in the fight against malaria. By combining therapeutic and transmission-blocking activity, these compounds offer a unique approach to tackling this persistent disease. Further research and development will be crucial to optimizing HHQs and exploring their potential in combination therapies, ultimately bringing us closer to malaria eradication.

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This article is based on research published under:

DOI-LINK: 10.1038/s41564-017-0007-4, Alternate LINK

Title: Hexahydroquinolines Are Antimalarial Candidates With Potent Blood-Stage And Transmission-Blocking Activity

Subject: Cell Biology

Journal: Nature Microbiology

Publisher: Springer Science and Business Media LLC

Authors: Manu Vanaerschot, Leonardo Lucantoni, Tao Li, Jill M. Combrinck, Andrea Ruecker, T. R. Santha Kumar, Kelly Rubiano, Pedro E. Ferreira, Giulia Siciliano, Sonia Gulati, Philipp P. Henrich, Caroline L. Ng, James M. Murithi, Victoria C. Corey, Sandra Duffy, Ori J. Lieberman, M. Isabel Veiga, Robert E. Sinden, Pietro Alano, Michael J. Delves, Kim Lee Sim, Elizabeth A. Winzeler, Timothy J. Egan, Stephen L. Hoffman, Vicky M. Avery, David A. Fidock

Published: 2017-08-14

Everything You Need To Know

What causes Malaria?

The disease is caused by the parasite Plasmodium falciparum. Although existing methods like artemisinin-based combination therapies have reduced mortality, Malaria remains persistent. This persistence is due to the parasites ability to transmit. The article highlights the need for new antimalarial drugs that can block the transmission of Plasmodium falciparum.

What are hexahydroquinolines (HHQs)?

Hexahydroquinolines (HHQs) are a new class of antimalarial drugs. They are promising because they have a dual action: they treat the disease by killing the parasites and also prevent the spread by blocking the parasite's ability to infect mosquitoes. This dual action is a significant advantage over existing treatments.

How effective are hexahydroquinolines (HHQs)?

HHQs exhibit nanomolar potency against both the pathogenic and transmissible forms of Plasmodium falciparum. This means that they are effective at very low concentrations, which is a positive indicator for drug efficacy. The potency was demonstrated through in vitro assays, such as inhibiting male gamete formation and in vivo studies in mice that showed the suppression of blood-stage parasite proliferation.

What is the significance of PfMDR1 in relation to hexahydroquinolines (HHQs)?

The article mentions that resistance to HHQs is associated with mutations in PfMDR1, a digestive vacuole membrane-spanning transporter. However, parasites resistant to HHQs show increased susceptibility to other first-line antimalarial drugs, like lumefantrine. This suggests HHQs work differently than other antimalarials, offering an opportunity to combine drugs with opposing selective pressures to combat multidrug-resistant malaria.

What are the implications of hexahydroquinolines (HHQs) in the context of Malaria?

The implications of HHQs are significant in the fight against Malaria. By combining treatment of the disease and transmission-blocking capabilities, HHQs could potentially accelerate malaria elimination efforts. Further research and development are necessary to optimize HHQs and explore them in combination therapies to achieve this goal.