Ivermectin hybrids – potential insecticidal and multistage antiplasmodial drugs for malaria control

Malaria remains a major health concern in the regions where it is endemic, being responsible for the death of over 600 000 people in 2020 alone, and taking its biggest toll on young children. Throughout the years, malaria control has relied on three different strategies: development of an effective vaccine, employment of preventive measures to control the mosquito population, and use of prophylactic and/or therapeutic drugs. The former has not yet been attained, as the malaria vaccine candidate recommended by the World Health Organization RTS,S/AS01 is only ~34% effective, and the latter two have been limited by the development of drug resistance by both mosquitoes and parasites. Thus, it is crucial that new tools are found to control this infectious disease, particularly drugs with multistage activity that can act throughout the complex life cycle of malaria’s etiologic agent, the Plasmodium parasite. Ivermectin IVM, an endectocide used in mass drug administration MDA to treat neglected tropical diseases, such as onchocerciasis and lymphatic filariasis, has shown promising potential for malaria control, either indirectly by killing the mosquito vector, or directly by impairing the parasite’s development. In the mammalian host, although IVM was shown to impact the liver stage bottleneck of infection, its effect on the subsequent, symptomatic blood stage of infection remains controversial.

With the aim of developing compounds that could tackle both infection stages, efficaciously, the team has previously designed two generations of IVM hybrid conjugates. In the first-generation of compounds, the IVM macrolide was covalently linked to an antimalarial pharmacophore, leading to a potent compound that displayed over 3-fold and 10-fold higher in vitro activity than IVM against the liver and blood stages of Plasmodium infection, respectively. However, this compound lacked the insecticidal activity observed with the parental molecule. The second-generation of IVM hybrids incorporated sub-structures of the 4- and 8-aminoquinolines commonly employed in the treatment of blood and liver stage Plasmodium infections, which resulted in a further improvement of their antiplasmodial activity, although their insecticidal activity remains to be evaluated. These dual-action molecules presented structure-dependent activity, suggesting that chemical modification of the IVM molecule may produce compounds with increased potency relative to that of the parental molecule. Thus, these results prompted the design and synthesis of a third-generation of IVM hybrid molecules, whose antiplasmodial and insecticidal activities remain to be characterized. The project will further seek to shed light on the mechanism of action of both newly designed and previously reported compounds by identifying the step of liver stage cell traversal, hepatocyte invasion, and/or intrahepatic development where they act upon. Finally, this study intends to characterize, for the first time, the liver and blood stage activities of the most potent compounds in vivo , in a rodent model of Plasmodium infection. This preclinical analysis will be crucial to support the subsequent pursuit of the clinical development of IVM hybrids as potential antiplasmodial drugs. The interdisciplinary team offers crucial complementary expertise on medicinal chemistry and parasitology. By combining the observations on compound activity against Plasmodium infection with the medicinal chemistry expertise, it will be able to extract structure-activity relationships that will lead to the design of new, improved hybrid molecules. Importantly, the host institution offers the exceptional possibility of assessing the impact of the hybrid molecules in every step of the parasite’s complex life cycle, including those that are dependent on the availability of the mosquito vector. Collectively, it is expected that this translational work will identify and characterize IVM-based compounds with potent multistage antiplasmodial activity, advancing their research and development towards an application in the prevention and treatment of malaria. On the long run, the clinical development and application of such drugs will contribute to end the malaria epidemics, in line with the 2030 United Nations Agenda for Sustainable Development, bringing healthier lives to the populations of endemic areas and decreasing the economic burden imposed by this disease.

Drug-based Strategies
Product Development

Jan 2023 — Jun 2024

$55,546

Portugal

Ivermectin for malaria