A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites.

Abstract

Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease via the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity. One molecule, named gamhepathiopine (denoted as "M1" herein), was active at submicromolar concentrations against both erythrocytic (50% effective concentration [EC50] = 0.045 μM) and liver (EC50 = 0.45 μM) forms of Plasmodium falciparum. Furthermore, gamhepathiopine efficiently blocked the development of the sporogonic cycle in the mosquito vector by inhibiting the exflagellation step. Moreover, M1 was active against artemisinin-resistant forms (EC50 = 0.227 μM), especially at the quiescent stage. Nevertheless, in mice, M1 showed modest activity due to its rapid metabolization by P450 cytochromes into inactive derivatives, calling for the development of new parent compounds with improved metabolic stability and longer half-lives. These results highlight the thienopyrimidinone scaffold as a novel antiplasmodial chemotype of great interest to search for new drug candidates displaying multistage activity and an original mechanism of action with the potential to be used in combination therapies for malaria elimination in the context of artemisinin resistance. IMPORTANCE This work reports a new chemical structure that (i) displays activity against the human malaria parasite Plasmodium falciparum at 3 stages of the parasitic cycle (blood stage, hepatic stage, and sexual stages), (ii) remains active against parasites that are resistant to the first-line treatment recommended by the World Health Organization (WHO) for the treatment of severe malaria (artemisinins), and (iii) reduces transmission of the parasite to the mosquito vector in a mouse model. This new molecule family could open the way to the conception of novel antimalarial drugs with an original multistage mechanism of action to fight against Plasmodium drug resistance and block interhuman transmission of malaria.

• Authors: Henriette Bosson-Vanga, Nicolas Primas, Jean-François Franetich, Catherine Lavazec, Lina Gomez, Kutub Ashraf, Maurel Tefit, Valérie Soulard, Nathalie Dereuddre-Bosquet, Roger Le Grand, Mélanie Donnette, Romain Mustière, Nadia Amanzougaghene, Shahin Tajeri, Peggy Suzanne, Aurélie Malzert-Fréon, Sylvain Rault, Patrice Vanelle, Sébastien Hutter, Anita Cohen, Georges Snounou, Pierre Roques, Nadine Azas, Prisca Lagardère, Vincent Lisowski, Nicolas Masurier, Michel Nguyen, Lucie Paloque, Françoise Benoit-Vical, Pierre Verhaeghe, Dominique Mazier
• Journal: Microbiology spectrum (Microbiol Spectr) Vol. 9 Issue 2 Pg. e0027421 (10 31 2021) ISSN: 2165-0497 [Electronic] United States
• PMID: 34724729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Artemisinins
• Pyrimidinones
• artemisinin

Topics

• Animals
• Antimalarials (chemistry, pharmacology)
• Artemisinins (pharmacology)
• Cell Line, Tumor
• Disease Models, Animal
• Dogs
• Drug Resistance (physiology)
• Female
• Hep G2 Cells
• Humans
• Liver (parasitology)
• Macaca fascicularis
• Madin Darby Canine Kidney Cells
• Malaria, Falciparum (drug therapy)
• Male
• Mice
• Mice, Inbred BALB C
• Plasmodium cynomolgi (drug effects)
• Plasmodium falciparum (drug effects)
• Plasmodium yoelii (drug effects)
• Pyrimidinones (chemistry, pharmacology)