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

Microbiol. Spectrum, 2021, 9 (2), e00274-21, https://journals.asm.org/doi/10.1128/spectrum.00274-21

H. Bosson-Vanga, N. Primas, J.-F. Franetich, C. Lavazec, L. Gomez, K. Ashraf, M. Tefit, V. Soulard, N. Dereuddre-Bosquet, R. Le Grand, M. Donnette, R. Mustière, N. Amanzougaghene, S. Tajeri, P. Suzanne, A. Malzert-Fréon, S. Rault, P. Vanelle, S. Hutter, A. Cohen, G. Snounou, P. Roques, N. Azas, P. Lagardère, V. Lisowski, N. Masurier, M. Nguyen, L. Paloque, F. Benoit-Vical, P. Verhaeghe, D. Mazier


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.