Dihydroorotate dehydrogenase (DHODH) is an enzyme involved in the de novo biosynthesis of pyrimidines. In humans, cells can acquire pyrimidines using two different pathways: the de novo biosynthesis and the salvage pathway. Plasmodium species, responsible for the transmission of Malaria, can gain pyrimidines only from the de novo pathway and, by reflex, blocking this biosynthesis offers a therapeutic opportunity to kill the parasite. P.falciparum DHODH (PfDHODH) has been validated as a drug target and, nowadays, two inhibitors are tested in clinical trials for Malaria [1]. Starting from compound 1, a PfDHODH inhibitor recently designed by our group [2], we here present a SAR study involving seven new analogues. Among them, compound 5 shows higher activity than 1 on Pf-infected erythrocytes. In this work, beside the design, synthesis, co-crystallization with PfDHODH protein, biological activities of new PfDHODH inhibitors are fully discussed.

Design, synthesis and co-crystallization of new Plasmodium falciparum dihydroorotate dehydrogenase inhibitors based on hydroxypyrazole scaffold

Noemi Villella;Agnese Chiara Pippione;Stefano Sainas;Donatella Boschi;Marco Lucio Lolli
2019

Abstract

Dihydroorotate dehydrogenase (DHODH) is an enzyme involved in the de novo biosynthesis of pyrimidines. In humans, cells can acquire pyrimidines using two different pathways: the de novo biosynthesis and the salvage pathway. Plasmodium species, responsible for the transmission of Malaria, can gain pyrimidines only from the de novo pathway and, by reflex, blocking this biosynthesis offers a therapeutic opportunity to kill the parasite. P.falciparum DHODH (PfDHODH) has been validated as a drug target and, nowadays, two inhibitors are tested in clinical trials for Malaria [1]. Starting from compound 1, a PfDHODH inhibitor recently designed by our group [2], we here present a SAR study involving seven new analogues. Among them, compound 5 shows higher activity than 1 on Pf-infected erythrocytes. In this work, beside the design, synthesis, co-crystallization with PfDHODH protein, biological activities of new PfDHODH inhibitors are fully discussed.
19th edition of the Merck Young Chemists' Symposium (MYCS-2019)
Rimini
25 - 27 Novembre, 2019.
Merck Young Chemists Symposium XIX edition (MEYCS 2019)
152
152
Noemi Villella, Agnese Chiara Pippione, Stefano Sainas, Donatella Boschi, Rosmarie Friemann, Alberto Gimenéz, Efrain Salamanca, Marco Lucio Lolli
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1852021
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