Malaria is one of the most widespread and ancient infectious diseases of humanity. In particular, Dihydroorotate dehydrogenase (DHODH) acts as a target for the development of new antimalarials. In addition, DHODH catalyzes the oxidation of dihydroorotate (DHO) to produce orotate, a key step in pyrimidine biosynthesis.

DHODH links mitochondrial bioenergetics, cell proliferation, ROS production, and apoptosis in certain cell types. In addition, DHODH inhibitors have great potential for use in prophylaxis. DSM705 shows good potency. DSM705 shows modest inhibition of CYP2C19 (IC50=6.3). DHODH is an essential enzyme that catalyzes the rate-limiting step of pyrimidine biosynthesis. Researchers demonstrated that resistance to DHODH inhibitors can be acquired through point mutations in the inhibitor-binding pocket or copy number variations (CNVs) at the dhodh locus. As a result, They chose the triazolopyrimidine inhibitor of DHODH, DSM705, for drug resistance studies in vitro and in vivo.

DHODH is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. DSM705 shows inhibitory activity against P. falciparum DHODH (PfDHODH), P. vivax DHODH (PvDHODH) and Pf3D7 cells. Moreover, DSM705 provides the maximum rate of parasite killing and fully suppresses parasitemia. Besides, DSM705 exhibits high oral bioavailability in Swiss outbred mice. DHODH is originally a target for the treatment of the non-neoplastic diseases involving rheumatoid arthritis and multiple sclerosis and is re-emerging as a validated therapeutic target for cancer therapy. Furthermore, DHODH also acts as a potential target in preclinical and clinical cancer therapies.

In summary, DSM705 is a potential dehydrogenase inhibitor with potent antimalarial activity.

Michael J Palmer, et al. Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series. J Med Chem. 2021 May 13;64(9):6085-6136.