TY - JOUR
T1 - Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria
AU - Kokkonda, Sreekanth
AU - Deng, Xiaoyi
AU - White, Karen L.
AU - El Mazouni, Farah
AU - White, John
AU - Shackleford, David M.
AU - Katneni, Kasiram
AU - Chiu, Francis C.K.
AU - Barker, Helena
AU - Mclaren, Jenna
AU - Crighton, Elly
AU - Chen, Gong
AU - Angulo-Barturen, Inigo
AU - Jimenez-Diaz, Maria Belen
AU - Ferrer, Santiago
AU - Huertas-Valentin, Leticia
AU - Martinez-Martinez, Maria Santos
AU - Lafuente-Monasterio, Maria Jose
AU - Chittimalla, Rajesh
AU - Shahi, Shatrughan P.
AU - Wittlin, Sergio
AU - Waterson, David
AU - Burrows, Jeremy N.
AU - Matthews, Dave
AU - Tomchick, Diana
AU - Rathod, Pradipsinh K.
AU - Palmer, Michael J.
AU - Charman, Susan A.
AU - Phillips, Margaret A.
N1 - Funding Information:
The authors thank Sibylle Sax (Swiss TPH) for technical assistance with the SCID mouse model. Results shown in this report are derived from work performed at the Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. This work was supported by funds from the United States National Institutes of Health grant, R01AI103947 (to MAP and PKR), and from Medicines for Malaria Venture (MMV). MAP acknowledges the support of the Welch Foundation (I-1257). MAP holds the Sam G. Winstead and F. Andrew Bell Distinguished Chair in Biochemistry.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/5/14
Y1 - 2020/5/14
N2 - Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
AB - Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
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U2 - 10.1021/acs.jmedchem.0c00311
DO - 10.1021/acs.jmedchem.0c00311
M3 - Article
C2 - 32248693
AN - SCOPUS:85084693436
SN - 0022-2623
VL - 63
SP - 4929
EP - 4956
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -