Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies

Author(s):Show less -

Pippione, Agnese C. ^[1] ; Sainas, Stefano ^[1] ; Goyal, Parveen ^{[2, 3]} ; Fritzson, Ingela ^[4] ; Cassiano, Gustavo C. ^[5] ; Giraudo, Alessandro ^[1] ; Giorgis, Marta ^[1] ; Tavella, Tatyana A. ^[5] ; Bagnati, Renzo ^[6] ; Rolando, Barbara ^[1] ; Caing-Carlsson, Rhawnie ^[2] ; Costa, Fabio T. M. ^[5] ; Andrade, Carolina Horta ^[7] ; Al-Karadaghi, Salam ^[8] ; Boschi, Donatella ^[1] ; Friemann, Rosmarie ^{[2, 9]} ; Lolli, Marco L. ^[1]

Affiliation

^[1] Univ Turin, Dept Sci & Drug Technol, Via Pietro Giuria 9, I-10125 Turin - Italy

^[2] Univ Gothenburg, Dept Chem & Mol Biol, Box 462, S-40530 Gothenburg - Sweden

^[3] Inst Stem Cell Biol & Regenerat Med, Technol Adv Sci, Bengaluru 560065 - India

^[4] Chemoswed, Celsiusgatan 35, S-21214 Malmo - Sweden

^[5] Univ Estadual Campinas, Dept Genet Evolut & Bioagents, Lab Trop Dis Prof Luiz Jacintho da Silva, BR-13083864 Campinas, SP - Brazil

^[6] Ist Ric Farmacol Mario Negri IRCCS, Via La Masa 19, I-20156 Milan - Italy

^[7] Univ Fed Goias, LabMol, Fac Pharm, BR-74605170 Goiania, Go - Brazil

^[8] Lund Univ, Dept Biochem & Struct Biol, Lund - Sweden

^[9] Univ Gothenburg, Ctr Antibiot Resistance Res CARe, Box 440, S-40530 Gothenburg - Sweden

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 163, p. 266-280, FEB 1 2019.
• Web of Science Citations: 3

Abstract

Plasmodium falciparum dihydroorotate dehydrogenase (PJDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PJDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles. Within this series, the hydroxythiadiazole 3 was identified as the best selective PJDHODH inhibitor (IC50 12.0 mu M). The second series was designed by modulating four different positions of the hydroxypyrazole scaffold. In particular, hydroxypyrazoles 7e and 7f were shown to be active in the low mu M range (IC50 2.8 and 5.3 mu M, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC50> 200 mu M), low cytotoxicity, and retained micromolar activity in P. falciparum-infected erythrocytes. The crystallographic structures of PJDHODH in complex with compounds 3 and 7e proved their binding mode, supplying essential data for future optimization of these scaffolds. (C) 2018 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 15/20774-6 - Identifying protein kinase inhibitors as antimalarial agents using chemogenomic, bioinfomatics and phenotypic strategies: focus in Plasmodium vivax.
• Grantee: Gustavo Capatti Cassiano
• Support Opportunities: Scholarships in Brazil - Post-Doctoral