Tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylates as inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase |
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| Institution: | 1. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, USA;2. Institute for Chemical Research, Kyoto University, Japan;1. Department of Organic Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don, 344090, Russian Federation;2. Center for X-ray Diffraction Studies and Chemical Analysis and Materials Research Centre, Saint Petersburg State University, Universitetskii Pr., 26, Peterhof, 198504, Russian Federation;1. Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA;2. Department of Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, NJ 08854, USA;3. Department of Environmental Science, New York Medical College, Valhalla, NY 10595, USA;4. Buckman Laboratories, 1256 N. McLean Blvd, Memphis, TN 38108, USA;5. Laboratoire de Chimie Organique, Université Libre de Bruxelles, B-1050 Brussels, Belgium |
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| Abstract: | The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo1,2-a]pyrazole-1-carboxylates as mixtures of syn- and anti-diastereomers. Testing for inhibition of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH) revealed high activity of some anti-isomers of the methyl esters, while the corresponding carboxylic acids and carboxamides were not active. The most active representative, methyl (1S*,3S*,5R*)-1,5-dimethyl-7-oxo-3-phenyltetrahydro-1H,5H-pyrazolo1,2-a]pyrazole-1-carboxylate (IC50 = 2.9 ± 0.3 μM), also exhibited very high selectivity of the parasite enzyme vs. the human enzyme, PfDHODH/HsDHODH > 350. According to the molecular docking score, this high activity is explainable by synergic interactions of the methyl, phenyl and the CO2Me substituent with the hydrophobic pockets in the active site of the enzyme. The carboxylic acid and carboxamides derived from this compound did not inhibit PfDHODH. |
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| Keywords: | Malaria Pyrazolidinones Dihydroorotate dehydrogenase Enzyme inhibition |
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