University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, 1000 Ljubljana, Slovenia.
University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, 1000 Ljubljana, Slovenia.
Bioorg Chem. 2019 Aug;89:102982. doi: 10.1016/j.bioorg.2019.102982. Epub 2019 May 15.
The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo[1,2-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-pyrazolo[1,2-a]pyrazole-1-carboxylate (IC = 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 COMe 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.
5-取代吡唑烷-3-酮、醛和甲基丙烯酸甲酯之间的反应提供了四氢吡唑并[1,2-a]吡唑-1-羧酸酯，它们是顺式和反式非对映异构体的混合物。对恶性疟原虫（PfDHODH）二氢乳清酸脱氢酶抑制作用的测试表明，一些甲酯的反式异构体具有很高的活性，而相应的羧酸和酰胺则没有活性。最具活性的代表物是甲基（1S*，3S*，5R*）-1,5-二甲基-7-氧代-3-苯基四氢-1H，5H-吡唑并[1,2-a]吡唑-1-羧酸酯（IC=2.9±0.3μM），它对寄生虫酶与人体酶PfDHODH/HsDHODH的选择性也非常高，超过 350。根据分子对接得分，这种高活性可以通过甲基、苯基和 COMe 取代基与酶活性位点的疏水口袋的协同相互作用来解释。来源于该化合物的羧酸和酰胺均不能抑制 PfDHODH。
