Cathepsin L inhibitors with activity against the liver fluke identified from a focus library of quinoxaline 1,4-di-N-Oxide derivatives

This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research IIInfections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC50 of less than 10 µM in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases

4-{[(E)-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl­idene]amino}-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one

The title Schiff base compound, C23H23N5O, was synthesized by the reaction of 4-amino­phenazone and 3,5-dimethyl-1-phenyl­pyrazole-4-carbaxaldehyde. The mol­ecule adopts an E configuration about the central C=N double bond. A weak intra­molecular C—H⋯O hydrogen bond generates an S(6) ring motif. The dihedral angle between the pyrazole rings is 24.72 (10)° and the dihedral angles between the pyrazole rings and the adjacent phenyl rings are 58.67 (10) and 46.58 (11)°. The crystal structure is stabilized by weak C—H⋯π inter­actions involving the pyrazolone and phenyl rings

Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes-6

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...]