Abstract
Infections 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.
Highlights
Liver flukes of Fasciola species infect cattle and sheep worldwide causing important economic global losses of over US$3 billion annually to the agricultural sector [1], and are responsible for increasing numbers of human infections, being recognized as an emerging human zoonosis by theWorld Health Organization
We chose a set of twenty-eight quinoxaline 1,4-di-N-oxide derivatives with different substituents in R1–R4 (Table 1) that were tested as inhibitors of two F. hepatica cysteine proteases
We performed a screening of twenty-eight quinoxaline 1,4-di-N-oxide derivatives with different substituents at R1–R4 to assess their ability to inhibit two Fasciola hepatica cathepsin Ls that take part in essential parasite processes
Summary
Liver flukes of Fasciola species infect cattle and sheep worldwide causing important economic global losses of over US$3 billion annually to the agricultural sector [1], and are responsible for increasing numbers of human infections, being recognized as an emerging human zoonosis by theWorld Health Organization. Liver flukes of Fasciola species infect cattle and sheep worldwide causing important economic global losses of over US$3 billion annually to the agricultural sector [1], and are responsible for increasing numbers of human infections, being recognized as an emerging human zoonosis by the. Since 1995, this is aggravated by several reports of parasite isolates resistant to triclabendazole, the drug of choice to treat humans and the only one that is effective against both the mature and juvenile forms of the parasite [5,6]. Despite sustained efforts, there is currently no available vaccine to prevent infection [7]. These facts highlight how important it is to design new control strategies to prevent and treat fascioliasis and find new targets for vaccines and drug development
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