2,3-Diphenyl-2,3-dihydro-4H-1,3-thiaza-4-one heterocycles inhibit growth and block completion of cytokinesis in kinetoplastid parasites.

Madeline F Malfara, Lee J Silverberg, John DiMaio, Anthony F Lagalante, Mark A Olsen, Ekaterina Madison, Megan L Povelones

Molecular and biochemical parasitology 2021 Sep

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Kinetoplastid parasites are model eukaryotes with a complex cell cycle that is highly regulated both spatially and temporally. In addition, diseases caused by these parasites continue to have a significant impact on human and animal health worldwide. While there have been advancements in chemotherapy for these diseases, there is a continual need for an arsenal of compounds that have robust anti-parasite activity with minimal impact on the human host. While investigating a series of 2,3-diphenyl-2,3-dihydro-4H-1,3-thiaza-4-one heterocycles with potential activity against these parasites, we found a pyridothiazinone that inhibits growth of the monoxenous parasite Crithidia fasciculata and two life cycle stages of Trypanosoma brucei. This inhibition is more pronounced in T. brucei and is associated with an unusual pre-abscission cell cycle arrest. Exploring the mode of action for these and related compounds in kinetoplastids may provide tools with which to explore cell cycle regulation in these important organisms. Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Madeline F Malfara, Lee J Silverberg, John DiMaio, Anthony F Lagalante, Mark A Olsen, Ekaterina Madison, Megan L Povelones. 2,3-Diphenyl-2,3-dihydro-4H-1,3-thiaza-4-one heterocycles inhibit growth and block completion of cytokinesis in kinetoplastid parasites. Molecular and biochemical parasitology. 2021 Sep;245:111396