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Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2

Version 2 2023-12-06, 05:53
Version 1 2021-04-21, 01:09
journal contribution
posted on 2023-12-06, 05:53 authored by William Nguyen, Erinna LeeErinna Lee, Marco Evangelista, Mihwa LeeMihwa Lee, Tiffany J Harris, Peter M Colman, Nicholas SmithNicholas Smith, Luke B Williams, Kate E Jarman, Kym N Lowes, Cécile Haeberli, Jennifer Keiser, Brian SmithBrian Smith, Walter FairlieWalter Fairlie, Brad E Sleebs
Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold (43) with potent sBCL-2 activity (IC50 30 nM). Human BCL-XL potency (IC50 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis.


This work was funded by the National Health and Medical Research Council of Australia (Development Grant 1135421 and Project Grant 1143974 to B.E.S.; Project Grant 1002227 to W.D.F; Program Grant 1113133 and Fellowship 1116934 to P.M.C.), the Victorian Cancer Agency Mid-Career Fellowship MCRF9045 to E.F.L., the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. B.E.S. is a Corin Centenary Fellow. J.K. is grateful to the Swiss National Science Foundation for financial support (320030_175585).


Publication Date



ACS Infectious Diseases






21pp. (p.1143-1163)


American Chemical Society (ACS)



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