3622-48-8Relevant articles and documents
Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2
Nguyen, William,Lee, Erinna F.,Evangelista, Marco,Lee, Mihwa,Harris, Tiffany J.,Colman, Peter M.,Smith, Nicholas A.,Williams, Luke B.,Jarman, Kate E.,Lowes, Kym N.,Haeberli, Cécile,Keiser, Jennifer,Smith, Brian J.,Fairlie, W. Douglas,Sleebs, Brad E.
, p. 1143 - 1163 (2021/02/22)
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.
Thiazolyl and benzothiazolyl hydrazones derived from α-(N)-acetylpyridines and diazines: Synthesis, antiproliferative activity and CoMFA studies
Easmon,Heinisch,Hofmann,Langer,Grunicke,Fink,Puerstinger
, p. 397 - 408 (2007/10/03)
The synthesis of a series of thiazolyl and benzothiazolyl hydrazones derived from α-(A3-acylpyridines, -quinolines, -isoquinolines, -pyridazines, -pyrimidines, and -pyrazines is reported. The stereochemistry of these compounds was determined by NMR spectroscopic methods. The antiproliferative activity of the novel compounds was quantified in tissue culture (melanoma, breast carcinoma, colon adenocarcinoma, epitheloid cervix carcinoma, Burkitt's lymphoma, leukemia, and hydroxyurea sensitive and resistant myelogenous leukemia sublines). All compounds exhibited profound antiproliferative activity, in particular against Burkitt's lymphoma cells. Out of this series, compounds 6b, 7b, 7c, 8c and 8i were found to be 13-900 times more potent than hydroxyurea and no cross-resistance to hydroxyurea was observed. A predictive 3D-QSAR model using the CoMFA approach was established.