321601-48-3Relevant articles and documents
Structure-guided design of antibacterials that allosterically inhibit DNA gyrase
Thalji, Reema K.,Raha, Kaushik,Andreotti, Daniele,Checchia, Anna,Cui, Haifeng,Meneghelli, Giovanni,Profeta, Roberto,Tonelli, Federica,Tommasi, Simona,Bakshi, Tania,Donovan, Brian T.,Howells, Alison,Jain, Shruti,Nixon, Christopher,Quinque, Geoffrey,McCloskey, Lynn,Bax, Benjamin D.,Neu, Margarete,Chan, Pan F.,Stavenger, Robert A.
, p. 1407 - 1412 (2019)
A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.
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.
SULFONYL-SUBSTITUTED BICYCLIC COMPOUND WHICH ACTS AS ROR INHIBITOR
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, (2020/08/16)
Provided is a sulfonyl-substituted bicyclic compound (A) which acts as a RORγ inhibitor, said compound has good RORγ inhibitory activity and is expected to be used for treating diseases mediated by a RORγ receptor in mammals.