3622-48-8

Upstream product

• 53078-85-6 2-bromo-5-methylaniline 
• 21303-50-4 2-mercapto-5-methyl benzothiazole 
• 74-88-4 methyl iodide 
• 140-89-6 potassium ethyl xanthogenate 
• 452-84-6 3-amino-4-fluorotoluene 
• 21303-50-4 5-methylbenzo[d]thiazole-2(3H)-thione 

Downstream Products

• 80945-66-0 (5-methyl-1,3-benzothiazol-2-yl)hydrazine 

Relevant academic research and scientific papers

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

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.

Exploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70)

Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site on Hsp70, interrupting its binding to nucleotide-exchange factors (NEFs) and promoting cell death in breast cancer cell lines. However, proof-of-concept molecules, such as JG-98, have relatively modest potency (EC50 ≈ 0.7-0.4 μM) and are rapidly metabolized in animals. Here, we explored this chemical series through structure- and property-based design of ～300 analogs, showing that the most potent had >10-fold improved EC50 values (～0.05 to 0.03 μM) against two breast cancer cells. Biomarkers and whole genome CRISPRi screens confirmed members of the Hsp70 family as cellular targets. On the basis of these results, JG-231 was found to reduce tumor burden in an MDA-MB-231 xenograft model (4 mg/kg, ip). Together, these studies support the hypothesis that Hsp70 may be a promising target for anticancer therapeutics.

Thiazolyl and benzothiazolyl hydrazones derived from α-(N)-acetylpyridines and diazines: Synthesis, antiproliferative activity and CoMFA studies

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.