80395-50-2Relevant articles and documents
Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors
Skok, ?iga,Baran?oková, Michaela,Benek, Ond?ej,Cruz, Cristina Durante,Tammela, P?ivi,Toma?i?, Tihomir,Zidar, Nace,Ma?i?, Lucija Peterlin,Zega, Anamarija,Stevenson, Clare E. M.,Mundy, Julia E. A.,Lawson, David M.,Maxwell, Anthony,Kikelj, Danijel,Ila?, Janez
, p. 2433 - 2440 (2020)
We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 μM), and efflux impaired E. coli strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.
From Bacteria to Cancer: A Benzothiazole-Based DNA Gyrase B Inhibitor Redesigned for Hsp90 C-Terminal Inhibition
Pugh, Kyler W.,Zhang, Zheng,Wang, Jian,Xu, Xiuzhi,Munthali, Vitumbiko,Zuo, Ang,Blagg, Brian S. J.
supporting information, p. 1535 - 1538 (2020/10/12)
Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding and maturation of client proteins that are associated with all ten hallmarks of cancer. Hsp90 N-terminal pan inhibitors have experienced unfavorable results in clinical trials due to induction of the heat shock response (HSR), among other concerns. Novobiocin, a well characterized DNA gyrase B inhibitor, was identified as the first Hsp90 C-terminal inhibitor that manifested anticancer effects without induction of the HSR. In this letter, a library of Hsp90 C-terminal inhibitors derived from a benzothiazole-based scaffold, known to inhibit DNA gyrase B, was designed, synthesized, and evaluated. Several compounds were found to manifest low micromolar activity against both MCF-7 and SKBr3 breast cancer cell lines via Hsp90 C-terminal inhibition.
Synthesis, ADMET Properties, and Biological Evaluation of Benzothiazole Compounds Targeting Chemokine Receptor 2 (CXCR2)
Mehanna, Wesam E.,Lu, Tiangong,Debnath, Bikash,Lasheen, Deena S.,Serya, Rabah A. T.,Abouzid, Khaled A.,Neamati, Nouri
, p. 1045 - 1054 (2017/07/11)
Herein we describe the synthesis and biological evaluation of a series of novel benzothiazoles based on a diaryl urea scaffold previously reported in some allosteric chemokine receptor 2 (CXCR2) inhibitors. From a library of 41 new compounds, 17 showed significant inhibition of CXCR2, with IC50 values less than 10 μm and selectivity over CXCR4. Our ADMET simulations suggest favorable drug-like properties for the active compounds. Importantly, we developed a predictive model that can distinguish active from inactive compounds; this will serve as a valuable tool to guide the design of optimized compounds to be evaluated in preclinical models.
