106331-50-4Relevant articles and documents
Design and synthesis of Mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease
Atherton, Richard L.,Kelly, John M.,Olmo, Francisco,Sanz-Serrano, Julen,Alcolea, Verónica,Beltran-Hortelano, Iván,Pérez-Silanes, Silvia,Rubio-Hernández, Mercedes
, (2021/07/14)
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline.
Isothiourea-Catalysed Acylative Kinetic Resolution of Aryl–Alkenyl (sp2vs. sp2) Substituted Secondary Alcohols
Musolino, Stefania F.,Ojo, O. Stephen,Westwood, Nicholas J.,Taylor, James E.,Smith, Andrew D.
supporting information, p. 18916 - 18922 (2016/12/26)
The non-enzymatic acylative kinetic resolution of challenging aryl–alkenyl (sp2vs. sp2) substituted secondary alcohols is described, with effective enantiodiscrimination achieved using the isothiourea organocatalyst HyperBTM (1 mol %) and isobutyric anhydride. The kinetic resolution of a wide range of aryl–alkenyl substituted alcohols has been evaluated, with either electron-rich or naphthyl aryl substituents in combination with an unsubstituted vinyl substituent providing the highest selectivity (S=2–1980). The use of this protocol for the gram-scale (2.5 g) kinetic resolution of a model aryl–vinyl (sp2vs. sp2) substituted secondary alcohol is demonstrated, giving access to >1 g of each of the product enantiomers both in 99:1 e.r.
New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds
Zhang, Yu,Liu, Bin,Wu, Xingyu,Lei, Ridong,Ning, Xianling,Liu, Yu,Liu, Zhenming,Ge, Zemei,Li, Runtao,Yin, Yuxin
, p. 4815 - 4823 (2015/08/03)
Pyruvate kinase M2 (PKM2) is a key protein responsible for cancer's Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogs were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analog 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line.
