- A green one-pot synthesis of 3(5)-substituted 1,2,4-triazol-5(3)-amines as potential antimicrobial agents
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Abstract: An efficient procedure was proposed for the synthesis of 3(5)-substituted 1,2,4-triazol-5(3)-amines via a one-pot reaction of thiourea, dimethyl sulfate and various hydrazides. 1,2,4-Triazole derivatives were prepared in aqueous media under mild conditions while adhering to some principles of green chemistry. The products were easily isolated in 83–95% yields without any need for further purification. Inhibitory activities of all synthetic compounds were assessed against a variety of Gram-positive and Gram-negative pathogenic bacteria as well as some fungal pathogens. The best antibacterial effects were observed with 3(5)-phenyl-1H-1,2,4-triazol-5(3)-amine according to its MIC values (4–8?μg?mL?1). All compounds were successful in blocking the growth of fungi. Acceptable antioxidant properties were observed only with 3(5)-(4-nitrophenyl)-1H-1,2,4-triazol-5(3)-amine. Graphic abstract: 3(5)-Substituted 1,2,4-triazol-5(3)-amines were efficiently prepared via a one-pot reaction of thiourea, dimethyl sulfate and various hydrazides in water as the solvent. Inhibitory activity of all synthesized derivatives was proved according to their MIC, MBC and MFC values. It is found that they are potential antifungal agents.[Figure not available: see fulltext.].
- Beyzaei, Hamid,Khosravi, Zahra,Aryan, Reza,Ghasemi, Behzad
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- Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy
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Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2MUT preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.
- Huang, Ying,Zhang, Jeff,Yu, Zhengtian,Zhang, Hailong,Wang, Youzhen,Lingel, Andreas,Qi, Wei,Gu, Justin,Zhao, Kehao,Shultz, Michael D.,Wang, Long,Fu, Xingnian,Sun, Yongfeng,Zhang, Qiong,Jiang, Xiangqing,Zhang, Jiangwei,Zhang, Chunye,Li, Ling,Zeng, Jue,Feng, Lijian,Zhang, Chao,Liu, Yueqin,Zhang, Man,Zhang, Lijun,Zhao, Mengxi,Gao, Zhenting,Liu, Xianghui,Fang, Douglas,Guo, Haibing,Mi, Yuan,Gabriel, Tobias,Dillon, Michael P.,Atadja, Peter,Oyang, Counde
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supporting information
p. 2215 - 2226
(2017/04/03)
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- Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA
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The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action. We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea. Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively. We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a K d of ~150 μM. Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB.
- Barker, Courtney A.,Allison, Sarah E.,Zlitni, Soumaya,Nguyen, Nick Duc,Das, Rahul,Melacini, Giuseppe,Capretta, Alfredo A.,Brown, Eric D.
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supporting information
p. 2426 - 2431
(2013/05/21)
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