Synthesis and Structure-Activity Relationship of Thioacetamide-Triazoles against Escherichia coli.
Synthesis and Structure-Activity Relationship of Thioacetamide-Triazoles against Escherichia coli.
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DOI：
10.3390/molecules27051518
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发表时间：
2022-02-24
期刊：
影响因子：
--
通讯作者：
Lee RE
中科院分区：
文献类型：
--
作者：
Dharuman S;Wallace MJ;Reeve SM;Bulitta JB;Lee RE
由于多重耐药菌株的传播，革兰氏阴性菌引起的感染越来越危险，强调迫切需要具有替代作用方式的新抗生素。我们之前已经确定了一类新的抗菌剂，硫代乙酰胺-三唑，使用抗叶酸靶向筛选，并确定了它们的作用模式，依赖于半胱氨酸合成酶a的激活。硫代乙酰胺-三唑类大肠杆菌的构效关系。合成了初始命中化合物的类似物，研究了芳基、硫乙酰胺和三唑部分的贡献。观察到明显的构效关系，生成具有良好抑制价值的化合物。对芳基环的取代通常是最好的耐受，包括引入噻唑和吡啶杂芳基体系。对中心硫代乙酰胺连接部分的取代更为细微；在硫乙酰胺连接体中引入甲基分支后，其抗菌活性显著降低，但异分异构体丙酰胺和n -苯甲酰胺系统仍保持活性。分子中三唑部分的变化显著降低了抗菌活性，进一步表明1,2,3-三唑对药效至关重要。从这些研究中，我们已经确定了具有理想的体外ADME特性和体内药代动力学特性的新的先导化合物。
Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode of action which is dependent on activation by cysteine synthase A. Herein, we report a detailed examination of the anti-E. coli structure–activity relationship of the thioacetamide-triazoles. Analogs of the initial hit compounds were synthesized to study the contribution of the aryl, thioacetamide, and triazole sections. A clear structure–activity relationship was observed generating compounds with excellent inhibition values. Substitutions to the aryl ring were generally best tolerated, including the introduction of thiazole and pyridine heteroaryl systems. Substitutions to the central thioacetamide linker section were more nuanced; the introduction of a methyl branch to the thioacetamide linker substantially decreased antibacterial activity, but the isomeric propionamide and N-benzamide systems retained activity. Changes to the triazole portion of the molecule dramatically decreased the antibacterial activity, further indicating that 1,2,3-triazole is critical for potency. From these studies, we have identified new lead compounds with desirable in-vitro ADME properties and in-vivo pharmacokinetic properties.
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影响因子：
6.7
作者：
Lang, Yinzhi;Shah, Nirav R.;Tao, Xun;Reeve, Stephanie M.;Zhou, Jieqiang;Moya, Bartolome;Sayed, Alaa R. M.;Dharuman, Suresh;Oyer, Jeremiah L.;Copik, Alicja J.;Fleischer, Brett A.;Shin, Eunjeong;Werkman, Carolin;Basso, Kari B.;Deveson Lucas, Deanna;Sutaria, Dhruvitkumar S.;Megroz, Marianne;Kim, Tae Hwan;Loudon-Hossler, Victoria;Wright, Amy;Jimenez-Nieves, Rossie H.;Wallace, Miranda J.;Cadet, Keisha C.;Jiao, Yuanyuan;Boyce, John D.;LoVullo, Eric D.;Schweizer, Herbert P.;Bonomo, Robert A.;Bharatham, Nagakumar;Tsuji, Brian T.;Landersdorfer, Cornelia B.;Norris, Michael H.;Soo Shin, Beom;Louie, Arnold;Balasubramanian, Venkataraman;Lee, Richard E.;Drusano, George L.;Bulitta, Juergen B.
通讯作者：
Bulitta, Juergen B.
影响因子：
64.8
作者：
Richter MF;Drown BS;Riley AP;Garcia A;Shirai T;Svec RL;Hergenrother PJ
通讯作者：
Hergenrother PJ
影响因子：
3.5
作者：
North EJ;Scherman MS;Bruhn DF;Scarborough JS;Maddox MM;Jones V;Grzegorzewicz A;Yang L;Hess T;Morisseau C;Jackson M;McNeil MR;Lee RE
通讯作者：
Lee RE
影响因子：
18.3
作者：
Miller, Marvin J.;Liu, Rui
通讯作者：
Liu, Rui
DOI：
10.1111/j.1469-0691.1998.tb00684.x
发表时间：
1998-03-01
期刊：
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
影响因子：
--
作者：
Hooper, David C.
通讯作者：
Hooper, David C.