Raj Raghu, Sharma Vaishali, Hopper Melissa J, Patel Neal, Hall Dominique, Wrischnik Lisa A, Land Kirkwood M, Kumar Vipan
1Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005 Punjab India.
2Department of Biological Sciences, University of the Pacific, Stockton, CA 95211 USA.
Med Chem Res. 2014;23(8):3671-3680. doi: 10.1007/s00044-014-0956-6. Epub 2014 Feb 22.
In this study, we describe the synthesis of mono- and bis-1-1,2,3-triazole-tethered β-lactam-isatin conjugates using copper-catalysed azide-alkyne cycloaddition reaction between mono- and di-propargylated azetidin-2-ones and -alkylazido isatins. The synthesized conjugates were evaluated for their preliminary in vitro analysis against at 50 μM. The efficacy of synthesized hybrids was observed to depend on the substituent at -1 position of β-lactam ring, as well as the presence of single/double 1-1,2,3-triazole linker. Among the synthesized conjugates, the presence of a -tolyl substituent at -1 of β-lactam ring was preferred for good activity profiles while the increase in spacer length did not influence the efficacy of the compounds. Compounds with high levels of potency were further analysed to determine their IC values, as well as cytotoxicity profiles against mammalian cells. The most active compound in the synthesized conjugates displayed an IC value of 10.49 μM against cultured G3 strain of and was non-toxic to cultured mammalian HeLa cells at the same concentration.
在本研究中，我们描述了使用单炔丙基化和二炔丙基化的氮杂环丁烷-2-酮与叠氮烷基异吲哚酮之间的铜催化叠氮化物-炔烃环加成反应，合成单-1,2,3-三唑连接和双-1,2,3-三唑连接的β-内酰胺-异吲哚酮共轭物。对合成的共轭物进行了初步体外分析，测试浓度为50 μM。观察到合成杂化物的疗效取决于β-内酰胺环-1位的取代基以及单/双1,2,3-三唑连接基的存在。在合成的共轭物中，β-内酰胺环-1位存在对甲苯基取代基时活性较好，而间隔长度的增加并不影响化合物的疗效。对高活性化合物进一步分析以确定其IC值以及对哺乳动物细胞的细胞毒性。合成共轭物中活性最高的化合物对培养的G3菌株显示出10.49 μM的IC值，并且在相同浓度下对培养的哺乳动物HeLa细胞无毒。
