Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive Callaghan, Newcastle, NSW 2308, Australia.
Community for Open Antimicrobial Drug Discovery, Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Molecules. 2022 Mar 22;27(7):2050. doi: 10.3390/molecules27072050.
Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.
基于我们实验室之前的研究，合成了五个聚焦化合物库（共 49 个化合物），并对其进行了抗生素和抗真菌活性筛选，以评估它们对金黄色葡萄球菌、大肠杆菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、白色念珠菌和新生隐球菌的抑制作用。在初始筛选浓度为 32 μg/mL 时，（Z）-2-（3,4-二氯苯基）-3-苯基丙烯腈类似物的活性较低，这些类似物构成了前两个生产的聚焦化合物库的一部分。最有前途的类似物在合成丙烯腈的末端芳环上具有额外的取代基。通过环氧化物安装和随后的通过流化学介导的环打开氨解，对末端芳族部分进行了修饰，与离散的胺组进行反应，得到相应的氨基醇。从取代苯胺、环状胺和苯连接的杂环胺中开发了三个新的聚焦化合物库。基于苯胺的化合物对筛选的细菌和真菌株均无活性。当在 32 μg/mL 化合物浓度下评估时，引入环状结构，如哌啶、哌嗪或吗啉，对耐甲氧西林金黄色葡萄球菌的抑制率超过 50%。通过环氧化物氨解对末端芳基取代基进行考察，可合成三个新的聚焦化合物库，得到氨基醇。取代的哌啶或哌嗪使芳香取代基的活性从抗菌活性转变为抗真菌活性，其中包括 ((Z)-2-（3,4-二氯苯基）-3-（4-（2-羟基-3-（4-甲基哌嗪-1-基）丙氧基）苯基）丙烯腈）、((Z)-2-（3,4-二氯苯基）-3-（4-（2-羟基-3-（4-（4-羟基苯基）哌嗪-1-基）丙氧基）-苯基）丙烯腈）和 ((Z)-3-（4-（3-（4-环己基哌嗪-1-基）-2-羟基丙氧基）-苯基）-2-（3,4-二氯苯基）-丙烯腈），在 32 μg/mL 时对新型隐球菌 var. grubii H99 的生长抑制率超过 95%。而 (Z)-3-（4-（3-（环己基氨基）-2-羟基丙氧基）-苯基）-2-（3,4-二氯苯基）-丙烯腈、(S,Z)-2-（3,4-二氯苯基）-3-（4-（2-羟基-3-（哌啶-1-基）丙氧基）苯基）丙烯腈、(R,Z)-2-（3,4-二氯苯基）-3-（4-（2-羟基-3-（哌啶-1-基）丙氧基）苯基）丙烯腈、(Z)-2-（3,4-二氯苯基）-3-（4-（2-羟基-3-（D-11-哌啶-1-基）丙氧基）苯基）-丙烯腈和 (Z)-3-（4-（3-（4-环己基哌嗪-1-基）-2-羟基丙氧基）-苯基）-2-（3,4-二氯苯基）-丙烯腈对金黄色葡萄球菌的抑制率为 32 μg/mL。
