Halogen-Dance-Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2-Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases.
Halogen-Dance-Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2-Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases.
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DOI：
10.1002/cmdc.202100568
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发表时间：
2022-01-05
期刊：
影响因子：
3.4
通讯作者：
Janeba Z
中科院分区：
文献类型：
--
作者：
Česnek M;Šafránek M;Dračínský M;Tloušťová E;Mertlíková-Kaiserová H;Hayes MP;Watts VJ;Janeba Z
以2-氨基-4-芳基噻唑取代腺嘌呤，设计了一系列无环核苷膦(ANPs)作为细菌腺苷环化酶(ACS)的抑制剂。通过卤素舞动反应制备了目标化合物。最终的ACS抑制剂通过基于细胞的分析(前药物)和无细胞的分析(磷酸二磷酸盐)进行评估。新的ANP是百日咳杆菌的腺苷环化酶毒素(ACT)和炭疽杆菌的水肿因子(EF)的有效抑制剂，对哺乳动物酶AC1、AC2和AC5具有良好的选择性。与阿德福韦二磷酸(PMEApp)相比，6个新的ANP是更有效或等同的ACT抑制剂(IC50=9-18 nM)，其中1个是更有效的EF抑制剂(IC50=12 nM)，其中ACT的IC50=18 nM，EF的IC50=36 nM。因此，这些化合物代表了迄今为止报道的基于ANP的最有效的ACT/EF抑制剂。磷二酸酯抑制J774A.1巨噬细胞ACT活性的效力较弱，其中最有效的衍生物的IC50=490 nM，而类似的阿德福韦磷二酸酯的IC50=150 nM。这些结果表明，为了继续开发ANP作为潜在的抗毒素药物，更有效的类型的磷酸盐前药将是可取的，以增加ANP类活性物质在细胞中的浓度。从取代的2-氨基噻唑衍生的新型无环核苷膦(ANPs)是以ANPs为基础的细菌腺苷环化酶(腺苷环化酶毒素和水肿因子)的最有效的抑制剂(在酶分析中以磷酸二磷酸的形式存在)。利用卤素舞动反应合成了目标ANPS。
A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2-amino-4-arylthiazoles. The target compounds were prepared using the Halogen Dance reaction. Final ACs inhibitors were evaluated in cell-based assays (prodrugs) and cell-free assays (phosphono diphosphates). Novel ANPs were potent inhibitors of adenylate cyclase toxin (ACT) from Bordetella pertussis and edema factor (EF) from Bacillus anthracis, with substantial selectivity over mammalian enzymes AC1, AC2, and AC5. Six of the new ANPs were more potent or equipotent ACT inhibitors (IC50 = 9–18 nM), and one of them was more potent EF inhibitor (IC50 = 12 nM), compared to adefovir diphosphate (PMEApp) with IC50 = 18 nM for ACT and IC50 = 36 nM for EF. Thus, these compounds represent the most potent ACT/EF inhibitors based on ANPs reported to date. The potency of the phosphorodiamidates to inhibit ACT activity in J774A.1 macrophage cells was somewhat weaker, where the most potent derivative had IC50 = 490 nM compared to IC50 = 150 nM of the analogous adefovir phosphorodiamidate. The results suggest that more efficient type of phosphonate prodrugs would be desirable to increase concentrations of the ANP-based active species in the cells in order to proceed with the development of ANPs as potential antitoxin therapeutics. Novel acyclic nucleoside phosphonates (ANPs) derived from substituted 2-aminothiazole represent the most potent inhibitors (in the form of phosphono diphosphates in enzymatic assays) of bacterial adenylate cyclases (adenylate cyclase toxin and edema factor) based on ANPs. The target ANPs were synthesized using Halogen Dance reaction.
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影响因子：
3.4
作者：
Brehova, Petra;Smidkova, Marketa;Skacel, Jan;Dracinsky, Martin;Mertlikova-Kaiserova, Helena;Velasquez, Monica P. Soto;Watts, Val J.;Janeba, Zlatko
通讯作者：
Janeba, Zlatko
DOI：
10.1073/pnas.0502983102
发表时间：
2005-05-31
影响因子：
11.1
作者：
Erion, MD;van Poelje, PD;Lipscomb, WN
通讯作者：
Lipscomb, WN
DOI：
10.1124/jpet.113.207449
发表时间：
2013-11-01
影响因子：
3.5
作者：
Conley, Jason M.;Brand, Cameron S.;Watts, Val J.
通讯作者：
Watts, Val J.
影响因子：
7.3
作者：
Brust, Tarsis F.;Alongkronrusmee, Doungkamol;Watts, Val J.
通讯作者：
Watts, Val J.
影响因子：
6.7
作者：
Břehová P;Chaloupecká E;Česnek M;Skácel J;Dračínský M;Tloušťová E;Mertlíková-Kaiserová H;Soto-Velasquez MP;Watts VJ;Janeba Z
通讯作者：
Janeba Z