Design,synthesis and biological evaluation of novel inhibitors against cyanobacterial pyruvate dehydrogenase multienzyme complex E1 |
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Institution: | 1. LimnoTech, 501 Avis Drive, Ann Arbor, MI 48108, USA;2. School of Natural Resources and Environment, University of Michigan, 440 Church St., Ann Arbor, MI 48109, USA;3. Graham Sustainability Institute, University of Michigan, School of Natural Resources and Environment, 625 East Liberty Road, Ann Arbor, MI 48193, USA;4. Cooperative Institute for Limnology and Ecosystems Research, School of Natural Resources and Environment, University of Michigan, 440 Church St., Ann Arbor, MI 48109, USA |
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Abstract: | Cyanobacterial pyruvate dehydrogenase multienzyme complex E1 (PDHc E1) is a potential target enzyme for finding inhibitors to control harmful cyanobacterial blooms. In this study, a series of novel triazole thiamin diphosphate (ThDP) analogs were designed and synthesized by modifying the substituent group of triazole ring and optimizing triazole-benzene linker as potential cyanobacterial PDHc E1 (Cy-PDHc E1) inhibitors. Their inhibitory activities against Cy-PDHc E1 in vitro and algicide activities in vivo were further examined. Most of these compounds exhibited prominent inhibitory activities against Cy-PDHc E1 (IC50 1.48–4.48 μM) and good algicide activities against Synechocystis PCC6803 (EC50 0.84–2.44 µM) and Microcystis aeruginosa FACHB905 (EC50 0.74–1.77 µM). Especially, compound 8d showed not only the highest inhibitory activity against Cy-PDHc E1 (IC50 1.48 μM), but also the most powerful inhibitory selectivity between Cy-PDHc E1 (inhibitory rate 98.90%) and porcine PDHc E1 (inhibitory rate only 9.54%). Furthermore, the potential interaction between compound 8d and Cy-PDHc E1 was analyzed by a molecular docking method and site-directed mutagenesis and enzymatic analysis and fluorescence spectral analysis. These results indicated that compound 8d could be used as a hit compound for further optimization and might have potential to be developed as a new algicide. |
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Keywords: | Pyruvate dehydrogenase multienzyme component E1 Inhibitor Cyanobacterial blooms Thiamin diphosphate (ThDP) analogs Algicide |
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