摘要：
The binding mode of 5-((4-((4-chlorophenoxy)methyl)-5-iodo-1H-1,2,3-triazol-1-yl)methyl)-2-methylpyrimidin-4-amine (PA-1) was studied using a combination of X-ray crystallography, DFT calculation, and molecular docking approaches. The crystal structure of PA-1 primarily indicated the formation of intermolecular hydrogen bonding and halogen bonding between N-H center dot center dot center dot N and C-I center dot center dot center dot N. DFT calculation demonstrated that the geometric structure of PA-1 is in excellent agreement with the crystal structure. The frontier molecular orbital analysis indicated the important role of the 5-iodo-1,2,3-triazole and benzene ring in the biological activities of PA-1. Further molecular electrostatic potential surface analysis confirmed the possibility of iodine atom participating in the halogen bonding with the negatively charged center; this was validated by the molecular docking study, which showed that the iodine atom of PA-1 could form a halogen bonding with the O atom of Asp521 in the active site of E. coli. PDHc-E1. These findings demonstrate that halogen bonding interaction could be used for the further optimization of PA-1 to discover more potent PDHc-E1 inhibitors and antifungal compounds. (C) 2019 Elsevier B.V. All rights reserved.
摘要：
Cyanobacteria harmful algal blooms are of global concern, but all currently available algicides in the market are nonselective and have potential side effects on nontarget species. In the present work, two series of compounds (4 and 6) comprising 16 novel 1,2,3-triazole aminopyrimidines were rationally designed and synthesized as control agent for cyanobacteria. Our design focus was the inhibiting cyanobacteria by inhibition against pyruvate dehydrogenase complex E1 (PDHc-E1). Compounds 4 and 6 showed potent inhibition against Escherichia coli PDHc-E1 (IC50 = 4.13-23.76 muM) and also strong algicidal activities against Synechocystis sp. PCC 6803 (EC50 = 1.7-8.1 muM) and Microcystis sp. FACHB905 (EC50 = 2.1-11.8 muM). In particular, the algicidal activities of 6d against four algal species were not only higher than that of prometryn; they were also comparable to or higher than that of copper sulfate. The analogues 4c, 4d, 6d, and 6e displayed potent algicidal activities and inhibition of E. coli PDHc-E1 but exhibited negligible inhibition of porcine PDHc-E1. As revealed by molecular docking, site-directed mutagenesis, enzymatic assays, and an inhibition kinetic analysis, 4c and 6d inhibited PDHc-E1 in a competitive manner. Our results suggest that highly selective, effective algicides can be developed by rationally designing competitive PDHc-E1 inhibitors.
摘要：
Harmful cyanobacteria bloom (HCB) has occurred frequently in recent years and it is urgent to develop novel algicides to deal with this problem. In this paper, a series of novel thiamin diphosphate (ThDP) analogs 5a-5g were designed and synthesized targeting cyanobacterial pyruvate dehydrogenase complex E1 (Cy-PDHc E1). Our results showed that compounds 5a-5g have higher inhibitory activities against Cy-PDHc E1 (IC50 9.56-3.48microM) and higher inhibitory activities against two model cyanobacteria strains Synechocystis sp PCC6803 (EC50 2.03-1.58microM) and Microcystis aeruginosa FACHB905 (EC50 1.86-0.95microM). Especially, compound 5b displayed highest inhibitory activities (IC50=3.48microM) against Cy-PDHc E1 and powerful inhibitory activities against cyanobacteria Synechocystis sp PCC6803 (EC50=1.58microM) and Microcystis aeruginosa FACHB905 (EC50=1.04microM). Moreover, the inhibitory activities of compound 5b were even higher than those of copper sulfate (EC50=2.02 and 1.71microM separately) which has been widely used as algicide against cyanobacteria PCC6803 and FACHB905. The more important was that compound 5b display much higher inhibitory selectivity between Cy-PDHc E1 (Inhibitory rate 97.4%) and porcine PDHc E1 (Inhibitory rate 11.8%) under the same concentration (100muM). The inhibition kinetic experiment and molecular docking research showed that compound 5b can inhibit Cy-PDHc E1 by occupying the ThDP-binding pocket and then blocking Cy-PDHc E1 bound to ThDP as competitive inhibitor. The imagines of SEM and TEM showed that cellular microstructures were heavily destroyed under compound 5b stress. Our results demonstrated compound 5b could be taken as a potential lead compound targeting Cy-PDHc E1 to obtain environment-friendly algicide for harmful cyanobacterial blooms control.
关键词：
Chemical;Rice bacterial brown stripe pathogen;Gene expression;Action mode
摘要：
Thiamin diphosphate (ThDP) analogs have been designed and synthesized based on the ThDP binding site of the pyruvate dehydrogenase multienzyme complex E1 of Escherichia coli. This study investigated the effect of 66 novel ThDP analogs on rice bacterial brown stripe pathogen Acidovorax avenae subsp. avenae strain RS-1. Results indicated that three of the 66 ThDP analogs (designated as 20, 21 and 53) significantly inhibited the in vitro growth of strain RS-1. However, no obvious cell lysis and destruction was found for this rice pathogenic bacterium, which were supported by morphological evidence of transmission electron microscope. In contrast, the three ThDP analogs significantly reduced biofilm formation and the activity of the pyruvate dehydrogenase of strain RS-1. Furthermore, the differential expression of ThDP target gene and 20 secretion system related genes were revealed by using quantitative real-time PCR. Among these, the expressions of ThDP target gene and VgrG-5 under the treatment of ThDP 20 were strongly induced compared to the control, which indicated that the antibacterial mechanism of ThDP analogs may be mainly due to the changed expression of ThDP target gene and secretion system related genes rather than causing damage to cell membrane. Taken together, the application of synthesized ThDP analogs might be a tractable strategy to overcome the pathogen of rice bacterial brown stripe.
摘要：
α-(Substituted phenoxyacetoxy) alkylphosphonates containing one chiral carbon atom have been demonstrated to be PDHc inhibitor with good herbicidal activity and some of them could be used as potential herbicide. In order to determine any difference in herbicidal activities between (R) and (S) isomers, the synthetic method of optically active substituted phenylalkylphosphonates IB were explored. A highly practical, enantioselective hydrophosphonylation was developed to prepare optically active O,O-dimethyl α-hydroxyalkylphosphonates 3 as key intermediate by asymmetric addition reaction of dimethylphosphite 1 and several kinds of aldehydes 2 using tridentate Schiff base Al(III) complexes as catalysts. A series of novel O,O-dimethyl α-(substituted phenoxyacetoxy)(substituted phenyl)methylphosphonates IB including (R) and (S) enantiomers were further synthesized with excellent enantioselectivity (95–99% ee) by the condensation of optically active α-hydroxyl (substituted phenyl)methylphosphonates 3 and substituted phenoxyacetyl chlorides 4. The herbicidal activities of title compound IB including their racemates, (R) and (S) enantiomers were evaluated in greenhouse for post-emergence application. All compounds IB showed significant inhibitory activity against dicotyledonous plants. A difference in herbicidal effect among racemate, (R) and (S) enantiomers were observed. Especially IB7 and IB10 showed obvious chiral selectivity in inhibitory activity against chickweed. (S)-IB7 with ED50 of 22.8 g ai/ha was found to be most effective enantiomer against chickweed and its inhibitory activity was 8.17 times higher than (R)-IB7. (S)-IB7 as potential herbicide would be effective at lower rates than (R)-IB7 or (rac)-IB7.
摘要：
By targeting the thiamin diphosphate (ThDP) binding site of Escherichia coli (E. coli) pyruvate dehydrogenase multienzyme complex E1 (PDHc E1), a series of novel 'open-chain' classes of ThDP analogs A, B, and C with N-acylhydrazone moieties was designed and synthesized to explore their activities against E. coli PHDc E1 in vitro and their inhibitory activity against microbial diseases were further evaluated in vivo. As a result, A1-23 exhibited moderate to potent inhibitory activities against E. coli PDHc E1 (IC50 = 0.15-23.55 mu M). The potent inhibitors A13, A14, A15, C2, had strong inhibitory activities with IC50 values of 0.60, 0.15, 0.39 and 0.34 mu M against E. coli PDHc E1 and with good enzyme-selective inhibition between microorganisms and mammals. Especially, the most powerful inhibitor A14 could 99.37% control Xanthimonas oryzae pv. Oryzae. Furthermore, the binding features of compound A14 within E. coli PDHc E1 were investigated to provide useful insights for the further construction of new inhibitor by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that A14 had most powerful inhibition against E. coli PDHc E1 due to the establishment of stronger interaction with Glu571, Met194, Glu522, Leu264 and Phe602 at active site of E. coli PDHc E1. It could be used as a lead compound for further optimization, and may have potential as a new microbicide. (C) 2017 Elsevier Ltd. All rights reserved.
