When inhibitors of enzymes that utilize isoprenoid pyrophosphates are based on the natural substrates, a significant challenge can be to achieve selective inhibition of a specific enzyme. One element in the design process is the stereochemistry of the isoprenoid olefins. We recently reported preparation of a series of isoprenoid triazoles as potential inhibitors of geranylgeranyl transferase II but these compounds were obtained as a mixture of olefin isomers. We now have accomplished the stereoselective synthesis of these triazoles through the use of epoxy azides for the cycloaddition reaction followed by regeneration of the desired olefin. Both geranyl and neryl derivatives have been prepared as single olefin isomers through parallel reaction sequences. The products were assayed against multiple enzymes as well as in cell culture studies and surprisingly a Z-olefin isomer was found to be a potent and selective inhibitor of geranylgeranyl diphosphate synthase.
In recent years, naturally occurring tetrahydro-β-carboline (THC) alkaloids and their derivatives have been of biological interest. However, few studies and developments have reported the use of such structures in managing plant bacterial diseases. Herein, an array of novel THC derivatives containing an attractive 1,3-diaminopropan-2-ol pattern were prepared to evaluate the antiphytopathogen activity in vitro and in vivo and explore innovative antibacterial frameworks. Notably, target compounds exhibited excellent activities against three rebellious phytopathogens, namely, Pseudomonas syringae pv. actinidiae (Psa), Xanthomonas axonopodis pv. citri, and Xanthomonas oryzae pv. oryzae, at related optimal EC 50 values of 2.39 (II 9 ), 2.06 (I 23 ), and 1.69 (II 9 ) μg/mL, respectively. These effects were superior to those of the parent structure 1,2,3,4-THC and positive controls. In vivo assays showed that II 9 exhibited excellent control efficiencies of 51.89 and 65.45% at 200 μg/mL against rice bacterial blight and kiwifruit bacterial canker, respectively, and I 23 substantially relieved the citrus canker on the leaves. Antibacterial mechanisms indicated that these THC compounds could induce the increment of reactive oxygen species and subsequently endow the tested bacteria with distinct apoptotic behavior. In addition, II 9 could alleviate the hypersensitive response and pathogenicity of Psa. Overall, these simple THC derivatives can be further developed as versatile antibacterial agents.
A small set of triazole bisphosphonates has been prepared and tested for the ability to inhibit geranylgeranyl transferase II (GGTase II). The compounds were prepared through use of click chemistry to assemble a central triazole that links a polar head group to a hydrophobic tail. The resulting compounds were tested for their ability to inhibit GGTase II in an in vitro enzyme assay and also were tested for cytotoxic activity in an MTT assay with the human myeloma RPMI-8226 cell line. The most potent enzyme inhibitor was the triazole with a geranylgeranyl tail, which suggests that inhibitors that can access the enzyme region that holds the isoprenoid tail will display greater activity.
Bacterial biofilms are the root cause of persistent and chronic phytopathogenic bacterial infections. Therefore, developing novel agrochemicals that target the biofilm of phytopathogenic bacteria has been regarded as an innovative tactic to suppress their invasive infection or decrease bacterial drug resistance. In this study, a series of natural pterostilbene (PTE) derivatives were designed, and their antibacterial potency and antibiofilm ability were assessed. Notably, compound C 1 displayed excellent antibacterial potency in vitro, affording an EC 50 value of 0.88 μg mL −1 against Xoo (Xanthomonas oryzae pv. oryzae). C 1 could significantly reduce biofilm formation and extracellular polysaccharides (EPS). Furthermore, C 1 also possessed remarkable inhibitory activity against bacterial extracellular enzymes, pathogenicity, and other virulence factors. Subsequently, pathogenicity experiments were further conducted to verify the above primary outcomes. More importantly, C 1 with pesticide additives displayed excellent control efficiency. Given these promising profiles, these pterostilbene derivatives can serve as novel antibiofilm agents to suppress plant pathogenic bacteria.
Emerging pesticide-resistant phytopathogenic bacteria have become a stumbling block in the development and use of pesticides. Quorum sensing (QS) blockers, which interfere with bacterial virulence gene expression, are a compelling way to manage plant bacterial disease without resistance. Herein, a series of isopropanolamine-decorated coumarin derivatives were designed and synthesized, and their potency in interfering with QS was investigated. Notably, compound A 5 exhibited a better bioactivity with median effective concentration (EC 50 ) values of 6.75 mg L −1 against Xanthomonas oryzae pv. oryzae (Xoo) than bismerthiazol (EC 50 = 21.9 mg L −1 ). Further biochemical studies revealed that compound A 5 disturbed biofilm formation and suppressed bacterial virulence factors and so forth. Moreover, compound A 5 decreased the expression of QS-related genes. Interestingly, compound A 5 had the acceptable control effect (53.2%) toward Xoo in vivo. Overall, this study identifies a novel lead compound for the development of bactericide candidates to control plant bacterial diseases by interfering with QS.
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