A new series comprising 7 analogs of N-(sulfanyl ethanoyl)-L-HSL derivatives, 2 analogs of N-(fluoroalkanoyl)-$_L$-HSL derivatives, N-(fluorosulfonyl)-L-HSL, and 2,2-dimethyl butanoyl HSL were synthesized using a solid-phase organic synthesis method. Each of the 11 synthesized compounds w...
A new series comprising 7 analogs of N-(sulfanyl ethanoyl)-L-HSL derivatives, 2 analogs of N-(fluoroalkanoyl)-$_L$-HSL derivatives, N-(fluorosulfonyl)-L-HSL, and 2,2-dimethyl butanoyl HSL were synthesized using a solid-phase organic synthesis method. Each of the 11 synthesized compounds was analyzed using NMR and mass spectroscopies, and molecular modeling studies of the 11 ligands were performed using SYBYL packages. Thereafter, a bacterial test was designed to identify their quorum-sensing inhibition activity and antifouling efficacy. Most of the synthesized compounds were found to be effective as quorum-sensing antagonists, where antagonist screening revealed that 10 among the 11 synthesized ligands were able to antagonize the quorum sensing of A. tumefaciens.
A new series comprising 7 analogs of N-(sulfanyl ethanoyl)-L-HSL derivatives, 2 analogs of N-(fluoroalkanoyl)-$_L$-HSL derivatives, N-(fluorosulfonyl)-L-HSL, and 2,2-dimethyl butanoyl HSL were synthesized using a solid-phase organic synthesis method. Each of the 11 synthesized compounds was analyzed using NMR and mass spectroscopies, and molecular modeling studies of the 11 ligands were performed using SYBYL packages. Thereafter, a bacterial test was designed to identify their quorum-sensing inhibition activity and antifouling efficacy. Most of the synthesized compounds were found to be effective as quorum-sensing antagonists, where antagonist screening revealed that 10 among the 11 synthesized ligands were able to antagonize the quorum sensing of A. tumefaciens.
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가설 설정
Hydrogen atoms have been removed for clarity (group II). C. Best poses of 5h, 5i, and 5j (hidden) at the binding site. Hydrogen atoms have been removed for clarity (group LEI).
제안 방법
Accordingly, this article focuses on a series of inhibitors that could act as antagonists against 7V-3-oxoalkanoyl HSL, a quorum-sensing signal of Pseudomonas aeruginosa and Agrobacterium tumefaciens. These species of Gramnegative bacteria cause various diseases and form a biofilm using signal transduction molecules, making it very important to develop antagonists against these autoinducers.
In the experiment designed to identify the quorum-sensing antagonist, Agrobacterium tumefaciens A136(pTiA136, pCF218, pCF372), which had been mutated to produce 伊galactosidase by expressing the lac gene when exposed to HSL, and Agrobacterium tumefaciens KYC6, which had been mutated to overproduce AHL, were used as the indicating microorganisms, along with 5-bromo-4-chloro-3-indolyl-P-D-galactopyranoside (X-gal), which gives off a green or blue color when degraded by the #galactosidase produced during the same process as an indicating material [8, 9, 18, 19]. For the experiment, the KYC6 type-culture strain was cultured overnight in an LB broth at 30℃, and then 10 |il of the KYC6 strain and 100 μ 1 of the sample elution were inoculated into 5 ml of an LB broth and cultured for 24 h at 30℃.
In this study, the molecular dockings between a receptor and the 11 deseed molecules were performed using FlexX to identify differences in the biological activities of the ligands. The structures of all the designed ligands were sketched and minimized usiii응 a Tripos force field [5] until the RMS gradient was less than 0.
After the chloroform was vaporized, 4, 000 μ 1 of the diluted strain culture was added and incubated for 3 h at 30℃. The LacZ bioassay was conducted using a Tropix-plus kit (T1011, Applied Biosystems, U.S.A.), the luminescence measured using a luminescence meter (Thermo electron Co., U.S.A.), and the OD600 values measured using a UV spectrophotometer (HP8452A, H.P., U.S.A.). The antagonist activities of the compounds were expressed as the relative luminescence/OD600 values.
The molecular modeling was performed using SYBYL packages, and the binding pose of the reference ligand used to identify important H bonds and hydrophobic interactions. Additionally, the bioactivities of the 11 designed ligands were explained based on their FlexX binding energies and best docking poses.
대상 데이터
The reaction yield was investigated based on the mass increase, which ranged from 90% to 94%. To prepare a series ofhomoserine lactones, the resin was treated with BrCN (860 mg, 8 mmol) and trifluoroacetic acid (TFA, 5%) in chloroform/ water (10 ml/5 ml) in each of the 11 filtered reactors. The homoserine lactone derivative products were then cleaved from the beads twice for 12 h using a chemical cleavage method.
이론/모형
Therefore, molecular modeling of the newly designed ligands was performed to examine the structural features of their interactions at an active site. The FlexX dockings of the ligands were modeled using the Run-Multiple ligand option of FlexX [13]. Optimal conformational poses were selected from among several possibilities based on the values obtained for the root-mean-square (RMS) deviation from the reference structure.
성능/효과
The collected solution was extracted several times with CHC13 and brine, and then the final chloroform solution was evaporated. As a result, homoserine lactone products with yields ranging from 68% to 79% were obtained from the AM PS resin [5a (79%), 5b (78%), 5c (68%), 5d (79%), 5e (71%), 5f (78%), 5g (70%), 5h (79%), 5i (73%), 5j (69%), 5k (77%)]. 2-Oxo-2-(2-oxotetrahydrofiiran-3-ylamino)ethyl benzodithioate (5d): rH NMR (CDC13, 400 MHz) 8=8.
In conclusion, new biologically active antagonists were discovered and 11 new Ae-(alkylsulfanylethanoyl)-L-HSL, 7V-(fluoroalkanoyl)-L-HSL, 7V-(fluorosulfonyl)-L-HSL, or 2, 2-dimethyl butanoyl-L-HSL QS antagonists were synthesized with considerably high yields due to the nature of the synthesis method used. The 10 new analogs of Nacyl HSL or 7V-sulfonylhomoserine lactone derivatives were also shown to act as antagonists against Ae-3-oxoalkanoyl HSL, one of the autoinducers of Agrobacterium tumefaciens and Pseudomonas aeruginosa.
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