Efficient Synthesis and Antibacterial Evaluation of (±)-Yanglingmycin and Its Analogues

Wenjia Dan, Huiling Geng, Jianwen Qiao, Rui Guo, Shaopeng Wei, Longbo Li, Wenjun Wu, Jiwen Zhang
2016 Molecules  
An efficient synthetic route was developed for the large-scale preparation of (˘)-Yanglingmycin and its analogues. Three series of derivatives of (˘)-Yanglingmycin were synthesized and the structures of all compounds were elucidated by analyses of NMR and ESI-MS spectra data. Moreover, their antibacterial activities against seven species of bacteria were systematically evaluated by the micro-broth dilution method, most of which displayed considerable activity. It was worth noting that compounds
more » ... ting that compounds 5b, 5c, 5d, 6g, and 7 were found to be the most promising leading candidates, with peak MIC values of 0.98 µg¨mL´1 for Bacillus subtilis, which is superior to positive controls (MIC = 3.91 µg¨mL´1). The above results might lay the firm foundation for the design and synthesis of novel antibacterial drugs based on (˘)-Yanglingmycin. Molecules 2016, 21, 96 2 of 16 all over the world [9] [10] [11] [12] [13] . In order to obtain more substrates for drug development, an efficient, low-cost, and convenient route was developed to synthesize (˘)-Yanglingmycin, based on our previous studies [5, 8, 14] . To our delight, (´)-Yanglingmycin showed considerable MIC values against all tested bacteria. Herein, a series of hydroxyl ester and hydroxyl ether derivatives of the racemic compound and its phenyl different-substituted analogues were designed and synthesized to further explore the antibacterial potency. Moreover, all compounds were successively screened against several Gram-negative and Gram-positive bacteria species, which consisted of Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas syringae pv. Actinidiae, Pseudomonas solanacearum, and Ralstonia solanacearum. Figure 1. The structure of (´)-Yanglingmycin. Results and Discussion Preparation of 2-Arylthiazoline Analogues Large scale synthesis of (˘)-Yanglingmycin and its analogues have been executed via an efficient pathway outlined in Scheme 1 [13] . In addition, series of derivatives of (˘)-Yanglingmycin were prepared as well as assayed the antibacterial activities. Twenty-six derivatives 5a-5z were afforded in 59%-86% yields by esterification reactions using catalytic amount of 4-N,N-dimethylaminepyridine and EDC¨HCl (Scheme 2) [15] . Simultaneously, etherification of the alcoholic hydroxyl groups of compound 4a provided fifteen derivatives 6a-6o with yields 63%-88% (Scheme 3) [16, 17] . Only one phenolic hydroxyl group usually reacted with an alkylating agent more easily than the alcoholic hydroxyl group under the base conditions. However, (˘)-Yanglingmycin took a prior reaction on the alcoholic hydroxyl. From its molecular structure, we could infer that the activation energy of phenolic hydroxyl may be increased because of the presence of intramolecular hydrogen bonds. A fluorinated compound was afforded via (˘)-Yanglingmycin reacted with DAST (Scheme 4) [18, 19] . The preliminary results proved that compounds 5a, 5b, 5c, 5d, 5e, 5f, 5g, 6f, 6g, and 7 were found to possess superior activity than (˘)-Yanglingmycin. According to the evaluation results of MIC values, compounds 5b, 5c, 5d, 6g, and 7 have more potential to be the leading compounds for further medicine-relevant studies, compared to none of the 4b-h MICs within 31.25 µg¨mL´1. Taking a comprehensive view of the relationship between the compounds structure and its antibacterial data, most compounds lost their activity after the alcoholic hydroxyl derivatized or the 2-hydroxy substitution of the phenyl ring disappeared. However, short-chain ester group and electron-deficient ether moiety contribute significantly to the potency of antibacterial activity. Meanwhile, alcoholic hydroxyl fluorinate increased the antibacterial activity greatly. Scheme 1. The synthetic route of (˘)-Yanglingmycin and its analogues. Molecules 2016, 21, 96 3 of 16 Scheme 2. The synthetic route of esterified derivatives of (˘)-Yanglingmycin. Scheme 3. The synthetic route etherified derivatives of (˘)-Yanglingmycin. Scheme 4. The synthetic route fluorinated derivatives of (˘)-Yanglingmycin. Antibacterial Activities Assay All the synthesized compounds were evaluated for their in vitro antibacterial activities against four Gram-negative (Escherichia coli, Pseudomonas syringae pv. Actinidiae, Pseudomonas solanacearum, Ralstonia solanacearum) and three Gram-positive bacteria (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus). The minimum inhibitory concentrations (MICs) were determined by the double-dilution method using ampicillin sodium and fosfomycin sodium as the positive controls. All data of MIC values were summarized in Tables 1 and 2.
doi:10.3390/molecules21010096 pmid:26784161 fatcat:7pbp277r7je6tj6yxatcw7wo3m