Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MβLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC50 value range of 0.032–15.64 μM except 7. The chlorine substituted compounds (1, 2 and 3) inhibited NDM-1 with an IC50 value of less than 0.96 μM, and the fluorine substituted 12 and 13 inhibited VIM-2 with IC50 values of 38.9 and 2.8 μM, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that 9 and 13 are mixed inhibitors for ImiS with Ki values of 0.074 and 0.27μM using imipenem as the substrate. Docking studies showed that 1 and 9, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.

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Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent. Biological activity assays identify the thiazolethioacetamides can inhibit ImiS with IC50 values of 0.17 to 0.70 μM. For two of them, the IC50 values against VIM-2 were 2.2 and 19.2 μM, which is lower than in our previous report. Eight of the thiazolethioacetamides are able to restore antibacterial activity of cefazolin against E.coli-ImiS by 2–4 fold. An analysis of the structure–activity relation and molecule docking show that the style and position of electron withdrawing groups in aromatic substituents play a crucial role in the inhibitory activity of thiazolethioacetamides. These results indicate that thiazolethioacetamides can serve as a potential skeleton of MβL inhibitors.

The metallo-β-lactamases (MβLs) produced by pathogens has issued a challenge to the treatment of bacterial infections worldwide. A number of oxazolethioacetamides were designed and synthesized as potential MβLs inhibitors. Most of the compounds displayed inhibitory activity against MβL L1 with an IC 50 value range of 0.19-0.38 μM. The fluorine substituted compounds also inhibited VIM-2 with IC 50 value of 2.1 to 6.8 μM. Molecule Docking showed the style and position of electron withdrawing groups played important role between the oxazolethioacetamides and MβLs.

Turning potential natural products into value-added fungicides is a bioactivity-guided mixed synthesis method. Thirty-two derivatives were designed and synthesized to improve the potential use of the osthole, a natural coumarin pharmacophore. Compound Os14 with 3-ClPh showed a high in vitro and in vivo antifungal activity than other derivatives. The preliminary structure-activity relationships (SARs) demonstrated that compounds with a short aliphatic chain or electron-withdrawing groups on phenyl ring would have more desirable potency.Meanwhile, the quantitative structure-activity relationship (QSAR) model (R 2 = 0.928, F = 83.54, S 2 = 0.0042) were performed using Gaussian and CODESSA software with optimal conformers and heuristic regression analysis, which revealed a correlation of antifungal activity and molecular structures. Thus, these results laid the foundation for further design of improved crop-protection agents based on osthole scaffold. activity was tested. Since the in vitro antifungal activity of fungicides does not always match the in vivo activity, the in vivo activities were also tested. Moreover, structure-activity relationships (SAR) and quantitative structure-activity relationship (QSAR) model which was established via Codessa software were investigated to provide a helpful insight into further lead optimization. RESULTS AND DISCUSSIONChemistry. The intermediate compound 2 (7-hydroxyosthole) were obtained by Cys/NaH catalytic system under DMF solution through demethylation reaction. In order to investigate the structure-activity relationships, ester compounds Os1-32 were synthesized by using dicyclohexylcarbodiimide (DCC) and catalytic dimethylaminopyridine (DMAP) in the coupling of carboxylic-acids with compound 2 in 38%～ 68% yields. The structures of all the derivatives were characterized by 1 H NMR, 13 C NMR and highresolution electrospray ionization mass spectrometry (HR-ESI-MS). Scheme 1. The synthetic routine to the target compounds Os1-32. Reagents and conditions: a) cysteine, NaH, osthole, DMF, 0 °C-80 °C; b) corresponding carboxylic acid, DMAP, DCC, CH2Cl2, 0 °C to rt.Antifungal activity and SARs. The in vitro screening results of the title compounds for preliminary antifungal activities against seven pathogenic fungi (Botrytis cinerea, Valsa mali Miyabe et Yamada, Alternaria brassicicola (Schweinitz) Wilts., Fusahum graminearum Sehw., Rhizoctonia solani, Colletotrichum gloeosporioides Penz. and Sclerotinia sclerotiorum) at 100 μg/mL were listed in Table 1 and Figure 2. The results showed most of the compounds exhibited certain to great inhibition activity against each of the fungi at 100 μg/mL. As shown therein, compound with meta-Cl of the phenyl group Os14 was active against those seven fungi to various extent at the concentration of 100 μg/mL and exhibited the highest inhibitory activity against Rhizoctonia solani with inhibition ratio of 91.3%.Particularly, the antifungal activity of compounds Os7, Os11, Os14, Os17, and Os31-32 were more potent than natural products osthole. Furth...