Changes in Cuticular Wax Composition of Two Blueberry Cultivars during Fruit Ripening and Postharvest Cold Storage

Cuticular wax plays an important role for the quality of blueberry fruits. In this study, the cuticular wax composition of two blueberry cultivars, ‘Legacy’ (Vaccinium corymbosum) and ‘Brightwell’ (Vaccinium ashei), was examined during fruit ripening and postharvest cold storage. The results showed that wax was gradually deposited on the epidermis of blueberry fruits and the content of major wax compounds, except that for diketones, increased significantly during fruit ripening. The total wax content was 2-fold greater in ‘Brightwell’ blueberries than that in ‘Legacy’ blueberries during fruit ripening. The total wax content of both cultivars decreased during 30 days of storage at 4 °C, and the variation of cuticular wax composition was cultivar-dependent. The content of diketones decreased significantly in ‘Legacy’ blueberries, while the content of triterpenoids and aliphatic compounds showed different fold changes in ‘Brightwell’ blueberries after 30 days of storage at 4 °C. Overall, our study provided a quantitative and qualitative overview of cuticular wax compounds of blueberry fruits during ripening and postharvest cold storage

Design, Synthesis, and Structure–Activity Relationship Studies of Novel Thioether Pleuromutilin Derivatives as Potent Antibacterial Agents

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure–activity relationship (SAR) studies resulted in compounds <b>52</b> and <b>55</b> with the most potent in vitro antibacterial activity among the series (MIC = 0.031–0.063 μg/mL). Further optimization to overcome the poor water solubility of compound <b>55</b> resulted in compounds <b>87</b>, <b>91</b>, <b>109</b>, and <b>110</b> possessing good in vitro antibacterial activity with increased hydrophilicity. Compound <b>114</b>, the water-soluble phosphate prodrug of compound <b>52</b>, was also prepared and evaluated. Among the derivatives, compound <b>110</b> showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound <b>110</b> was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4

Design, Synthesis, and Structure–Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility

Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]­triazolo­[1,5-<i>a</i>]­pyrazine and tetrahydro-thiazolo­[5,4-<i>c</i>]­pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds <b>27aa</b> and <b>45x</b>, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against <i>Candida</i>, <i>Cryptococcus</i>, and <i>Aspergillus</i> spp., as well as selected fluconazole-resistant strains. A high water-soluble compound <b>58</b> (the disulfate salt of <b>45x</b>) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with <i>C</i>.<i>alb</i>. SC5314 and <i>C</i>.<i>alb</i>. 103 (fluconazole-resistant strain) and administered with <b>27aa</b> displayed significantly improved survival rates. <b>27aa</b> also showed favorable pharmacokinetic (PK) profiles

Solubility-Driven Optimization of (Pyridin-3-yl) Benzoxazinyl-oxazolidinones Leading to a Promising Antibacterial Agent

The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure–activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound <b>85</b> exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound <b>85</b> displayed an ED₅₀ = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid

Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections

Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4­(1<i>H</i>)-one and the aminothiazole oxime were designed and synthesized. Structure–activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound <b>12c</b>) and methylthiomethyl (compound <b>16a</b>) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound <b>12c</b> exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound <b>12c</b> shows an ED₅₀ of 10.20 mg/kg. Taken together, the results indicate that compound <b>12c</b> is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens