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 52 and 55 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 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.

Adiponectin is an adipocyte-derived insulin-sensitizing hormone with antidiabetic, antiinflammatory, and antiatherosclerotic properties. A decreased serum level of adiponectin in obesity has been identified as an independent risk factor for diabetes and cardiovascular complications, suggesting that pharmacological intervention aimed at elevating adiponectin production might hold promise for the treatment and/or prevention of these diseases. Here we report the identification of two structurally related natural compounds (astragaloside II and isoastragaloside I) from the medicinal herb Radix Astragali that possess such an activity. Astragaloside II and isoastragaloside I selectively increased adiponectin secretion in primary adipocytes without any obvious effects on a panel of other adipokines. Furthermore, an additive effect on induction of adiponectin production was observed between these two compounds and rosiglitazone, a thiazolidinedione class of insulin-sensitizing drugs. Chronic administration of astragaloside II and isoastragaloside I in both dietary and genetic obese mice significantly elevated serum levels of total adiponectin and selectively increased the composition of its high molecular weight oligomeric complex. These changes were associated with an alleviation of hyperglycemia, glucose intolerance, and insulin resistance. By contrast, the beneficial effects of these two compounds on insulin sensitivity and glucose metabolism were diminished in adiponectin knockout mice. In conclusion, our results suggest that pharmacological elevation of circulating adiponectin alone is sufficient to ameliorate insulin resistance and diabetes and support the use of adiponectin as a biomarker for future drug discovery. The two natural compounds might provide the lead as a novel class of therapeutics for obesity-related diseases.

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-a]pyrazine and tetrahydro-thiazolo[5,4-c]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 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.