ABSTRACT
In developing inhibitors of therapeutic target enzymes, significant time and effort are committed to the preparation of large numbers of compounds. In an effort to develop a potent inhibitor of protein tyrosine phosphatase (PTP) 1B as an anti-obesity and/or anti-diabetic agent, we constructed an isoxazolone chemical library by using a simplified procedure that circumvents tedious workup and purification steps. The 10×7 isoxazolone derivatives were synthesized by coupling the two halves of the target compounds. When mixed and heated in test tubes, the precursors produced the reaction products as precipitates. After brief washing, the products were pure enough to be used for enzymatic experiments. With the precursors for the coupling reactions prepared, the 10×7 library compounds could be prepared in a day by using the present protocol. The library compounds thus obtained were examined for their inhibitory activities against PTP1B. Among them, compound C3 was the most potent inhibitor of PTP1B with an IC(50) of 2.3 µM. The in vivo effect of C3 was also examined in an obesity-prone mouse strain. Diet-induced obese (DIO)/diabetic mice were divided into two groups and each group was fed a high-fat diet (HFD) or HFD+C3 for four weeks. The group of C3-fed mice gained significantly less weight relative to the HFD-fed control group during the four weeks of the drug feeding period. In contrast to the anti-obesity effect of C3, no difference was observed in the glycemic control of the HFD and HFD+C3 mice groups.
Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Obesity/drug therapy , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Animals , Male , Mice , Mice, Inbred C57BL , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolismABSTRACT
New bile acid-based amino sterols were synthesized in good yields from C-3beta-oxiranes as key intermediates. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. These compounds showed better antibacterial activity as compared to antifungal activity. Compounds 21 and 22 showed comparable antibacterial activity to gentamicin against Staphylococcus aureus with IC50 values of 5.14 and 4.46 microg/mL. This is the first report for the synthesis of C-3beta-oxiranes on the steroids having A/B cis ring junction and these oxiranes have been used for the synthesis of amino sterols 17, 18, 21, and 22.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Bile Acids and Salts/chemistry , Bile Acids and Salts/pharmacology , Sterols/chemistry , Sterols/pharmacology , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Anti-Infective Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Bacteria/drug effects , Bile Acids and Salts/chemical synthesis , Fungi/drug effects , Microbial Sensitivity Tests , Models, Molecular , Sterols/chemical synthesis , Structure-Activity RelationshipABSTRACT
Fluconazole based novel mimics containing 1,2,3-triazole were designed and synthesized as antifungal agents. Their antifungal activities were evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 12, 15, and 16 were found to be more potent against Candida fungal pathogens than control drugs fluconazole and amphotericin B. The studies presented here provide structural modification of fluconazole to give 1,2,3-trazole containing molecules. Furthermore, these molecules were evaluated in vivo against Candida albicans intravenous challenge in Swiss mice and antiproliferative activities were tested against human hepatocellular carcinoma Hep3B and human epithelial carcinoma A431. It was found that compound 12 resulted in 97.4% reduction in fungal load in mice and did not show any profound proliferative effect at lower dose (0.001 mg/ml).
