A Divergent Route to Eravacycline.

A convergent route to eravacycline (1) has been developed by employing Michael-Dieckmann cyclization between enone 3 and a fully built and protected left-hand piece (LHP, 2). After construction of the core eravacycline structure, a deprotection reaction was developed, allowing for the isoxazole ring opening and global deprotection to be achieved in one pot. The LHP is synthesized from readily available 4-fluoro-3-methylphenol in six steps featuring a palladium-catalyzed phenyl carboxylation in the last step.

Synthesis and biological evaluation of 8-aminomethyltetracycline derivatives as novel antibacterial agents.

The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.

Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent.

This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on rats with persistent inflammation.

OBJECTIVE: Ruxiang, or Gummi olibanum, an herbal medicine derived from the gum resin of Boswellia carterii Birdw. (BC) of the family Burseraceae, has been used traditionally in China to alleviate pain and reduce inflammation. The present study is an investigation of the effects of a BC extract on persistent hyperalgesia and edema in rats with peripheral inflammation. DESIGN: In this randomized, blinded study, the antihyperalgesic and antiedema effects of 3 dosages of BC were compared to a vehicle control. Inflammation was induced in rats by injecting complete Freund's adjuvant (CFA) into one hind paw. A single oral dose of the BC extract was administered daily for 7 days, beginning one day before CFA. Hyperalgesia was assessed using a paw withdrawal latency (PWL) test pre-CFA and 2 hours, 5 hours, 1 day, and 5 days post-CFA. Edema was determined by measuring paw thickness at the same time points. Spinal Fos protein expression was analyzed 2 hours post-CFA. Adverse effects of the extract were monitored by observing the animals closely for unusual behavioral changes. RESULTS: Compared to control, a dosage of 0.45 g/kg BC significantly lengthened PWL and reduced paw edema on day 5 post-CFA. At 0.90 g/kg, BC significantly lengthened PWL at 5 hours, 1 day, and 5 days, and reduced paw edema at 2 hours, 5 hours, 1 day, and 5 days. This dosage also significantly suppressed spinal Fos expression in the medial half of laminae I-II. At 1.80 g/kg, BC significantly lengthened PWL and reduced paw edema at all time points. No noticeable adverse effects were observed in animals given the lower dosages of BC, but adverse effects in some animals were observed at 1.80 g/kg per day. In the acute toxicity study, the maximal single dose of 2.50 g/kg produced no adverse effects in the treated rats during the 14 days of observation. CONCLUSIONS: The data suggest that BC produces significant antihyperalgesia and anti-inflammation effects and that the antihyperalgesia may be mediated by suppressed inflammation-induced Fos expression in the spinal dorsal horn neurons.