Novel antibiotics for the treatment of gram-positive bacterial infections.

The natural dipeptide antibiotic TAN 1057 A,B displays excellent antibacterial activity against staphylococci including methicillin resistant Staphylococcus aureus. However, the in vitro activity against additional Gram-positive strains, in particular pneumococci and Enterococcus faecalis, proved to be considerably lower. We report the synthesis and pharmacological evaluation of new derivatives of this natural product that displayed increased antibacterial potency against staphylococci and were also active against pneumococci. In particular, the analogues bearing modified beta-homoarginine side chains with methylated guanidine moieties were shown to be significantly more potent than the natural product TAN 1057 A,B.

Mechanistic Insights into Cu-Catalyzed Asymmetric Aldol Reactions: Chemical and Spectroscopic Evidence for a Metalloenolate Intermediate.

In situ IR spectroscopy and transmetalation experiments confirm a postulated catalytic cycle. The metalloenolate 1 describes the active intermediate in the aldol reaction catalyzed by [CuF2 {(S)-tol-binap}] (see reaction scheme). (S)-tol-binap=(S)-(-)-2,2'-bis(di-p-tolylphosphanyl)-1,1'-binaphthyl.

Ultrasound studies on the shift of cervical tissues in different head and neck positions--impact on transoral endoscopic, minimally invasive and conventional thyroid surgery.

During the development of a transoral endoscopic, minimally invasive approach for thyroidectomy, the question arose as to how the distances of the submandibular gland (SG)-hyoid bone (HB)-thyroid gland (TG) change in differing head positions and how the TG itself changes shape. In a prospective, two-armed ultrasound study we studied 20 healthy volunteers each, all with no history of neck surgery or thyroid disease. Distances were measured in normal, reclined and "reclined with open mouth" positions. We found no remarkable differences and the distances were comparable with conventional open or minimally invasive thyroidectomy approaches. The TG lengthened significantly during reclination. This may result in a difficult preparation in the region of the suspensory ligament and may therefore increase the rate of postoperative vocal cord palsy caused by stretching of the recurrent laryngeal nerve. A supine flat position may minimize the risk of this postoperative complication of thyroidectomy.

IKCa-channel blockers. Part 2: discovery of cyclohexadienes.

Novel cyclohexadienes have been identified as potent and specific IK(Ca)-channel blockers. In this communication we describe their synthesis as well as their chemical and biological properties. A selected derivative is being enriched in rat brain and reduces the infarct volume, intracranial pressure as well as the water content in a rat subdural hematoma model of traumatic brain injury after iv administration.

Dihydropyrimidinones--a new class of anti-staphylococcal antibiotics.

We report the synthesis and pharmacological evaluation of new derivatives of natural dipeptide antibiotic TAN-1057 A, B. In the course of this program, we identified novel analogues of the natural product that display similar antibacterial activity and showed improved tolerability.

Pyrimidinone antibiotics--heterocyclic analogues with improved antibacterial spectrum.

We report the synthesis and pharmacological evaluation of new derivatives of the natural dipeptide antibiotic TAN 1057 A,B containing heterocycles either in the beta-amino acid side chain or as mimics of the urea function. In the course of this program, we identified novel analogues that display activity towards a broader panel of Gram-positive bacteriae.