Optimization of a ß-Lactam Scaffold for Antibacterial Activity via the Inhibition of Bacterial Type I Signal Peptidase.

ß-Lactam antibiotics, one of the most important class of human therapeutics, act via the inhibition of penicillin-binding proteins (PBPs). The unparalleled success in their development has inspired efforts to develop them as inhibitors of other targets. Bacterial type I signal peptidase is evolutionarily related to the PBPs, but the stereochemistry of its substrates and its catalytic mechanism suggest that ß-lactams with the 5S stereochemistry, as opposed to the 5R stereochemistry of the traditional ß-lactams, would be required for inhibition. We report the synthesis and evaluation of a variety of 5S penem derivatives and identify several with promising activity against both a Gram-positive and a Gram-negative bacterial pathogen. To our knowledge these are the first 5S ß-lactams to possess significant antibacterial activity and the first ß-lactams imparted with antibacterial activity via optimization of the inhibition of a target other than a PBP. Along with the privileged status of their scaffold and the promise of bacterial signal peptidase I (SPase) as a target, this activity makes these compounds promising leads for development as novel therapeutics.

A case of severe hypoalbuminemia associated with chronic congestive heart failure: the role of the tricuspid regurgitation.

Hypoalbuminemia is considered an independent predictor of mortality, especially in elderly patients. It is common in patients with congestive heart failure, when is due to several mechanisms: increased volume of distribution, significant stasis in the mesenteric circulation and altered protein metabolism in the liver. These alterations are even more pregnant when tricuspid regurgitation is associated or aggravated by different risk factors (recent infections, anemia, hyperthyroidism). We present the case of an elderly patient with severe hypoproteinemia and important hypoalbuminemia associated with congestive heart failure and aggravation of tricuspid regurgitation. The differential diagnosis concluded that hypoalbuminemia was influenced by tricuspid regurgitation as it enhanced liver dysfunction and enteral protein absorption due to increased stasis in mesenteric system. On the other hand, hypoalbuminemia contributed to the progression of heart failure by favoring myocardial edema, volume overload, and diuretic resistance. This is why correct management of this situation should include removal of subclinical excess of fluid and renutrition. A multidisciplinary approach is needed in order to achieve a good control of the symptoms and a significant improvement of quality of life.

Approaching frailty as the new geriatric syndrome.

Ageing is inevitably associated with a decline in physiologic reserves. Frailty results from reaching a threshold of decline across multiple organ systems. By consequence, it is associated with a high vulnerability and reduced ability to maintain homeostasis. This vulnerability is not only age-related, but also related to disability and comorbidity, as illustrated by three clinical cases. Sarcopenia, which is defined as age-related loss of muscle mass, is considered to be a central manifestation of frailty. In addition to being highly prevalent in elderly population, frailty also exerts a substantial impact on quality of life. As it is extremely challenging by defying conventional medication and involving new therapeutically approaches, frailty fully qualifies as a new geriatric syndrome.

Guided desaturation of unactivated aliphatics.

The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal-free conditions is outlined. This 'portable desaturase' (Tz(o)Cl) is a bench-stable, commercial entity (Aldrich, catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group.

A bifurcated pathway to thiazoles and imidazoles using a modular flow microreactor.

A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles as distinct regioisomeric products using a modular flow microreactor has been devised. The process makes use of microfluidic reaction chips and packed immobilized-reagent columns to effect bifurcation of the reaction pathway.