Asymmetric synthesis of 4-formyl-1-(ω-haloalkyl)-β-lactams and their transformation to functionalized piperazines and 1,4-diazepanes

Chiral piperazine and 1,4-diazepane annulated β-lactams, prepared from the corresponding (3R,4S)-4-imidoyl-1-(ω-haloalkyl)azetidin-2-ones through reduction with sodium borohydride in ethanol, were transformed into novel methyl (R)-alkoxy-[(S)-piperazin-2-yl]acetates and methyl (R)-alkoxy-[(S)-1,4-diazepan-2-yl]acetates upon treatment with hydrogen chloride in methanol. On the other hand, bromination of (3R,4R)-1-allyl-4-formyl-β-lactams and (3R,4S)-1-allyl-4-imidoyl-β-lactams in dichloromethane, followed by sodium borohydride reduction of the resulting dibrominated azetidin-2-ones in ethanol, did not afford the envisaged bicyclic β-lactams but unexpectedly furnished (3R,4S)-1-(2-bromo-2-propenyl)azetidin-2-ones instead.     

The efficiency of indicator-based local search for multi-objective combinatorial optimisation problems

In the last few years, a significant number of multi-objective metaheuristics have been proposed in the literature in order to address real-world problems. Local search methods play a major role in many of these metaheuristic procedures. In this paper, we adapt a recent and popular indicator-based selection method proposed by Zitzler and Künzli in 2004, in order to define a population-based multi-objective local search. The proposed algorithm is designed in order to be easily adaptable, parameter independent and to have a high convergence rate. In order to evaluate the capacity of our algorithm to reach these goals, a large part of the paper is dedicated to experiments. Three combinatorial optimisation problems are tested: a flow shop problem, a ring star problem and a nurse scheduling problem. The experiments show that our algorithm can be applied with success to different types of multi-objective optimisation problems and that it outperforms some classical metaheuristics. Furthermore, the parameter sensitivity analysis enables us to provide some useful guidelines about how to set the parameters.     

Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross-Linking Activity of a Transpeptidase of l,d Specificity

The carbapenem class of β-lactams has been optimized against Gram-negative bacteria producing extended-spectrum β-lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d -transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β-lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido-carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems.     

Detecting network backbones against time variations in node properties

Nonlinear Dynamics - Many real systems can be described through time-varying networks of interactions that encapsulate information sharing between individual units over time. These interactions can...     

Markov-modulated Brownian motions perturbed by catastrophes

ABSTRACT

We consider a one-sided Markov-modulated Brownian motion perturbed by catastrophes that occur at some rates depending on the modulating process. When a catastrophe occurs, the level drops to zero for a random recovery period. Then the process evolves normally until the next catastrophe. We use a semi-regenerative approach to obtain the stationary distribution of this perturbed MMBM. Next, we determine the stationary distribution of two extensions: we consider the case of a temporary change of regime after each recovery period and the case where the catastrophes can only happen above a fixed threshold. We provide some simple numerical illustrations.