RESUMO
A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (Râ¯=â¯CH2CH2CH2NBu2) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required.
Assuntos
Dronedarona/síntese química , Benzofuranos/química , Dronedarona/química , Cetonas/química , Estrutura Molecular , Quinonas/químicaRESUMO
OBJECTIVES: LK-157 is a novel 10-ethylidene tricyclic carbapenem that resembles the structure of the broad-spectrum antibiotic sanfetrinem and acts as a potent inactivator of beta-lactamases of classes A, C and D. LK-157 is a highly soluble but poorly permeable drug. Since most of the beta-lactams are poorly absorbed, ester prodrugs LK-159, LK-157E1 and LK-157E2 were designed to enhance membrane permeability. This study investigated the permeability of LK-157 and the three ester prodrugs across rat intestine in vitro. The morpholinoethyl ester of sanfetrinem was also investigated. METHOD: Permeability across rat jejunum was determined using EasyMount side-by-side diffusion chambers. KEY FINDINGS: The solubility and permeability of morpholinoethyl ester LK-157E2 were superior to those of LK-159 and LK-157E1. The morpholinoethyl ester of sanfetrinem LK-176E1 had the highest observed permeability coefficient and consequently the highest predicted absorption in humans. CONCLUSIONS: These results suggest that the morpholinoethyl esters of LK-157 and sanfetrinem could be further investigated to assess bioavailability in vivo.
Assuntos
Antibacterianos/química , Antibacterianos/farmacocinética , Carbapenêmicos/farmacocinética , Ésteres/farmacocinética , Jejuno/metabolismo , Lactamas/farmacocinética , Morfolinas/farmacocinética , Pró-Fármacos/farmacocinética , Inibidores de beta-Lactamases , Animais , Carbapenêmicos/química , Ésteres/química , Técnicas In Vitro , Lactamas/síntese química , Lactamas/química , Masculino , Estrutura Molecular , Morfolinas/síntese química , Permeabilidade , Pró-Fármacos/síntese química , Ratos , Ratos Wistar , Solubilidade , Solventes/química , Tensoativos/químicaRESUMO
A wide variety of pathogens have acquired antimicrobial resistance as an inevitable evolutionary response to the extensive use of antibacterial agents. In particular, one of the most widely used antibiotic structural classes is the beta-lactams, in which the most common and the most efficient mechanism of bacterial resistance is the synthesis of beta-lactamases. Class C beta-lactamase enzymes are primarily cephalosporinases, mostly chromosomally encoded, and are inducible by exposure to some beta-lactam agents and resistant to inhibition by marketed beta-lactamase inhibitors. In an ongoing effort to alleviate this problem a series of novel 4-substituted trinems was designed and synthesized. Significant in vitro inhibitory activity was measured against the bacterial beta-lactamases of class C and additionally against class A. The lead compound LK-157 was shown to be a potent mechanism-based inactivator. Acylation of the active site Ser 64 of the class C enzyme beta-lactamase was observed in the solved crystal structures of two inhibitors complexes to AmpC enzyme from E. cloacae. Structure-activity relationships in the series reveal the importance of the trinem scaffold for inhibitory activity and the interesting potential of the series for further development.
Assuntos
Antibacterianos/síntese química , Azetidinas/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Farmacorresistência Bacteriana , Compostos Heterocíclicos com 3 Anéis/síntese química , Inibidores de beta-Lactamases , Acilação , Antibacterianos/química , Azetidinas/química , Proteínas de Bactérias/química , Sítios de Ligação , Cristalografia por Raios X , Enterobacter cloacae/enzimologia , Compostos Heterocíclicos com 3 Anéis/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , beta-Lactamases/químicaRESUMO
The molecular structure of the title tricyclic compound, C(17)H(21)NO(4), which is the immediate precursor of a potent synthetic inhibitor [Lek157: sodium (8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylate] with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclohexyl ring and the carbonyl group of the beta-lactam ring, which takes part in the formation of the initial tetrahedral acyl-enzyme complex. In this hydrophobic molecule, the overall geometry is influenced by C[bond]H...O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) A, with corresponding normalized H.O distances of 2.30 and 2.46 A], whereas the molecules are interconnected through intermolecular C[bond]H...O hydrogen bonds [3.335 (4)-3.575 (5) A].
Assuntos
Compostos Aza/química , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/química , Inibidores de beta-Lactamases , Cristalografia por Raios X , Modelos Moleculares , Estrutura MolecularRESUMO
Known carbapenem compounds with inhibitory effect towards beta-lactamase enzymes are formed from bicyclical beta lactam structural scaffolds. On the basis of results from theoretical computational methods and molecular modelling we have designed and developed a synthetic route towards novel, biologically active tricyclic derivatives of carbapenems.