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NoteIn connection with our synthetic studies in the search for new bioactive lead compounds, some molecular modifications of b-aminoalanines to the class of oxazolidinones (linezolid mimetic molecules) have been reported.1,2) Some of the synthesized compounds were evaluated for antibacterial activity with gram-negative (Escherichia coli) and gram-positive (Staphylococcus aureus) strains, and we found that most of the 4-dialkylaminomethyloxazolidinone-related derivatives (A) 1) showed no significant antibacterial activities against either gram-positive or gram-negative strains. Therefore, we carried out further molecular modification of linezolid to the hydantoin analogue (B). Molecular modification to the represented structure (B) can be considered to be a bioisosteric replacement 3) of the oxazolidinone ring in linezolid by a hydantoin nucleus (Fig. 1).Through our pre-screening, we found that some hydantoin derivatives in this class showed significant antibacterial activities against both gram-negative (E. coli) and gram-positive (S. aureus) strains. In the early stage of invasion of bacteria such as E. coli, the surface glycans of bacteria recognize host cell lectin.4) For such molecular recognition of glycans, the major recognition patterns between the host and target guest molecules are through intermolecular hydrogen bonding interactions. This interaction process is a logical path and is thought to direct a controlled biological response. 5) We have been interested in target compounds that interfere with such a recognition process in order to find new leads. In terms of donor-acceptor for hydrogen bondings, compound B has both donor and acceptor functionalities in the molecules, in contrast to molecule A having no donor for hydrogen bonding. Bioactive linezolid (R 1 ϭH, and R 2 ϭCOCH 3 ) as a lead in this study has both donor and acceptor groups for hydrogen bonding in supramolecular interactions. [6][7][8] From this point of view, further molecular modifications of this class of compounds (B) seemed to be interesting in the search for new antibacterial leads. We therefore carried additional synthetic investigation and biological evaluation of these 5-dialkylaminomethylhydantoin derivatives (B).In this article, additional synthetic applications of baminoalanines 9-11) to some new hydantoins and biological evaluation of the hydantoin-related derivatives for antibacterial activity with gram-negative (E. coli) and gram-positive (S. aureus) strains are described.
Synthesis of 5-Dialkylaminomethyl-3-aryl-hydantoins (3) and Related CompoundsIn our synthetic studies on b-aminoalanines (1), 9) we have already reported target molecules of 5-dialkylaminomethyl-3-aryl-hydantoins (3) which are easily prepared by cyclization of urea derivatives (2) readily obtained by addition of b-aminoalanines to arylisocyanates (or arylisothiocyanates).10,11) The hydantoin derivatives (3) described in this paper were prepared in a manner similar to that reported previously. Synthesis of the compounds (2, 3a, 3b, 3d-3j, 3n, 3p-3t, 4, ...
A conventional new route to the novel oxazolidin-2-one derivatives (3a-f) having two substituents on N-3 and C-4 in the oxazolidin-2-one ring was established with racemic b b-aminoalanine derivatives (1) as the key starting materials.
In connection with our studies on antibacterial compounds in the class of 5-dialkylaminomethylhydantoins against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains, some molecular modifications were attempted. The antibacterial activities of all of the synthesized hydantoin derivatives were evaluated. Among the hydantoin derivatives designed in this study, C 2 -symmetrical twin-drug type compound (7) showed the highest level of antibacterial activity against S. aureus strain.
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