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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.

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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.

In connection with our studies on hydantoin derivatives, a conventional regioselective chemical transformation of 5-methylene hydantoins 4a-c to 5-aminomethyl-substituted hydantoins 5-10 or to 5-amino-5-methyl-disubstituted hydantoins 11-14 is described. Synthesis of bivalent twin-drug type hydantoin derivatives 19-24 and the binding property of a bivalent symmetrical hydantoin derivative 24b to sulfated glycosaminoglycans are also described.

In connection with our studies on synthetic applications of a new type of amino acid b-aminoalanines 1 [7][8][9][10] and our search for biologically active compounds, we have already reported that the compounds 1 are useful starting materials to prepare 5-dialkylaminomethylhydantoins (3: XϭO, YϭCH) via cyclization of corresponding urea derivatives 2, which are easily prepared by the addition of a primary amino group in compounds 1 to aryl isocyanates. 7) We carried out further preparation of new analogues of 5-dialkylaminomethylhydantoins and 2-thio-analogues. In this paper, we report the synthesis of these new derivatives 3 and the chemical properties observed in the synthesized compounds.The desired compounds 3 were obtained in good yields by cyclization of the corresponding urea derivatives 2 prepared by condensation of aryl(thio)isocyanates with b-aminoalanines 1 (Chart 1). Since purification of the intermediates urea derivatives (2b and 2h-j) was difficult, compound 3b and the 2-thio-analogues 3h-j were prepared by a "one-pot" procedure (1→3) without further purification of the corresponding intermediate urea derivatives. The results of the reaction stages (1→2 and 2→3) are summarized in Tables 1 and 2, respectively. The structures of these new products were established by spectroscopic and elemental analyses. All of the assignments were confirmed by two-dimensional (2D) -NMR spectroscopic analysis.By treatment with a large excess amount of H 2 O, deamination (elimination of dialkylamines 5) of 2-thiohydantoin derivative 3b took place to give 5-methylene-2-thiohydantoin 4b (Chart 2). This behavior was easily confirmed by 1 H-NMR spectroscopic analysis. Thus, by 2 ) is also confirmed by the 13 C-NMR spectrum. We observed that this deamination of 2-thiohydantoin 3b to give 5-methylene-2-thiohydantoin 4b proceeded more easily than that of corresponding hydantoin (3a→4a) 7) through the above NMR experiments. 5-Methylene-2-thiohydantoin analogue 4b could be isolated in good yield (76%, see Experimental). Throughout our repeated trials for the isolation of compound 4b, we found that 5-methylene-2-thiohydantoin is not a stable species at elevated temperatures (over 80°C in solution), giving unknown polymerized products. Methylenehydantoin 4a or the 2-thio-analogue 4b (by retro-Michael addition of 3a or 3b) is formed probably via a 6-membered tautomeric intermediacy state (A) (shown in Chart 2).In 1 H-NMR spectra of 5-methylene-2-thiohydantoin 4b, the N-H proton of the hydantoin ring was easily deuterated by treatment with D 2 O. Interestingly, two 5-methylene protons were further deuterated smoothly at room temperature. This result obviously indicates that 5-methylene-2-thiohydantoin 4b exists in an equilibrium state through keto-enol tautomerism of a thioamido functionality conjugated with a 5-methylene group in the 2-thiohydantoin ring (4b-I → ←4b-II → ←4b-III → ←4b-IV) (see Chart 3). The 5-dialkylaminomethylhydantoin system 3 may exist as many constituted tautomers that are in equilibrium with each other and ...

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