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The oxazolidinones, exemplified by , 2) are a new class of synthetic antibacterial agents with activity against gram-positive bacteria. Pharmacia group found linezolid (2) 3) which was known to be the first candidate of effective oxazolidinones against serious gram-positive human pathogens caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) without severe toxicity.In our preceding paper, 1) we demonstrated from our SAR study that the antibacterial activity was greatly affected by the conversion of 5-substituent. (S)-N- phenyl]-2-oxo-5-oxazolidinyl]methyl] thiourea (3), which has a 5-thiourea group, was found to show more excellent in vitro antibacterial activity than linezolid against gram-positive bacteria including MRSA and VRE.Concerning a substituent on the benzene ring, on the other hand, Gregory et al. proposed earlier that the co-planarity between 4Ј-substituent and benzene ring is related to the antibacterial activity in case of 5-acetamide derivatives. 4) They also reported that there might be a small pocket around 3Ј-position on the benzene ring in the binding mode of 5-acetamide oxazolidinones.5) While considering their suggestions, we focused our attention on lipophilicity to further study 5-thiocarbonyl oxazolidinones. Partition coefficient (log P), which is well known as an index of lipophilicity, is an important physicochemical parameter in the development of antibacterial agent because it is known to be closely related to the permeation through a lipid coat of bacteria. Concerning the lipophilicity on oxazolidinones, it has been reported that the balance between 5-hydrophilic substituent and hydrophobic substituent on the aromatic ring is important for the antibacterial activity. 2,4) In this paper, we describe our SAR study, especially the relationship between lipophilicity and antibacterial activity, on (4Ј-cycloalkylamino)phenyl oxazolidinones bearing 5-thiocarbonyl groups.Chemistry 5-Thiourea oxazolidinones 4 and 5-dithiocarbamate oxazolidinones 5 were synthesized as shown in Chart 2. They were prepared from key intermediates 12, which were easily derived from 6 by the usual method.3b) The key intermediates 12 were treated with carbon disulfide followed by ethyl chloroformate to give isothiocyanates 13. Thiourea derivatives 4 were synthesized from 13 by treatment with ammonia (method A), or prepared from 14 (method B). Dithiocarbamate derivatives 5 were synthesized from the corresponding key intermediates 12 by treatment with carbon disulfide and iodomethane. The physicochemical data of compounds 4 and 5 are shown in the experimental April 2001 Chem. Pharm. Bull. 49(4) 353-360 (2001) 353 * To whom correspondence should be addressed. Research and Development Division, Hokuriku Seiyaku Co., Ltd., 37-1-1, Inokuchi, Katsuyama, Fukui 911-8555, Japan. Received July 21, 2000; accepted December 22, 2000 5-Thiourea and 5-dithiocarbamate oxazolidinones were synthesized as a continuation of research on 5-thiocarbonyl oxazolidinone antibacteria...

A structure-activity relationship (SAR) study on 5-substituted oxazolidinones as an antibacterial agent is described. The oxazolidinones, of which 5-acetylaminomethyl moiety was converted into other functions, were prepared and evaluated for antibacterial activity. Elongation of the methylene chain (8) and conversion of the acetamido moiety into guanidino moiety (12) decreased the antibacterial activity. The replacement of carbonyl oxygen (‫؍‬O) by thiocarbonyl sulfur (‫؍‬S) enhanced in vitro antibacterial activity. Especially, compound 16, which had the 5-thiourea group, showed 4-8 stronger in vitro activity than linezolid. Our SAR study revealed that the antibacterial activity was greatly affected by the conversion of 5-substituent.

A series of 5-thiocarbamate oxazolidinones was prepared and tested for in vitro and in vivo antibacterial activities. The results of in vitro antibacterial activity indicated that the 5-thiocarbamate group was a suitable substituent for the activity by the 5-moderate hydrophilicity. The compounds within a favorable log P value range were found to have potent in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Compounds 3a and 4h were superior to linezolid in both in vitro and in vivo potency and were considered to be hopeful compounds. We also discuss the pharmacokinetic properties of several compounds in mice.Key words oxazolidinone; antibacterial activity; structure-activity relationship; 5-thiocarbamate oxazolidinone Chart 1Chart 2 5-thiocarbamate derivatives for antibacterial activities. The results of antibacterial activities are summarized in Table 1. The activity of compound 3a showed 4 times stronger than that of linezolid (1). However, the introduction of lengthened alkyl groups or cycloalkyl group at R 1 position decreased antibacterial activities. Thus, we focused O-methyl thiocarbamate group at 5-position, and synthesized some 4Ј-substituted oxazolidinones in this series. The antibacterial activities and hydrophobic parameter (calculated log P value) of 5-thiocarbamate oxazolidinones are summarized in Table 2.In our previous paper, 1b) we reported that the balance between 5-hydrophobic (or hydrophilic) substituent and hydrophilic (or hydrophobic) substituents on the benzene ring is one of the important factors in antibacterial activity in the 5-thiocarbonyl oxazolidinones. In this series, the prominent decrease of antibacterial activity was not observed. We assume that 5-O-methyl thiocarbamate group would be suitable for various substituents on the benzene ring because of its moderate hydrophilic substituent (paϭ0.30) compared with 5-thiourea (paϭϪ0.66) or 5-dithiocarbamate (paϭ0.88) groups. 1b)We described earlier 1b) that the favorable calculated log P value for antibacterial activity in the case of 5-thiocarbonyl oxazolidinones was Ϫ1 to ϩ2. In this series, we also measured the calculated log P value.5) The compounds within the favorable calculated log P value range provided stable antibacterial activities as we expected. Among them, compounds 4b (calculated log P value: 1.51), 4h (1.01), and 4i (0.73) showed stronger in vitro activities than linezolid (1). On the contrary, compound 4e, whose calculated log P value was 3.10, showed weak activity. It was recently reported that the azole analogues at 4Ј-position have interesting levels of antibacterial activity in 5-acetamide oxazolidinones.6) Compounds 4n and 4p also showed strong in vitro activities. The activities of compounds 4b, 4h, 4i, 4n and 4p were 8-16 times stronger than that of linezolid (1).In Vivo Activity The compounds that exhibited more potent in vitro antibacterial activity than linezolid (1) were actually tested for i...