Structure-Activity Relationship (SAR) Studies on Oxazolidinone Antibacterial Agents. 2. Relationship between Lipophilicity and Antibacterial Activity in 5-Thiocarbonyl Oxazolidinones.

Abstract

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...

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