Structure-Activity Relationship (SAR) Studies on Oxazolidinone Antibacterial Agents. 3. Synthesis and Evaluation of 5-Thiocarbamate Oxazolidinones.

Abstract

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...

Synthesis and Evaluation of Urea and Thiourea Derivatives of Oxazolidinones as Antibacterial Agents

“…It was clear from the study that the mono halo substitution on ring D showed comparatively potent activity than the others. (9) and p-dichloro (10) substitution of D ring showed moderate activity against gram-positive organisms and exhibited poor activity against gram-negative organisms.…”

“…1) potent in vitro and in vivo antibacterial agents. [6][7][8][9] In 1987, DUP 721 was selected as an antibacterial new candidate for clinical trials. However, its further development was discontinued due to toxicity observed in phase-I clinical trials.…”

Synthesis and Antibacterial Activity of Substituted Oxotriazolylphenyl Oxazolidinones

“…As replacement of 5‐acetyl group with different functionalized groups, such as chlorine or a thiocarbonyl group maintained or even increased activities against Sta. aureus (25–27), the effect of substituted acetyl groups at the 5‐position such as chloroacetyl ( 13e ), dichloroacetyl ( 13f ) and trifluoroacetyl ( 13g ) was investigated. Interestingly, 13e–g showed similar activities against Sta.…”

Synthesis and Application of [1,2,5]Triazepane and [1,2,5]Oxadiazepane as Versatile Structural Units for Drug Discovery

“…The target compounds were synthesized from 3a and 3b via similar routes to those reported for the original compounds, respectively. 22,25) The new compounds 10a 26) and 10b 27) showed excellent in vitro antibacterial activity against MRSA or line- …”

“…The target compounds were synthesized from 3a and 3b via similar routes to those reported for the original compounds, respectively. 22,25) The new compounds 10a 26) and 10b 27) showed excellent in vitro antibacterial activity against MRSA or line- 28) in comparison with linezolid (Table 1). Furthermore, compound 10a exhibited good in vivo efficacy when administered intravenously in a murine model of systemic infection, with MRSA SR3637 as the infectious organism.…”