Design, synthesis and biological evaluation of spiropyrimidinetriones oxazolidinone derivatives as antibacterial agents

• Published in: Bioorganic & medicinal chemistry letters 2018-04, Vol.28 (7), p.1198-1206
• Main Authors: Siddiqui, Asher M., Sattigeri, Jitendra A., Javed, Kalim, Shafi, Syed, Shamim, M., Singhal, Smita, Malik, Zubbair M.
• Format: Article
• Language: English
• Subjects: [1,5]-Hydride shift; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Dose-Response Relationship, Drug; Drug Design; Drug resistance; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Oxazolidinone; Oxazolidinones - chemical synthesis; Oxazolidinones - chemistry; Oxazolidinones - pharmacology; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Spiropyrimidinetrione; Staphylococcus epidermidis - drug effects; Structure-Activity Relationship; Vancomycin-Resistant Enterococci - drug effects
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.02.055

[Display omitted] Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved the use of tert-amino reaction with [1,5]-hydride shift leading to the new CC bond formation. Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E. faecalis. Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S RNA ribosome.