Synthesis of Conformationally Constrained Analogues of Linezolid: Structure−Activity Relationship (SAR) Studies on Selected Novel Tricyclic Oxazolidinones

Citations Over TimeTop 13% of 2002 papers

Abstract

In an effort to discover potent antibacterials based on the entropically favored "bioactive conformation" approach, we have designed and synthesized a series of novel tricyclic molecules mimicking the conformationally constrained structure of the oxazolidinone antibacterial, Linezolid 1. The structure 3 obtained by this approach was synthesized and found to be moderately active against a panel of Gram-positive organisms tested. Further introduction of a fluorine atom in the aromatic ring of compound 3 as in Linezolid resulted in some excellent compounds possessing potent antibacterial activity. The thus obtained lead molecule 16 was further fine-tuned by structure-activity relationship studies on the amide functionality leading to a number of novel tricyclic oxazolidinone derivatives. Some particularly interesting compounds include the thioamides 36 and 37, thiocarbamate 41, and thiourea 45. The in vitro activity results of amide homologues of 16 (compounds 25-30) revealed that compounds up to four carbon atoms on the amide nitrogen retain the activity. In general, thioamides and thiocarbamates are more potent when compared to the corresponding amides and carbamates.

Related Papers

• → Preference of cis-Thioamide Structure in N-Thioacyl-N-methylanilines(2020)19 cited
• → Sequential mono-N-arylation of piperazine nitrogens. Part 1: A simplified method and its application to the preparation of a key N,N′-biaryl piperazine antifungal intermediate(1999)27 cited
• → Intestinal Anthelmintics. I. The Preparation of Bis(2,4,5-trichlorophenol)-Piperazine Salt (Triclofenol Piperazine) and Other Phenol-Piperazine Salts(1962)9 cited
• → Frontispiece: Progress in Lanthionine and Protected Lanthionine Synthesis(2018)
• → Thioamide Effects on Protein Structure(2019)