Synthesis of conformationally constrained analogues of linezolid: structure-activity relationship (SAR) studies on selected novel tricyclic oxazolidinones.
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.
Selvakumar
Natesan
N
Anti-Infectives Discovery Group, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India.
Srinivas
Deekonda
D
Khera
Manoj Kumar
MK
Kumar
Magadi Sitaram
MS
Mamidi
Rao N V S
RN
Sarnaik
Hemanth
H
Charavaryamath
Chandrashekar
C
Rao
Bonthu Srinivasa
BS
Raheem
Mohammed A
MA
Das
Jagattaran
J
Iqbal
Javed
J
Rajagopalan
Ramanujam
R
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D018716:Molecular Mimicry; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid