Design and Synthesis of the Linezolid Bioisosteres to Resolve the Serotonergic Toxicity Associated with Linezolid
Rukaiyya T. Girase, Iqrar Ahmad, Jong‐Min Oh, Bijo Mathew, Siva K. Vagolu, Tone Tønjum, Dharmarajan Sriram, Jyothi Kumari, Nisheeth C. Desai, Yogesh Agrawal, Hoon Kim, Harun Patel
Abstract
Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis ( Mtb ) H 37 Rv cells with an MIC of 2.01 μM compared to linezolid (MIC = 2.31 μM). Bioisostere R7 also exhibited remarkable activity (MIC 50 ) against drug-resistant Mtb clinical isolates, with values of 0.14 μM (INH R, inhA+ ), 0.53 μM (INH R, katG+ ), 0.24 μM (RIF R, rpoB+ ), and 0.92 μM (INH R INH R, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.