Optimizing Linezolid: Transforming It into a Selective MAO-B Inhibitor via a Toxicity-to-Activity Optimization Approach

  • ACS Med Chem Lett. 2024 Dec 16;16(1):40-50. doi: 10.1021/acsmedchemlett.4c00354.
Mayur S Dhangar  1 ,  Iqrar Ahmad  1 ,  Jong Min Oh  2 ,  Bhatu R Patil  1 ,  Sampath Chinnam  3 ,  Dharmarajan Sriram  4 ,  Jyothi Kumari  4 ,  Bijo Mathew  5 ,  Rais A Sayyed  1 ,  Shubham B Chaudhari  6 ,  Siddique Akber Ansari  7 ,  Nishant Rai  8  9 ,  Hoon Kim  2 ,  Harun M Patel  1
Affiliations
  • 1. Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra 425405, India.
  • 2. Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
  • 3. Department of Chemistry, M. S. Ramaiah Institute of Technology (Autonomous Institute, Affiliated to Visvesvaraya Technological University, Belgaum), Bengaluru, Karnataka 560054, India.
  • 4. Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, R. R. District, Hyderabad, Telagana 500078, India.
  • 5. Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi 690525, India.
  • 6. Department of Pharmaceutical Technology and Process Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160002, India.
  • 7. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 8. Graphic Era (Deemed to be University), Clement Town, Dehradun 248002, India.
  • 9. Graphic Era Hill University, Clement Town, Dehradun 248002, India.
PMID: 39811132 DOI: 10.1021/acsmedchemlett.4c00354
Abstract

Linezolid, a widely used Oxazolidinone antibiotic, exhibits potent activity against resistant Bacterial infections but is associated with serotonergic toxicity, primarily due to its inhibition of Monoamine Oxidase (MAO). MAOs, consisting of MAO-A and MAO-B isoforms, play crucial roles in neurotransmitter metabolism, with implications for neurodegenerative disorders like Parkinson's and Alzheimer's diseases. This study aims to optimize Linezolid's structure to transform it into a selective MAO-B Inhibitor. Utilizing structure-activity and structure-toxicity relationship approaches, novel analogues of Linezolid were synthesized by replacing its Oxazolidinone ring with a thiadiazole scaffold. Among the synthesized compounds, 6b emerged as a lead candidate, displaying a remarkable MAO-B inhibitory activity (IC50 = 0.03 μM) and 464-fold selectivity over MAO-A, compared to the standard drugs Pargyline (IC50 = 0.14 μM) and Clorgyline (IC50 = 1.85 μM). Furthermore, docking and molecular dynamics simulations corroborated the high affinity and stability of compound 6b in the MAO-B enzyme's binding pocket. These findings suggest that optimized Linezolid analogues, particularly compound 6b, hold promise as selective MAO-B inhibitors, offering therapeutic potential for treating neurodegenerative diseases while avoiding the risks associated with serotonergic toxicity.

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