Synthesis, Antibacterial Evaluation, and Computational Studies of a Diverse Set of Linezolid Conjugates

Riham M Bokhtia; Adel S Girgis; Tarek S Ibrahim; Fatma Rasslan; Eman S Nossier; Reham F Barghash; Rajeev Sakhuja; Eatedal H Abdel-Aal; Siva S Panda; Amany M M Al-Mahmoudy

doi:10.3390/ph15020191

Synthesis, Antibacterial Evaluation, and Computational Studies of a Diverse Set of Linezolid Conjugates

Pharmaceuticals (Basel). 2022 Feb 3;15(2):191. doi: 10.3390/ph15020191.

Authors

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
² Department of Chemistry and Physics, Augusta University, Augusta, GA 30912, USA.
³ Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622, Egypt.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
⁵ Department of Microbiology and Immunology, Faculty of Pharmacy (Girls), Al Azhar University, Cairo 11651, Egypt.
⁶ Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt.
⁷ Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031, India.

Abstract

The development of new antibiotics to treat multidrug-resistant (MDR) bacteria or possess broad-spectrum activity is one of the challenging tasks. Unfortunately, there are not many new antibiotics in clinical trials. So, the molecular hybridization approach could be an effective strategy to develop potential drug candidates using the known scaffolds. We synthesized a total of 31 diverse linezolid conjugates 3, 5, 7, 9, 11, 13, and 15 using our established benzotriazole chemistry with good yield and purity. Some of the synthesized conjugates exhibited promising antibacterial properties against different strains of bacteria. Among all the synthesized compounds, 5d is the most promising antibacterial agent with MIC 4.5 µM against S. aureus and 2.25 µM against B. subtilis. Using our experimental data pool, we developed a robust QSAR (R² = 0.926, 0.935; R²cvOO = 0.898, 0.915; R²cvMO = 0.903, 0.916 for the S. aureus and B. subtilis models, respectively) and 3D-pharmacophore models. We have also determined the drug-like properties of the synthesized conjugates using computational tools. Our findings provide valuable insight into the possible linezolid-based antibiotic drug candidates.

Keywords: QSAR; antibacterial; conjugates; linezolid; pharmacophore.

Grants and funding

RG-18-166-41/King Abdulaziz University