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

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

doi:10.3390/ph15020191

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.

Highlights

Antibiotics are among the most clinically used drugs for the treatment of various serious diseases in humans [1,2]
We introduced amino acids as part of the conjugates, as amino acids are well known for improving the antibacteria as part of the conjugates, as amino acids are well known for improving the antibacterial propertyand and cell permeability property cell permeability
To synthesize a set of hybrid conjugates of linezolid, amino acid, and heteroaromatic acid, we treated benzotriazole-activated pyrazinoic acid-amino acid conjugate 8a–c in dichloromethane methane (DCM) in the presence of TEA at 0 ◦ C for 4–6 h (Scheme 4)

Summary

Introduction

Antibiotics are among the most clinically used drugs for the treatment of various serious diseases in humans [1,2]. Due to overuse and abuse of antibiotics under the influence of various man-made and external factors, the drug resistance for both Gram-positive and Gram-negative bacteria is increasing at an alarming rate [3,4,5]. MDR has attracted increasing attention because of the recent statistics reported by the World Health. According to the WHO, around 50,000 patients die from infectious diseases every day worldwide [6]. Oxazolidinones are a new class of antimicrobial agents that have a unique structure and show good activity against different pathogenic bacteria, including methicillin- and vancomycin-resistant staphylococci, vancomycin-resistant enterococci, penicillin-resistant pneumococci, and anaerobes [7].

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Results

Conclusion