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

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

doi:10.3390/ph15020191

Cited by 8 publications

(7 citation statements)

References 30 publications

(33 reference statements)

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“…Crystallography of linezolid binding to ribosomal subunits has shown that the area around the acyl amide motif fits deep into the active site [54] and so while modification is tolerated, activity can be easily lost by the inclusion of bulky groups in this area. [50] Linezolid was, therefore, chosen as a model amide drug for our proofof-concept studies due to the lack of available release strategies and the importance of the drug clinically. Linking the drug via the amide could greatly reduce activity, therefore ensuring the model construct would only show a biological effect upon fragmentation.…”

Section: Resultsmentioning

confidence: 99%

“…One of the best examples of this is linezolid, a synthetic oxazolidinone antibiotic used mainly for the treatment of Grampositive and mycobacteria infections, where it prevents protein synthesis initiation by binding to ribosomal subunits. [42][43][44][45][46][47] Whilst libraries of analogues have been synthesised to try improve the properties of linezolid, [48][49][50] the number of strategies that release the native molecule remain scarce due to the lack of a conventional free amine, alcohol or thiol function group. [39,41] Herein, a general and modular synthesis of an aminomethyl carbamate linker system that allows for complete choice over the amide and trigger components is described.…”

Section: Introductionmentioning

confidence: 99%

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Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Wharton,

Crawshay‐Williams,

Schober

et al. 2024

Angewandte Chemie

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The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload‐release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide‐containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof‐of‐concept, the FDA‐approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Wharton,

Crawshay‐Williams,

Schober

et al. 2024

Angewandte Chemie

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show abstract

“…Manipulating the chemical structure based on the physic-chemical parameters (descriptors) can turn the inactive or mildly active agents into potent effective ones. This explains the interest of medicinal chemistry researchers in QSAR/QSPR studies [ 119 , 169 , 170 ].…”

Section: In Silico Predicted Anti-sars-cov-2 Indolesmentioning

confidence: 99%

Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2

Girgis,

Panda,

Kariuki

et al. 2023

Molecules

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The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads.

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“…From the extensive spread of skin disorders, the prevalence of bacterial infections has appeared widely and should be handled wisely using antibacterial agents named antibiotics [ 20 ]. Neomycin sulfate (NEO) is one of the antibiotics that has revealed a broad-spectrum activity against Gram-positive and Gram-negative bacterial strains [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Tea Tree Oil Nanoemulsion-Based Hydrogel Vehicle for Enhancing Topical Delivery of Neomycin

Elsewedy

Shehata

Soliman

2022

Life

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The present investigation aims to improve the antimicrobial influence of certain antibacterial drugs, namely, neomycin (NEO), exploiting the benefits of natural oils such as tea tree oil (TTO). Therefore, a distinctive nanolipid formulation, namely, a nanoemulsion (NE), was developed using a Central Composite Factorial Design (CCD) approach depending on the amount of TTO and tween 80 as surfactant. The optimized NEO-NE formula exhibiting minimum globular size and maximum in vitro release was selected. For efficient topical delivery, NEO-NE was incorporated into a pre-formulated hydrogel. The developed NEO-NE-hydrogel was characterized by its physical characteristics such as pH, viscosity, and spreadability. Next, it was tested for stability under different conditions for 3 months. Ultimately, an irritation test was conducted followed by an antibacterial examination. The preparation demonstrated acceptable properties to be successfully applied topically. It showed non-significant changes in stability in both conditions up to 3 months storage when compared to a fresh preparation. It exhibited no irritation when applied on hairless animal skin. Finally, TTO revealed a good inhibition for the bacterial growth that could improve the influence of NEO antibacterial activity, indicating the efficiency of NE containing NEO prepared with TTO to be a promising antibacterial nanocarrier.

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

Cited by 8 publications

References 30 publications

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2

Tea Tree Oil Nanoemulsion-Based Hydrogel Vehicle for Enhancing Topical Delivery of Neomycin

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