Synthesis, microbiological evaluation and structure activity relationship analysis of linezolid analogues with different C5-acylamino substituents

Matsingos, Christos; Al-Adhami, Taha; Jamshidi, Shirin Taraz; Hind, Charlotte K.; Clifford, Melanie; Sutton, J. Mark; Rahman, Khondaker M.

doi:10.1016/j.bmc.2021.116397

Cited by 14 publications

(11 citation statements)

References 18 publications

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“…To test the reliability of our QSPR model, molecules that were not introduced in our initial dataset were employed as an external validation set to obtain their predicted p MIC values. Three sets of compounds were used as follows: (a) the first set of molecules reported by Matsingos et al [ 52 ]; (b) compounds reported by Singh [ 53 ], Wang [ 54 ], and Zhou [ 55 ] as the second set, and finally, (c) chemical structures described by Lyons and collaborators [ 56 ]. For the three sets of data, there is a good correlation between experimental and predicted p MIC values with

values of 75.54, 71.64, and 71.56, respectively.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Family of Glycoside Derivatives Biologically Active against Acinetobacter baumannii and Other MDR Bacteria Using a QSPR Model

et al. 2023

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As the rate of discovery of new antibacterial compounds for multidrug-resistant bacteria is declining, there is an urge for the search for molecules that could revert this tendency. Acinetobacter baumannii has emerged as a highly virulent Gram-negative bacterium that has acquired multiple resistance mechanisms against antibiotics and is considered of critical priority. In this work, we developed a quantitative structure-property relationship (QSPR) model with 592 compounds for the identification of structural parameters related to their property as antibacterial agents against A. baumannii. QSPR mathematical validation (R2 = 70.27, RN = −0.008, a(R2) = 0.014, and δK = 0.021) and its prediction ability (Q2LMO = 67.89, Q2EXT = 67.75, a(Q2) = −0.068, δQ = 0.0, rm2¯ = 0.229, and Δrm2 = 0.522) were obtained with different statistical parameters; additional validation was done using three sets of external molecules (R2 = 72.89, 71.64 and 71.56). We used the QSPR model to perform a virtual screening on the BIOFACQUIM natural product database. From this screening, our model showed that molecules 32 to 35 and 54 to 68, isolated from different extracts of plants of the Ipomoea sp., are potential antibacterials against A. baumannii. Furthermore, biological assays showed that molecules 56 and 60 to 64 have a wide antibacterial activity against clinically isolated strains of A. baumannii, as well as other multidrug-resistant bacteria, including Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. Finally, we propose 60 as a potential lead compound due to its broad-spectrum activity and its structural simplicity. Therefore, our QSPR model can be used as a tool for the investigation and search for new antibacterial compounds against A. baumannii.

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values of 75.54, 71.64, and 71.56, respectively.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Family of Glycoside Derivatives Biologically Active against Acinetobacter baumannii and Other MDR Bacteria Using a QSPR Model

et al. 2023

View full text Add to dashboard Cite

show abstract

“…To test the reliability of our QSPR model, molecules which were not introduced in our initial dataset were employed as an external validation set to obtain their predicted pMIC values. Three sets of compounds were used as follows: a) the first set from molecules reported from Matsingos et al [52]; b) compounds reported by Singh [53], Wang [54], and Zhou [55] as the second set, and finally, c) chemical structures described by Lyons and collaborators [56]. For the three sets of data there is a good correlation between experimental and predicted pMIC values, with 𝑅 2 values of 72.89, 71.64 and 71.56 respectively.…”

Section: Qspr Model Validationmentioning

confidence: 99%

Identification of a Family of Glycoside Derivatives Biologically Active Against <em>Acinetobacter baumannii</em> and Other MDR Bacteria Using a QSPR Model

Palacios-Can¹,

Silva-Sánchez²,

León‐Rivera³

et al. 2023

Preprint

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As the rate of discovery of new antibacterial compounds towards multidrug resistant bacteria is declining, there is an urge for the search of molecules that could revert this tendency. Acinetobacter baumannii has emerged as a highly virulent Gram-negative bacterium that has acquired multiple mechanisms against antibiotics and is considered of critical priority. In this work we developed a quantitative structure-property relationship (QSPR) model with 592 compounds for the identification of structural parameters related to their property as antibacterial agents against A. baumannii. QSPR mathematical validation (R2 = 70.27, RN = -0.008, aR2 = 0.014 and δK = 0.021) and its prediction ability (Q2LMO= 67.89, Q2EXT = 67.75, a(Q2)= -0.068, δQ = 0.0, rm2 = 0.229, and ∆rm2 = 0.522) were obtained with different statistical parameters; additional validation jobs were done using three sets of external molecules (R2 = 72.89, 71.64 and 71.56). We used the QSPR model to perform a virtual screening on the BIOFACQUIM natural product database. From this screening our model showed that molecules 32 to 35 and 54 to 68, isolated from different extracts of plants of the Ipomoea sp., are potential antibacterial against A. baumannii. Furthermore, biological assays showed that molecules 56 and 60 to 64 have a wide antibacterial activity against clinical isolated strains of A. baumannii, as well as other multidrug resistant bacteria including Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. Finally, we propose 60 as a potential lead compound due to its broad-spectrum activity and its structural simplicity. Therefore, our QSPR model can be used as a tool for the investigation and search of new antibacterial compounds against A. baumannii.

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“…While small substituents such as hydroxyl groups can be tolerated, larger substituents such as phenyl groups result in a loss of activity. In prior attempts to replace the side chain with various heterocycles, all resulting analogues had either reduced or no antimicrobial activity ( S. aureus strains ATCC 9144, NCTC 13616, USA 300 and 1199B; E. faecalis strains VSE NCTC 775 and VRE NCTC 12201, the E. faecium strain VRE NCTC 12204, K. pneumoniae strains NCTC 13368 and M6; A. baumannii strains AYE and ATCC 17978; P. aeruginosa strains PA01 and NCTC 13437; E. coli strain NCTC 12923) [126] . However activity in a different group of bacterial strains ( M. tuberculosis ATCC 27294, MRSA strain SAU1009, a range of MRSA, MRSE, MSSE, Staphylococcus hemolyticus, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mitis strains) was shown to increase when the morpholino unit is also simultaneously modified with a 5‐acetamidomethyl group as seen in the oxazolidinone contezolid (where the morpholino group is replaced with 2,3‐dihydro‐1 H ‐pyridin‐4‐one and the 5‐acetamidomethyl moiety is replaced with N ‐methyl‐1,2‐oxazol‐3‐amine) [60] and posizolid (which also incorporates N ‐methyl‐1,2‐oxazol‐3‐amine as the C5 side chain but replaces the morpholino unit with ( S )‐1‐(3,6‐dihydropyridin‐1(2 H )‐yl)‐2,3‐dihydroxypropan‐1‐one) [127] .…”

Section: Biofilm Activity Of Structural Variants Of Linezolidmentioning

confidence: 99%

Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

Ndukwe

Wiedbrauk

Boase

et al. 2022

Chemistry An Asian Journal

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Biofilms are part of the natural lifecycle of bacteria and are known to cause chronic infections that are difficult to treat. Most antibiotics are developed and tested against bacteria in the planktonic state and are ineffective against bacterial biofilms. The oxazolidinones, including the last resort drug linezolid, are one of the main classes of synthetic antibiotics progressed to clinical use in the last 50 years. They have a unique mechanism of action and only develop low levels of resistance in the clinical setting. With the aim of providing insight into strategies to design more potent antibiotic compounds with activity against bacterial biofilms, we review the biofilm activity of clinically approved oxazolidinones and report on structural modifications to oxazolidinones and their delivery systems which lead to enhanced anti‐biofilm activity.

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Synthesis, microbiological evaluation and structure activity relationship analysis of linezolid analogues with different C5-acylamino substituents

Cited by 14 publications

References 18 publications

Identification of a Family of Glycoside Derivatives Biologically Active against Acinetobacter baumannii and Other MDR Bacteria Using a QSPR Model

Identification of a Family of Glycoside Derivatives Biologically Active against Acinetobacter baumannii and Other MDR Bacteria Using a QSPR Model

Identification of a Family of Glycoside Derivatives Biologically Active Against <em>Acinetobacter baumannii</em> and Other MDR Bacteria Using a QSPR Model

Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

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