Synthesis, molecular docking and antibacterial activity of an oxadiazole-based lipoteichoic acid inhibitor and its metabolites

Serpi, Michaela; Pertusati, Fabrizio; Morozzi, Chiara; Novelli, Giulia; Giannantonio, Daniele; Duggan, Katrina; Vittorio, Serena; Fallis, Ian A.; Luca, Laura De; Williams, David Wynne

doi:10.1016/j.molstruc.2023.134977

Cited by 3 publications

(13 citation statements)

References 38 publications

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“…Using this approach, 1771 did not show inhibitory activity; however, the azo dye Congo red blocked LtaS function. 11 On the contrary, our 21 and others 14 in silico investigations highlighted that 1771 might behave as a competitive inhibitor of LtaS, in line with biophysical data indicating binding between 1771 and derivatives with the extracellular domain of LtaS (eLtaS). 12,14 In this study, we sought to design and synthesize a small series of derivatives of 1771 with the aim to not only improve the antistaphylococcal activity of 1771 but also correlate the compound's activity with its in silico interaction with LtaS.…”

supporting

confidence: 79%

“…Chemistry. Compounds 9−14 were synthesized using the same convergent synthesis method previously reported for 1771, 21 as shown in Scheme 1. Briefly, transesterification of ethyl 4-chloro-3-oxobutanoate 2 with naphthalen-2-ol (3a) or 6-methoxynaphthalen-2-ol (3b) after Pechmann condensation yielded the corresponding desired angular chlorocoumarines 4a,b, which under basic conditions underwent a rearrangement to give compounds 5a,b.…”

Section: Resultsmentioning

confidence: 99%

“…The docking poses of the newly synthesized derivatives 9–14 was compared to that of the parent compound 1771 previously reported . As shown in Figure b, the phenyl-1,3,4-oxadiazole portion of 1771 (cyan sticks) can fit into a deep part of the LtaS active site, while the same moiety is located in the rim of the pocket in the case of compounds 9–14 .…”

Section: Resultsmentioning

confidence: 99%

“…Richter et al observed that 1771 inhibited eLtaS binding to and cleavage of PG in vitro using size exclusion chromatography, nitro-benzoxadiazole glycerol-phosphate as a substrate for eLtaS, and mass spectrometry . We and others have performed molecular docking of 1771 in the eLtaS catalytic site. Overall, both in silico investigations highlighted that 1771 might function as a competitive inhibitor of LtaS and emphasized the key role of the oxadiazole ring in the ligand–protein recognition process, in agreement with the experimental studies according to which this moiety is crucial for activity .…”

Section: Discussionmentioning

confidence: 99%

“…The docking poses of the newly synthesized derivatives 9− 14 was compared to that of the parent compound 1771 previously reported. 21 As shown in Figure 6b, the phenyl-1,3,4oxadiazole portion of 1771 (cyan sticks) can fit into a deep part of the LtaS active site, while the same moiety is located in the rim of the pocket in the case of compounds 9−14. Significantly, the oxadiazole ring, which appeared to play a pivotal role in the binding to LtaS in the docking model reported by both us 21 and Chee Wezen et al, 14 is not involved in the interaction between the enzyme and compounds 9−14.…”

Section: Molecular Modeling Of Compounds 9−14 With Ltasmentioning

confidence: 99%

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Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function

Douglas,

Marshall,

Alghamadi

et al. 2023

ACS Infect. Dis.

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The lipoteichoic acid (LTA) biosynthesis pathway has emerged as a promising antimicrobial therapeutic target. Previous studies identified the 1,3,4 oxadiazole compound 1771 as an LTA inhibitor with activity against Gram-positive pathogens. We have succeeded in making six 1771 derivatives and, through subsequent hit validation, identified the incorporation of a pentafluorosulfanyl substituent as central in enhancing activity. Our newly described derivative, compound 13, showed a 16- to 32-fold increase in activity compared to 1771 when tested against a cohort of multidrug-resistant Staphylococcus aureus strains while simultaneously exhibiting an improved toxicity profile against mammalian cells. Molecular techniques were employed in which the assumed target, lipoteichoic acid synthase (LtaS), was both deleted and overexpressed. Neither deletion nor overexpression of LtaS altered 1771 or compound 13 susceptibility; however, overexpression of LtaS increased the MIC of Congo red, a previously identified LtaS inhibitor. These data were further supported by comparing the docking poses of 1771 and derivatives in the LtaS active site, which indicated the possibility of an additional target(s). Finally, we show that both 1771 and compound 13 have activity that is independent of LtaS, extending to cover Gram-negative species if the outer membrane is first permeabilized, challenging the classification that these compounds are strict LtaS inhibitors.

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supporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Molecular Modeling Of Compounds 9−14 With Ltasmentioning

confidence: 99%

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Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function

Douglas,

Marshall,

Alghamadi

et al. 2023

ACS Infect. Dis.

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Syntheses, reactivity, and biological applications of coumarins

Citarella,

Vittorio,

Dank

et al. 2024

Front. Chem.

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This comprehensive review, covering 2021–2023, explores the multifaceted chemical and pharmacological potential of coumarins, emphasizing their significance as versatile natural derivatives in medicinal chemistry. The synthesis and functionalization of coumarins have advanced with innovative strategies. This enabled the incorporation of diverse functional fragments or the construction of supplementary cyclic architectures, thereby the biological and physico-chemical properties of the compounds obtained were enhanced. The unique chemical structure of coumarine facilitates binding to various targets through hydrophobic interactions pi-stacking, hydrogen bonding, and dipole-dipole interactions. Therefore, this important scaffold exhibits promising applications in uncountable fields of medicinal chemistry (e.g., neurodegenerative diseases, cancer, inflammation).

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Probing Antibacterial and Anticancer Potential of Selenicereus undatus, Pistacia vera L. and Olea europaea L. against Uropathogens, MCF-7 and A2780 Cancer Cells

Safdar,

Shamim,

Khan

et al. 2023

Molecules

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Urinary tract infection is an infectious disease that requires immediate treatment. It can occur in any age group and involves both genders equally. The present study was to check the resistance of some antibiotics and to assess the antibacterial potential of three extracts of three plants against notorious bacteria involved in urinary tract infections. Along with assessing the antibacterial activity of plant extracts, we checked for the anticancer potential of these extracts against the cancer cell lines MCF-7 and A2780. Cancer is the leading cause of mortality in developed countries. Determinations of total flavonoid content, total phenolic content, total alkaloid content, total tannin content, total carotenoid content, and total steroid content were performed. The disk diffusion method was used to analyze the antibacterial activity of plant extracts. Ethanolic extract of Selenicereus undatus showed sensitivity (25–28 mm) against bacteria, whereas chloroform and hexane extracts showed resistance against all bacteria except Staphylococcus (25 mm). Ethanolic extract of Pistacia vera L. showed sensitivity (22–25 mm) against bacteria, whereas chloroform and hexane extracts showed resistance. Ethanolic extract of Olea europaea L. showed sensitivity (8–16 mm) against all bacteria except Staphylococcus, whereas chloroform and hexane extracts showed resistance. Positive controls showed variable zones of inhibition (2–60 mm), and negative control showed 0–1 mm. The antibiotic resistance was much more prominent in the case of hexane and chloroform extracts of all plants, whereas ethanolic extract showed a sensitivity of bacteria against extracts. Both cell lines, MCF-7 and A2780, displayed decreased live cells when treated with plant extracts.

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Synthesis, molecular docking and antibacterial activity of an oxadiazole-based lipoteichoic acid inhibitor and its metabolites

Cited by 3 publications

References 38 publications

Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function

Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function

Syntheses, reactivity, and biological applications of coumarins

Probing Antibacterial and Anticancer Potential of Selenicereus undatus, Pistacia vera L. and Olea europaea L. against Uropathogens, MCF-7 and A2780 Cancer Cells

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