Pharmacophoric features for a very potent 5‐spirofluorenehydantoin inhibitor of cancer efflux pump <scp>ABCB</scp>1, based on X‐ray analysis

Żesławska, Ewa; Kincses, Annamária; Spengler, Gabriella; Nitek, Wojciech; Tejchman, Waldemar; Handzlik, Jadwiga

doi:10.1111/cbdd.13473

Cited by 13 publications

(6 citation statements)

References 31 publications

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“…The angle between the corresponding planes amounts to 88.26(5)°. This arrangement is similar to other 5-spirofluorenehydantoin derivatives with determined crystal structures [32,33,37,38]. The linker between the hydantoin and piperazine rings, consisting of four methylene moieties, is flexible.…”

Section: Crystallographic Studiessupporting

confidence: 76%

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

Witek,

Kaczor,

Żesławska

et al. 2023

Antibiotics

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In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7–9) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants.

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Section: Crystallographic Studiessupporting

confidence: 76%

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

Witek,

Kaczor,

Żesławska

et al. 2023

Antibiotics

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“…In our previous studies we have explored the importance of a basic BPA skeleton 48 , and concluded that BPA could serve as a “pharmacophore”, necessary to retain anti-glioblastoma activity 49 , 50 . The amide part of the BPA skeleton can be specifically modelled to obtain a more desirable anti-tumor activity.…”

Section: Resultsmentioning

confidence: 99%

Anti-glioblastoma effects of phenolic variants of benzoylphenoxyacetamide (BPA) with high potential for blood brain barrier penetration

Stalińska

Vittori

Ingraham

et al. 2022

Sci Rep

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Glioblastomas are the most aggressive brain tumors for which therapeutic options are limited. Current therapies against glioblastoma include surgical resection, followed by radiotherapy plus concomitant treatment and maintenance with temozolomide (TMZ), however, these standard therapies are often ineffective, and average survival time for glioblastoma patients is between 12 and 18 months. We have previously reported a strong anti-glioblastoma activity of several metabolic compounds, which were synthetized based compounds, which were synthetized based on the chemical structure of a common lipid-lowering drug, fenofibrate, and share a general molecular skeleton of benzoylphenoxyacetamide (BPA). Extensive computational analyses of phenol and naphthol moieties added to the BPA skeleton were performed in this study with the objective of selecting new BPA variants for subsequent compound preparation and anti-glioblastoma testing. Initially, 81 structural variations were considered and their physical properties such as solubility (logS), blood–brain partitioning (logBB), and probability of entering the CNS calculated by the Central Nervous System—Multiparameter Optimization (MPO-CNS) algorithm were evaluated. From this initial list, 18 compounds were further evaluated for anti-glioblastoma activity in vitro. Nine compounds demonstrated desirable glioblastoma cell toxicity in cell culture, and two of them, HR51, and HR59 demonstrated significantly improved capability of crossing the model blood–brain-barrier (BBB) composed of endothelial cells, astrocytes and pericytes.

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“…Overall Chemical Design: In our previous studies we have explored the importance of a basic BPA skeleton 31 , and concluded that BPA could serve as a "pharmacophore", necessary to retain anti-glioblastoma activity 32,33 . The amide part of the BPA skeleton can be specifically modelled to obtain a more desirable anti-tumor activity.…”

Section: Results and Discussonmentioning

confidence: 99%

Anti-glioblastoma Effects of Structural Variants of Benzoylphenoxyacetamide (BPA): II. Synthesis Strategies for Phenolic Variants of BPAs With Potential for Blood Brain Barrier Penetration.

Stalińska

Vittori

Ingraham

et al. 2021

Preprint

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Glioblastomas are the most aggressive brain tumors for which therapeutic options are limited. Current therapies against glioblastoma include surgical resection, followed by radiotherapy plus concomitant and maintenance with temozolomide (TMZ), however, these standard therapies are often ineffective, and average survival time for glioblastoma patients is between 12 and 18 months. We have previously reported a strong anti-glioblastoma activity of several metabolic compounds, which were synthetized based the chemical structure of a common lipid-lowering drug, fenofibrate, and share a general molecular skeleton of benzoylphenoxyacetamide (BPA). Extensive computational analyses of phenol and naphthol moieties added to the BPA skeleton were performed in this study with the objective of selecting new BPA variants for subsequent compound preparation and anti-glioblastoma testing. Initially, 81 structural variations were considered and their physical properties such as solubility (logS), blood-brain partitioning (logBB), and probability of entering the CNS calculated by the Central Nervous System – Multiparameter Optimization (MPO-CNS) algorithm were evaluated. From this initial list, 18 compounds were further evaluated for anti-glioblastoma activity in vitro. Nine compounds demonstrated desirable glioblastoma cell toxicity in cell culture, and two of them, HR51, and HR59 demonstrated significantly improved capability of crossing the model blood-brain-barrier (BBB) composed of endothelial cells, astrocytes and pericytes.

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Pharmacophoric features for a very potent 5‐spirofluorenehydantoin inhibitor of cancer efflux pump ABCB1, based on X‐ray analysis

Cited by 13 publications

References 31 publications

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

Anti-glioblastoma effects of phenolic variants of benzoylphenoxyacetamide (BPA) with high potential for blood brain barrier penetration

Anti-glioblastoma Effects of Structural Variants of Benzoylphenoxyacetamide (BPA): II. Synthesis Strategies for Phenolic Variants of BPAs With Potential for Blood Brain Barrier Penetration.

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