Design, Synthesis, and Development of pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part I—Indole Derivatives

Stypik, Mariola; Zagozda, Marcin; Michałek, Stanisław; Dymek, Barbara; Zdżalik-Bielecka, Daria; Dziachan, Maciej; Orłowska, Nina; Gunerka, Paweł; Turowski, Paweł; Hucz-Kalitowska, Joanna; Stańczak, Aleksandra; Stańczak, Paulina Seweryna; Mulewski, Krzysztof; Smuga, Damian; Stefaniak, Filip; Gurba-Bryśkiewicz, Lidia; Leniak, Arkadiusz; Ochal, Zbigniew; Mach, Mateusz; Dzwonek, Karolina; Lamparska‐Przybysz, Monika; Dubiel, Krzysztof; Wieczorek, Maciej

doi:10.3390/ph15080949

Cited by 3 publications

(2 citation statements)

References 46 publications

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“…The compounds 1-14 discussed in this work were synthesized following the general procedures presented in our previous papers [19,23]. The synthesis pathway has multiple steps, of which the last one is described here.…”

Section: Chemistrymentioning

confidence: 99%

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Tuning the Biological Activity of PI3Kδ Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

et al. 2023

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As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3Kδ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs.

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Section: Chemistrymentioning

confidence: 99%

“…Compounds 1 and 2 were synthesized according to the procedures described in our previous publications [19,23].…”

Section: Synthesismentioning

confidence: 99%

Tuning the Biological Activity of PI3Kδ Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

et al. 2023

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Recent advances in the chemistry of pyrazolo[1,5-a]pyrimidines

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2024

Advances in Heterocyclic Chemistry

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Design, Synthesis, and Development of Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part II—Benzimidazole Derivatives

et al. 2022

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Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, β, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC50 values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC50 value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kβ/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.

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Design, Synthesis, and Development of pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part I—Indole Derivatives

Cited by 3 publications

References 46 publications

Tuning the Biological Activity of PI3Kδ Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

Tuning the Biological Activity of PI3Kδ Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

Recent advances in the chemistry of pyrazolo[1,5-a]pyrimidines

Design, Synthesis, and Development of Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part II—Benzimidazole Derivatives

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