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      CF 3-Cyclobutanes: Synthesis, Properties, and Evaluation as a Unique tert-Butyl Group Analogue

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          Abstract

          Isosteric replacement of functional groups is an emerging strategy for optimizing bioactive molecules in drug discovery. tert-Butyl group is a particularly important moiety, yet its isosteric replacement with 1-trifluoromethyl-cyclobutyl group has been rather neglected. To enable the advance of this molecular fragment in drug discovery programs, we report the synthesis of over 30 small-molecule building blocks featuring the trifluoromethyl-cyclobutyl fragment, achieved by reacting sulfur tetrafluoride with cyclobutylcarboxylic acids on a gram-to-multigram scale. Furthermore, we characterized the structural properties of this group through X-ray analysis, studied its effect on acid–base transitions, and evaluated its Hammett parameters. Finally, we evaluated the replacement of tert-butyl with 1-trifluoromethyl-cyclobutyl in several bioactive compounds that represent commercial drugs and agrochemicals. Our findings indicate that while the trifluoromethyl-cyclobutyl group exhibited slightly larger steric size and moderately increased lipophilicity, it preserved the original mode of bioactivity in the examined cases and, in some cases, enhanced resistance to metabolic clearance.

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          Most cited references55

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          A survey of Hammett substituent constants and resonance and field parameters

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            Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome.

            On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNFα)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.
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              Difluoro-Substituted Bicyclo[1.1.1]pentanes for Medicinal Chemistry: Design, Synthesis, and Characterization

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                Author and article information

                Journal
                JACS Au
                JACS Au
                au
                jaaucr
                JACS Au
                American Chemical Society
                2691-3704
                11 November 2024
                25 November 2024
                : 4
                : 11
                : 4507-4517
                Affiliations
                []Enamine Ltd , Winston Churchill st. 78, 02094 Kyiv, Ukraine
                []Kukhar Institute of Bioorganic Chemistry and Petrochemistry NAS of Ukraine , 02094 Kyiv, Ukraine
                [§ ]Institute of Botany of the National Academy of Sciences of Ukraine , 02000 Kyiv, Ukraine
                []Bienta , Winston Churchill st. 78, 02094 Kyiv, Ukraine
                []Faculty of Chemistry, Taras Shevchenko National University of Kyiv , Volodymyrska 60, 01601 Kyiv, Ukraine
                Author notes
                Author information
                https://orcid.org/0000-0002-8214-9604
                https://orcid.org/0000-0003-1821-9011
                Article
                10.1021/jacsau.4c00864
                11600199
                39610719
                e1bf8ff4-9dbb-4332-afbc-6bbe5cdcdd80
                © 2024 The Authors. Published by American Chemical Society

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 September 2024
                : 30 October 2024
                : 29 October 2024
                Categories
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                Custom metadata
                au4c00864
                au4c00864

                bioisostere,medicinal chemistry,tert-butyl,cf3-cyclopropane,cf3-cyclobutane

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