Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 64(19), С. 14046 - 14128

Опубликована: Сен. 30, 2021

The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity drug design either as a pharmacophore or scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at beginning 21st century highlighted indiscriminate deployment phenyl rings an important contributor to poor physicochemical properties advanced molecules, which limited their prospects being developed into effective drugs. This Perspective deliberates on and applications bioisosteric replacements for have provided practical solutions range developability problems frequently encountered lead optimization campaigns. While effect compound contextual nature, substitution can enhanced potency, solubility, metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, inhibition cytochrome P450 enzymes hERG channel.

Язык: Английский

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Photocatalytic Late-Stage C–H Functionalization

Chemical Reviews, Год журнала: 2023, Номер 123(8), С. 4237 - 4352

Опубликована: Янв. 24, 2023

The emergence of modern photocatalysis, characterized by mildness and selectivity, has significantly spurred innovative late-stage C–H functionalization approaches that make use low energy photons as a controllable source. Compared to traditional strategies, photocatalysis paves the way toward complementary and/or previously unattainable regio- chemoselectivities. Merging compelling benefits with workflow offers potentially unmatched arsenal tackle drug development campaigns beyond. This Review highlights photocatalytic strategies small-molecule drugs, agrochemicals, natural products, classified according targeted bond newly formed one. Emphasis is devoted identifying, describing, comparing main mechanistic scenarios. draws critical comparison between established ionic chemistry photocatalyzed radical-based manifolds. aims establish current state-of-the-art illustrate key unsolved challenges be addressed in future. authors aim introduce general readership functionalization, specialist practitioners evaluation methodologies, potential for improvement, future uncharted directions.

Язык: Английский

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A Perspective on Late-Stage Aromatic C–H Bond Functionalization

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(6), С. 2399 - 2414

Опубликована: Янв. 27, 2022

Late-stage functionalization of C-H bonds (C-H LSF) can provide a straightforward approach to the efficient synthesis functionalized complex molecules. However, LSF is challenging because bond must be in presence various other functional groups. In this Perspective, we evaluate aromatic on basis four criteria─reactivity, chemoselectivity, site-selectivity, and substrate scope─and our own views current challenges as well promising strategies areas growth going forward.

Язык: Английский

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Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules

Chemical Reviews, Год журнала: 2023, Номер 123(12), С. 7692 - 7760

Опубликована: Май 10, 2023

Site-predictable and chemoselective C–H bond functionalization reactions offer synthetically powerful strategies for the step-economic diversification of both feedstock fine chemicals. Many transition-metal-catalyzed methods have emerged selective activation bonds. However, challenges regio- chemoselectivity with application to highly complex molecules bearing significant functional group density diversity. As molecular complexity increases within structures risks catalyst intolerance limited applicability grow number groups potentially Lewis basic heteroatoms. Given abundance bonds already diversified such as pharmaceuticals, natural products, materials, design selection reaction conditions tolerant catalysts has proved critical successful direct functionalization. such, innovations formation carbon–carbon been discovered developed overcome these limitations. This review highlights progress made metal-catalyzed C–C forming including alkylation, methylation, arylation, olefination targets.

Язык: Английский

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Late-stage diversification of indole skeletons through nitrogen atom insertion

Science, Год журнала: 2022, Номер 377(6610), С. 1104 - 1109

Опубликована: Сен. 1, 2022

Compared with peripheral late-stage transformations mainly focusing on carbon-hydrogen functionalizations, reliable strategies to directly edit the core skeleton of pharmaceutical lead compounds still remain scarce despite recent flurry activity in this area. Herein, we report skeletal editing indoles through nitrogen atom insertion, accessing corresponding quinazoline or quinoxaline bioisosteres by trapping an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This reactivity relies strategic use a silyl group as labile protecting that can facilitate subsequent product release. The utility highly functional group-compatible methodology context several commercial drugs is demonstrated.

Язык: Английский

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Radical C(sp3)–H functionalization and cross-coupling reactions

Nature Reviews Chemistry, Год журнала: 2022, Номер 6(6), С. 405 - 427

Опубликована: Май 17, 2022

Язык: Английский

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A general arene C–H functionalization strategy via electron donor–acceptor complex photoactivation

Nature Chemistry, Год журнала: 2022, Номер 15(1), С. 43 - 52

Опубликована: Дек. 5, 2022

Язык: Английский

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Electrochemical Late-Stage Functionalization

Chemical Reviews, Год журнала: 2023, Номер 123(19), С. 11269 - 11335

Опубликована: Сен. 26, 2023

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical biological activities. LSF can thus greatly accelerate development medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical synthesis has emerged as an environmentally friendly platform transformation organic compounds. Over past decade, electrochemical late-stage (eLSF) gained major momentum, which is summarized herein up to February 2023.

Язык: Английский

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Skeletal Editing: Interconversion of Arenes and Heteroarenes

Helvetica Chimica Acta, Год журнала: 2023, Номер 106(3)

Опубликована: Янв. 13, 2023

Abstract Skeletal editing involves making specific point‐changes to the core of a molecule through selective insertion, deletion or exchange atoms. It thus represents potentially powerful strategy for step‐economic modification complex substrates and is perfect complement methods such as C−H functionalization that target molecular periphery. Given their ubiquity in biologically active compounds, ability perform skeletal on – therefore interconvert between aromatic heterocycles especially valuable. This review summarizes both recent key historical examples applied interconversion rings; we anticipate it will serve highlight not only innovative enabling nature current methods, but also tremendous opportunities still exist field.

Язык: Английский

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Late-Stage C–H Functionalization of Azines

Chemical Reviews, Год журнала: 2023, Номер 123(12), С. 7655 - 7691

Опубликована: Май 3, 2023

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite physiochemical properties that match key criteria in drug design is tunable by varying their substituents. Developments synthetic chemistry, therefore, directly impact these efforts, methods can install various groups azine C–H bonds particularly valuable. Furthermore, there growing interest late-stage functionalization (LSF) reactions focus on advanced candidate compounds often complex structures with multiple heterocycles, functional groups, reactive sites. Because factors electron-deficient nature the effects Lewis basic N atom, distinct arene counterparts, application LSF contexts difficult. However, have been many significant advances reactions, this review will describe progress, much which has occurred over past decade. It possible to categorize radical addition processes, metal-catalyzed activation transformations occurring via dearomatized intermediates. Substantial variation reaction within each category indicates both rich reactivity heterocycles creativity approaches involved.

Язык: Английский

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