Bioisosteric heterocyclic analogues of natural bioactive flavonoids by scaffold-hopping approaches: State-of-the-art and perspectives in medicinal chemistry

Bioorganic & Medicinal Chemistry, Год журнала: 2024, Номер 109, С. 117791 - 117791

Опубликована: Июнь 9, 2024

The flavonoid family is a set of well-known bioactive natural molecules, with wide range potential therapeutic applications. Despite the promising results obtained in preliminary vitro/vivo studies, their pharmacokinetic and pharmacodynamic profiles are severely compromised by chemical instability. To address this issue, scaffold-hopping approach strategy for structural optimization leads to discover more potent analogues. In scenario, Perspective provides critical analysis on how replacement chromon-4-one core other bioisosteric nitrogen/sulphur heterocycles might affect chemical, pharmaceutical biological properties resulting new entities. investigated derivatives were classified basis activity indications. For each session, target(s), specific mechanism action, if available, key pharmacophoric moieties highlighted, as revealed X-ray crystal structures silico structure-based studies. Biological data, examined: particular focus was given improvements observed heterocyclic analogues compared flavonoids. This overview advantages compounds great interest medicinal chemistry community better exploit vast these molecules identify molecules.

Язык: Английский

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Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Ноя. 19, 2024

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than century research, Ciamician-Dennstedt (C-D) rearrangement limited to halocarbene precursors. Herein, we report general methodology reaction using α-halogen-free carbenes generated situ from N-triftosylhydrazones. This one-pot, two-step protocol enables various carbenes, including those previously unexplored C-D chemistry, indoles/pyrroles scaffolds access 3-functionalized quinolines/pyridines. Mechanistic studies reveal pathway involving intermediacy 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative form different carbon-atom products. Ciamician–Dennstedt authors

Язык: Английский

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Discovery of 2(1H)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal drug target in cancers bearing homozygous methylthioadenosine phosphorylase (MTAP) gene deletion. Despite the remarkable progress discovery and development of MAT2A inhibitors, current understanding about selectivity these compounds toward MTAP-deficient is relatively limited. To improve inhibitors for remains significant challenge. We herein reported series novel with 2(1

Язык: Английский

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Microwave-Assisted Synthesis of Heterocycles via Rhodium(III)-Catalyzed C–H Activation: Norbornadiene as an Acetylene Equivalent

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

General procedures for the rhodium-catalyzed annulation of aryl/heteroaryl O-pivaloyl hydroxamic acids and norbornadiene have been developed. Employing as an acetylene equivalent enables utilization diverse heterocyclic substrates this transformation which fail to react or undergo competitive Lossen rearrangement under previously reported conditions. Microwave heating significantly reduces reaction times compared conventional protocols allows a one-step process be realized. The conditions described herein adapted gram-scale synthesis applied formal Pfizer clinical candidates.

Язык: Английский

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Ylide-Induced Ring Contraction of Coumarins to Benzofurans: Applications to the Synthesis of Bis-Heterocycles

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 15, 2025

We report an unusual ring contraction of 4-chlorocoumarin to benzofuranoyl sulfoxonium ylides using a Corey-ylide. These stabilized were subsequently utilized for the synthesis various valuable bis-heterocycles under both metal and metal-free conditions. The synthetic utility this method is illustrated through known bioactive compounds. Detailed mechanistic investigations quantum chemical calculations have provided insights into mechanism reaction.

Язык: Английский

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The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Hit to Lead

ChemMedChem, Год журнала: 2025, Номер unknown

Опубликована: Фев. 16, 2025

Abstract The Hit to Lead (H2L) process is an integral part of contemporary drug discovery, encompassing the optimisation validated structures into molecules. High quality leads build confidence, through activity and property profiles as well preliminary biological data, which might include validating pharmacologic hypotheses along way, indicating that further investment in structure(s) target would be worthwhile. Leads have line sight a development candidate bring understanding what priorities Optimisation should address. In this set best practices, we detail essential criteria characterise good lead, establishing SAR from analogues assessing DMPK indicators, selectivity early safety parameters. We highlight importance identifying liabilities lead series demonstrating each can individually modulated whilst maintaining on potency. make case for having physicochemical properties critical parameters how ligand efficiency metrics enable this. Then go over general tactics used convert hits series. These steps that, when performed early, increase chance success such deconstructive SAR, pharmacophore bioactive conformation determination scaffold optimisation. Finally, suggest decision‐making substantiate confidence or, importantly, making recommendation cease work

Язык: Английский

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Design, synthesis and biological evaluation of sulfur-containing tetrahydroxanthones as potential anti-tumor agents

Bioorganic & Medicinal Chemistry Letters, Год журнала: 2025, Номер unknown, С. 130154 - 130154

Опубликована: Фев. 1, 2025

Язык: Английский

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Discovery of a novel quinoline RIP1 inhibitor and its treatment of acute liver injury in mice

Bioorganic Chemistry, Год журнала: 2025, Номер 159, С. 108365 - 108365

Опубликована: Март 12, 2025

Язык: Английский

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Enhancing Unconditional Molecule Generation via Online Knowledge Distillation of Scaffolds

Molecules, Год журнала: 2025, Номер 30(6), С. 1262 - 1262

Опубликована: Март 12, 2025

Generating new drug-like molecules is an essential aspect of drug discovery, and deep learning models significantly accelerate this process. Language have demonstrated great potential in generating novel realistic SMILES representations molecules. Molecular scaffolds, which serve as the key structural foundation, can facilitate language discovering chemically feasible biologically relevant However, directly using scaffolds prior inputs introduce bias, thereby limiting exploration To combine above advantages address limitation, we incorporate molecular scaffold information into via Online knowledge distillation framework for unconditional Molecule Generation task (OMG), consists a GPT model that generates strings from scratch Transformer generate scaffolds. The complete structures deeply integrated through mutual two models. Experimental results on well-known molecule generation benchmarks show OMG enhances both validity novelty GPT-based model. Furthermore, comprehensive property-specific evaluation indicate generated achieve favorable balance across multiple chemical properties biological activity, demonstrating our method viable candidates.

Язык: Английский

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A Molecular Representation to Identify Isofunctional Molecules

Molecular Informatics, Год журнала: 2025, Номер 44(3)

Опубликована: Март 1, 2025

Abstract The challenges of drug discovery from hit identification to clinical development sometimes involves addressing scaffold hopping issues, in order optimise molecular biological activity or ADME properties, mitigate toxicology concerns a candidate. Docking is usually viewed as the method choice for isofunctional molecules, i. e. highly dissimilar molecules that share common binding modes with protein target. However, structure may not be suitable docking because low resolution, even unknown. This problem frequently encountered case membrane proteins, although they constitute an important category druggable proteome. In such cases, ligand‐based approaches offer promise but are often inadequate handle large‐step hopping, rely on structure. Therefore, we propose Interaction Fingerprints Profile (IFPP), representation captures based experiments against panel diverse high‐quality proteins structures. Evaluation LH benchmark demonstrates interest IFPP molecules. Nevertheless, computation IFPPs expensive, which limits its scalability screening very large libraries. We overcome this limitation by leveraging Metric Learning approaches, allowing fast estimation similarities, thus providing efficient pre‐screening strategy applicable Overall, our results suggest provides interesting and complementary tool alongside existing methods, address challenging problems effectively discovery.

Язык: Английский

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