Revisiting Pyrimidine-Embedded Molecular Frameworks to Probe the Unexplored Chemical Space for Protein–Protein Interactions DOI Creative Commons
Jeong Yeon Yoo, Yoona Choi, Heejun Kim

и другие.

Accounts of Chemical Research, Год журнала: 2024, Номер 57(22), С. 3254 - 3265

Опубликована: Окт. 31, 2024

ConspectusProtein–protein interactions (PPIs) are essential in numerous biological processes and diseases, making them attractive yet challenging drug targets. While many advances have been made traditional discovery, targeting PPIs has difficult due to a lack of specialized chemical libraries designed modulate these interactions. Current mainly focus on conventional target proteins like enzymes or receptors as substrate analogs rather than small-molecule modulators PPIs. These targets behave differently from Conventional druggable relatively small surfaces binding pockets that allowed be targeted with current libraries, but As result, there is an urgent need for innovative approach expand the space.To address this, we developed privileged substructure-based diversity-oriented synthesis (pDOS) strategy, aimed at creating maximal skeletal diversity explore broader biochemical space. Pyrimidine serves substructure our approach, which employs several strategies: (i) silver-catalyzed iodine-mediated tandem cyclizations generate pyrimidine-embedded polyheterocycles; (ii) diverse pairing strategies produce pyrimidodiazepine-containing polyheterocyclic skeletons enhanced scaffold saturation; (iii) transformation develop pyrimidine-fused medium-sized azacycles via chemoselective cleavages migrations N–N C–N bond; (iv) design peptidomimetics systematically mimic three pivotal protein secondary structures using pyrimidodiazepine-based scaffolds; (v) identification small-molecules allosterically inhibits interaction between human ACE2 receptor-binding domain (RBD) SARS-CoV-2 spike block viral entry into host cells.Through approaches, generated 39 distinct frameworks, demonstrating significant molecular validated by chemoinformatic analyses such Tanimoto similarity principal moment inertia (PMI) analysis. This extends pyrimidine beyond linear bicyclic forms, polyheterocycles 3D structural diversity. novel frameworks overcome limitation simpler scaffolds, offering promising tools modulating PPIs.Our pDOS highlights how structure-embedded polyheterocycles, particularly those based pyrimidine, can effectively previously undruggable strategy provides new direction allowing development molecules operate drug-like rules. In addition expanding space PPI modulation, enables creation scaffolds suited complex dynamic interfaces. innovation could significantly impact therapeutic development, solutions intractable By scope pyrimidine-based opened up possibilities advancing biology.This perspective demonstrates potential outlines structurally platform discovery facilitating exploration untapped spaces potentially transforming way

Язык: Английский

Multicomponent reactions (MCRs) yielding medicinally relevant rings: a recent update and chemical space analysis of the scaffolds DOI Creative Commons

Mukesh Tandi,

Vaibhav Sharma, B. Gopal

и другие.

RSC Advances, Год журнала: 2025, Номер 15(2), С. 1447 - 1489

Опубликована: Янв. 1, 2025

We have reviewed the recently reported multicomponent reactions (MCRs) yielding cyclic frameworks in a single pot from simple building blocks under mild conditions. These MCRs may prove to be useful for drug discovery projects.

Язык: Английский

Процитировано

2
Design and Synthesis of New Dihydropyrimidine Derivatives with a Cytotoxic Effect as Dual EGFR/VEGFR-2 Inhibitors DOI Creative Commons
Lamya H. Al-Wahaibi,

Ali M. Elshamsy,

Taha F. S. Ali

и другие.

ACS Omega, Год журнала: 2024, Номер 9(32), С. 34358 - 34369

Опубликована: Авг. 1, 2024

We developed and synthesized tetrahydropyrimidine derivatives as possible cytotoxic agents to inhibit EGFR VEGFR-2 in the present study. Our study completely assesses efficiency of pyrimidine-based

Язык: Английский

Процитировано

11
Design and Synthesis of Novel 2, 5-Substituted Pyrido[4,3-d]Pyrimidines: In silico, Anti-diabetic and Anti-inflammatory Studies DOI

Rajendra Swami Mareedu,

M. Pandeeswaran

Oriental Journal Of Chemistry, Год журнала: 2025, Номер 40(6), С. 1634 - 1646

Опубликована: Янв. 3, 2025

Recently, there has been a growing interest in small drug molecules due to their ability be easily customized with specific active sites of biomolecules. Sulfonyl-based compounds, particular, have shown promise for various pharmacological applications and many these are now available the commercial market. As result, is significant increase demand molecule compounds studies applications. In this context, we presented range pyridopyrimidine derivatives functionalized piperazine sulfonamides O-benzyl derivatives, characterized using analytical tools. These demonstrated anti-diabetic anti-inflammatory activities. The therapeutic activity was also assessed through molecular docking studies, which supported obtained results.

Язык: Английский

Процитировано

1
4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies DOI Creative Commons
Ashanul Haque, Khalaf M. Alenezi,

Mohd. Saeed Maulana Abdul Rasheed

и другие.

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Янв. 20, 2025

Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that significantly impacts the cognitive function and memory of person. Despite significant research efforts, ability to completely prevent or effectively treat AD its related dementias remains limited. Protein kinases are integral pathology represent promising targets for therapeutic intervention. Methods A series pyrimidine-based compounds 4-(4-(arylsulfonyl)piperazin-1-yl)-6-(thiophen-3-yl)pyrimidine derivatives ( 8 - 14 ) were synthesized characterised. ATPase inhibition was carried out against MARK4 enzyme. Molecular docking molecular dynamics (MD) simulation at 500 ns (PDB: 5ES1). The drug-likeness feature toxicity molecules evaluated using QikProp other tools. Results Compounds following multi-step approach characterized multi-nuclear magnetic resonance 1 H/ 13 C-NMR) mass spectrometry. assay showed an IC 50 value in micromolar (μM) range. results studies consistent with in-vitro experiments identified 9 as candidates highest affinity towards MARK4. MD further supported these results, showing binding ligands stabilises target protein. Conclusion Using experimental theoretical approaches, we demonstrated reported class pyrimidine excellent starting point developing next-generation anti-AD drugs.

Язык: Английский

Процитировано

1
Antibiofilm Activities of Halogenated Pyrimidines Against Enterohemorrhagic Escherichia coli O157:H7 DOI Open Access
Hyejin Jeon, Yong‐Guy Kim, Jin-Hyung Lee

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(3), С. 1386 - 1386

Опубликована: Фев. 6, 2025

Enterohemorrhagic Escherichia coli (EHEC) is a significant public health concern due to its ability form biofilms, enhancing resistance antimicrobials and contributing persistence in food processing environments. Traditional antibiotics often fail target these biofilms effectively, leading increased bacterial resistance. This study aims explore the efficacy of novel antibiofilm agents, specifically halogenated pyrimidine derivatives, against EHEC. We screened 31 derivatives for their antimicrobial activities EHEC using biofilm quantification assays, SEM analysis, motility, curli production assessments. Our findings reveal that certain notably 2-amino-5-bromopyrimidine (2A5BP), 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (2A4CPP), 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2,4DC5IPP) at 50 µg/mL, exhibited inhibitory effects on formation without affecting growth, suggesting targeted action. These compounds effectively reduced essential factors integrity development. qRT-PCR analysis revealed two active downregulated expression key genes (csgA csgB), adhesion formation. Additionally, silico ADME-Tox profiles indicated exhibit favorable drug-like properties lower toxicity compared with traditional pyrimidine. highlights potential as effective agents EHEC, offering promising strategy safety controlling infections. The distinct mechanisms action compounds, particularly inhibiting virulence promoting resistance, underscore therapeutic potential.

Язык: Английский

Процитировано

1
Current strategies in design and synthesis of antifungals hybrid and chimeric diazine derivatives DOI Creative Commons
Dumitrela Diaconu,

Marius Savu,

Catalina Ionica Ciobanu

и другие.

Bioorganic & Medicinal Chemistry, Год журнала: 2025, Номер 119, С. 118069 - 118069

Опубликована: Янв. 13, 2025

Язык: Английский

Процитировано

0
Triazination/IEDDA Cascade Modular Strategy Installing Pyridines/Pyrimidines onto Tyrosine Enables Peptide Screening and Optimization DOI
Quan Zuo,

Xinyi Song,

Jie Yan

и другие.

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Modular chemical postmodification of peptides is a promising strategy that supports the optimization and innovation hit peptide therapeutics by enabling rapid derivatization. However, current methods are primarily limited to traditional bio-orthogonal strategies ligation techniques, which require preintroduction non-natural amino acids impose fixed limit diversity. Here, we developed Tyrosine-1,2,3-Triazine Ligation (YTL) strategy, constructs novel linkages (pyridine pyrimidine) through "one-pot, two-step" process combining SNAr IEDDA reactions, promoting modular post modification Tyr-containing peptides. After optimizing YTL establishing standard procedures, successfully applied it solid-phase various biorelated peptides, such as synthesis dual-mode imaging probes long-acting GLP-1 analogs. As proof concept, library 384 amphipathic was constructed using based on 96-well microfiltration plates. modifications were then performed screened template tripeptide RYR, leading generation 20 derivatives. The antibacterial activity these derivatives systematically characterized, identifying Z8 potential candidate.

Язык: Английский

Процитировано

0
Green Approach for Pd-Catalyzed C–N Bond Formation with Weak Nitrogen Nucleophiles Using Saponin-Based Micellar Catalysis: Arylation of Anilines, Amides, Carbamates, Ureas, and Sulfonamides DOI
Vinothkumar Vinayagam, Subir Kumar Sadhukhan,

Dhurwasulu Baledi

и другие.

ACS Sustainable Chemistry & Engineering, Год журнала: 2025, Номер unknown

Опубликована: Апрель 11, 2025

Язык: Английский

Процитировано

0
Pyrimidine-based dual-target inhibitors targeting epidermal growth factor receptor for overcoming drug resistance in cancer therapy(2006-present) DOI

Yufeng An,

Xinya Lv,

Shidi Xu

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 286, С. 117268 - 117268

Опубликована: Янв. 13, 2025

Язык: Английский

Процитировано

0
General structure-activity relationship models for the inhibitors of Adenosine receptors: A machine learning approach DOI Creative Commons

Mona Janbozorgi,

Sara Kaveh, M. S. Neiband

и другие.

Molecular Diversity, Год журнала: 2025, Номер unknown

Опубликована: Янв. 20, 2025

Язык: Английский

Процитировано

0