Diverse Scaffolds Research Articles

Nat-UV DB: A Natural Products Database Underlying of Veracruz-Mexico

Background Natural products databases are well-structured data sources that offer new molecular development opportunities in drug discovery, agrochemistry, food, cosmetics, and several other research disciplines or chemical industries. The crescent world’s interest in the development of these databases is related to the exploration of chemical diversity in geographical regions with rich biodiversity. Methods In this work, we introduce and discuss Nat-UV DB, the first natural products database from a coastal zone of Mexico. We discuss its construction, curation, and chemoinformatic characterization of their content, and chemical space coverage compared with other compound databases, like approved drugs, and other Mexican (BIOFACQUIM and UNIIQUIM databases) and the Latin American natural products database (LaNAPDB). Results Nat-UV DB comprises 227 compounds that contain 112 scaffolds, of which 52 are not present in previous natural product databases. The compounds present in Nat-UV DB have a similar size, flexibility, and polarity to previously reported natural products and approved drug datasets. Conclusions Nat-UV DB compounds have a higher structural and scaffold diversity than the approved drugs, but they have low structural and scaffold diversity in contrast with other natural products in the reference datasets. This database serves as a valuable addition to the global natural products landscape, bridging gaps in exploring biodiversity-rich regions.

High potency 3-carboxy-2-methylbenzofuran pendrin inhibitors as novel diuretics

Pendrin (SLC26A4) is an anion exchanger expressed in epithelial cells of kidney and lung. Pendrin inhibition is a potential treatment approach for edema, hypertension and inflammatory lung diseases. We have previously identified first-in-class pendrin inhibitors by high-throughput screening, albeit with low potency for pendrin inhibition (IC50 ∼10 μM). Here, we performed a de novo small molecule screen with follow-on structure-activity studies to identify more potent pendrin inhibitors. Screening of 50,000 synthetic small molecules identified four novel classes of pendrin inhibitors with diverse scaffolds, including 5-benzyloxy-2-methylbenzofurans, N-aryl urea substituted 5-methyltryptamines, N-aryl urea substituted anthranilic acid, and substituted N-benzyl 3-carboxyindoles. The most potent inhibitor from the initial screen, a 3-carboxy-2-methylbenzofuran (1a), had IC50 of 4.1 μM. Structure-activity studies using 732 benzofuran analogs identified 1d with IC50 ∼ 0.5 μM for pendrin inhibition. Selectivity studies showed that 1d has minimal or no activity against related ion channels/transporters including SLC26A3, SLC26A6, SLC26A9 and CFTR at high concentrations. 1d administration to mice at 10 mg/kg had no effect on urine volume when used alone, but potentiated the diuretic effect of furosemide by 45%. In conclusion, we have identified novel pendrin inhibitors with greatly improved potency and good in vivo efficacy. These compounds can be used as pharmacological tools to study the roles of pendrin, and potentially developed as drug candidates for edema, hypertension and lung diseases.

Facile Approach to Diverse Diarylmethane Scaffolds via DBU-Catalyzed 1,6-Addition Reaction: Discovery of an Antibacterial Agent.

Herein, a DBU-catalyzed 1,6-Michael addition of para-quinone methides (p-QMs) under mild reaction conditions with high efficiency (turnover number up to 103) and good to excellent yields is reported. The transformation proceeds smoothly with a range of nucleophiles, providing diverse diarylmethane scaffolds with good efficiency. Mechanistic studies revealed that DBU is an excellent proton acceptor and donor and that DBU can promote the addition of methanol to p-QMs. A preliminary investigation was also conducted of the antibacterial properties of the products.

Building Three-Dimensional Complexity by Intramolecular 2-Aminoallyl Cation-Diene (4+3) Cycloaddition.

Reliable methods for rapidly constructing C(sp3)-rich three-dimensional polycycles are in high demand for organic synthesis and medicinal chemistry. Although there are various mature systems for synthesizing five- or six-membered polycycles, a catalytic platform for accessing diverse cycloheptanoid-containing polycyclic scaffolds is lacking. Herein, we describe a method for copper-catalyzed intramolecular 2-aminoallyl cation-diene (4+3) cycloaddition reactions. By using 1,3-diene-tethered ethynyl methylene cyclic carbamates as substrates, we were able to construct various cycloheptanoid-containing polycyclic scaffolds, which are present in many bioactive molecules. The cycloaddition products were rich in functionality that could undergo various chemical transformations. The synthetic utility of the method was illustrated by total synthesis of the natural products (±)-mint ketone and (±)-aphanamol I. Mechanistic studies indicated that the cycloadditions proceed by a concerted [4π+2π] mechanism and that an endo-selective pathway is favored.

DNA-compatible one-pot synthesis of multi-substituted dihydrofuran via pyridinium ylide-mediated cyclization.

Synthesis of chemically diverse heterocyclic scaffolds in DNA-encoded libraries is highly demanded. We herein reported a convenient one-pot multi-component on-DNA synthetic strategy to afford multi-substituted 2,3-dihydrofuran scaffolds via pyridinium ylide-mediated cyclization. This reaction exhibited modest to excellent conversions for a broad range of DNA-conjugated aldehydes, β-ketonitriles and pyridinium salts under mild reaction conditions. Furthermore, the compatibility of this strategy with DEL construction was verified by enzymatic DNA ligation, PCR amplification and mock library synthesis.

High-Resolution Isolation of Natural Products: Efficient Combination of Dryload Injection and HPLC Gradient Transfer.

The isolation of pure compounds from complex extracts is a crucial step in natural products (NPs) research. Historically, this process has been recognized to be slow and laborious. However, significant advancements have been made in isolation methods. Efficient separation conditions can now be efficiently determined at the analytical scale using high- or ultra-high-performance liquid chromatography and transferred to the preparative scale by chromatographic calculations. This ensures consistent selectivity at both scales, offering precise separation predictions. High-resolution chromatographic conditions at the preparative scale can be achieved through optimized sample preparation and dry load sample introduction. Monitoring chromatographic traces issued from ultraviolet (UV), mass spectrometry (MS), and/or universal detectors such as evaporative light-scattering detectors (ELSD) can precisely guide the isolation or trigger the collection of specific NPs with diverse structural scaffolds. These approaches can be applied across different scales depending on the amounts of NPs targeted for isolation. This chapter presents a detailed description of an isolation protocol, using the aforementioned methodologies.

Epithelia Are Scaffolds for Electricity-Dependent Molecular Interactions.

Once multicellularity was thriving, a key development involved the emergence of epithelial layers that separated "inside" from "outside". Most epithelia then generate their own transepithelial electrical signals. So electrical forces were instrumental in the development of epithelial tissues, which themselves generate further electrical signals. Epithelia also developed extracellular basement membranes which act as spatially diverse scaffolds to organize multiple molecular interactions, dependent on electrical forces.Epithelia and basement membranes were constructed using electrical forces and their evolution had electrophysiological consequences.

Cheminformatics Exploration of Structural Physicochemical Properties, Molecular Fingerprinting, and Diversity of the Chemical Space of Compounds from Betel Nut (Areca catechu L.).

In this work, the characterization and diversity of 347 compounds from betel nut (Areca catechu L.) were analyzed for the first time. The dataset of compounds from betel nut (BNC) was compared to compounds from food. They were analyzed in terms of physicochemical properties, scaffold diversity, molecular fingerprints, and global diversity. Approximately 48% of compounds in the BNC confirm Lipinski's and Pfizer's rules. The pharmacological and toxicological properties of edible betel nut were evaluated based on their composition. This work applied the research methods of cheminformatics to food science, and it provided theoretical support and data for betel nut pharmacological research, development of betel nut-related novel medication, and healthy products.

Overview of Phenylhydrazine‐Based Organic Transformations

AbstractPhenylhydrazines, comprised of a phenyl group attached with hydrazine unit, contribute potentially to organic synthetic transformations. Because of the myriad of synthetic applications, the last decade has witnessed a considerable upsurge of interest to perform various reactions catalyzed/mediated/promoted by phenylhydrazines. Some of these reactions have shown high regioselectivity in short reaction time under mild reaction conditions. The emergence of innumerable synthetic transformations utilizing phenylhydrazine has unleashed numerous openings for the development of diverse heterocyclic scaffolds. Given the synthetic importance of this valuable chemical entity, this review highlights the methodologies utilizing phenylhydrazines. Moreover, the present article will contribute considerably to the organic synthesis as well as in pharmaceutical chemistry. Academically, this review article will be interesting and informative for the researchers attempting to develop new synthetic routes for the heterocyclic structures.

Functionalized Sugar Oximes: Synthesis and Utilization for Structurally Diverse Scaffolds

Functionalized Sugar Oximes: Synthesis and Utilization for Structurally Diverse Scaffolds

Combining crystallographic and binding affinity data towards a novel dataset of small molecule overlays

Although small molecule superposition is a standard technique in drug discovery, a rigorous performance assessment of the corresponding methods is currently challenging. Datasets in this field are sparse, small, tailored to specific applications, unavailable, or outdated. The newly developed LOBSTER set described herein offers a publicly available and method-independent dataset for benchmarking and method optimization. LOBSTER stands for “Ligand Overlays from Binding SiTe Ensemble Representatives”. All ligands were derived from the PDB in a fully automated workflow, including a ligand efficiency filter. So-called ligand ensembles were assembled by aligning identical binding sites. Thus, the ligands within the ensembles are superimposed according to their experimentally determined binding orientation and conformation. Overall, 671 representative ligand ensembles comprise 3583 ligands from 3521 proteins. Altogether, 72,734 ligand pairs based on the ensembles were grouped into ten distinct subsets based on their volume overlap, for the benefit of introducing different degrees of difficulty for evaluating superposition methods. Statistics on the physicochemical properties of the compounds indicate that the dataset represents drug-like compounds. Consensus Diversity Plots show predominantly high Bemis–Murcko scaffold diversity and low median MACCS fingerprint similarity for each ensemble. An analysis of the underlying protein classes further demonstrates the heterogeneity within our dataset. The LOBSTER set offers a variety of applications like benchmarking multiple as well as pairwise alignments, generating training and test sets, for example based on time splits, or empirical software performance evaluation studies. The LOBSTER set is publicly available at https://doi.org/10.5281/zenodo.12658320, representing a stable and versioned data resource. The Python scripts are available at https://github.com/rareylab/LOBSTER, open-source, and allow for updating or recreating superposition sets with different data sources. Graphical abstractSimplified illustration of the LOBSTER dataset generation.

Aza-Michael addition-elimination led synthesis, characterization and X-ray crystallography of novel trifluoromethylated-enaminone derivatives

Enaminones are important synthetic intermediates for the construction of diverse heterocyclic scaffolds owing to their push-pull electronic structures. A series of novel (Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(aryl/alkyl)prop-2-en-1-ones (5, 6) and (Z)-3-(aryl/alkylamino)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-ones (9, 10) were synthesized with (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one (2) & (E)-3-(dimethylamino)-1-(4-(trifluoromethyl)phenyl) prop-2-en-1-one (8) as starting materials. The structures of the fluorinated enaminones were established with the help of spectral and analytical data. X-ray crystallographic study for a model compound (6a) gave a vivid image showing the existence of the product in Z-form unlike the corresponding intermediate that exists in E-form.

Systematic, computational discovery of multicomponent and one-pot reactions

Discovery of new types of reactions is essential to organic chemistry because it expands the scope of accessible molecular scaffolds and can enable more economical syntheses of existing structures. In this context, the so-called multicomponent reactions, MCRs, are of particular interest because they can build complex scaffolds from multiple starting materials in just one step, without purification of intermediates. However, for over a century of active research, MCRs have been discovered rather than designed, and their number remains limited to only several hundred. This work demonstrates that computers taught the essential knowledge of reaction mechanisms and rules of physical-organic chemistry can design – completely autonomously and in large numbers – mechanistically distinct MCRs. Moreover, when supplemented by models to approximate kinetic rates, the algorithm can predict reaction yields and identify reactions that have potential for organocatalysis. These predictions are validated by experiments spanning different modes of reactivity and diverse product scaffolds.

Structurally Diverse Nitrogen-Rich Scaffolds via Continuous Photo-Click Reactions.

Continuous flow technology was exploited for the effective generation of nitrile imines via photolysis of substituted aryl tetrazoles. The resulting photo-click process rapidly affords advanced nitrogen-rich scaffolds upon the subsequent trapping of the reactive dipole with alkenes, alkynes, and benzylic amines. Crucially, this approach uncovers the differential reactivity for ether vs amine tethers, thus providing facile and scalable access to underexplored medicinally relevant heterocyclic entities.

Homobarrelenones: Versatile Building Blocks for the Construction of Novel and Structurally Diverse Scaffolds

AbstractWe describe the derivatization of tropolone–based homobarrelenones through simple transformations, including catalytic hydrogenations, base‐catalyzed solvolysis, and hydride reductions. Despite being structurally complex and highly functionalized, the novel compounds had no significant cytotoxicity in sperm motility assays, underscoring the importance of Michael acceptor moieties in the biological activity of this class of compounds.

Hydrogel-Enhanced Autologous Chondrocyte Implantation for Cartilage Regeneration-An Update on Preclinical Studies.

Autologous chondrocyte implantation (ACI) and matrix-induced ACI (MACI) have demonstrated improved clinical outcomes and reduced revision rates for treating osteochondral and chondral defects. However, their ability to achieve lasting, fully functional repair remains limited. To overcome these challenges, scaffold-enhanced ACI, particularly utilizing hydrogel-based biomaterials, has emerged as an innovative strategy. These biomaterials are intended to mimic the biological composition, structural organization, and biomechanical properties of native articular cartilage. This review aims to provide comprehensive and up-to-date information on advancements in hydrogel-enhanced ACI from the past decade. We begin with a brief introduction to cartilage biology, mechanisms of cartilage injury, and the evolution of surgical techniques, particularly looking at ACI. Subsequently, we review the diversity of hydrogel scaffolds currently undergoing development and evaluation in preclinical studies for articular cartilage regeneration, emphasizing chondrocyte-laden hydrogels applicable to ACI. Finally, we address the key challenges impeding effective clinical translation, with particular attention to issues surrounding fixation and integration, aiming to inform and guide the future progression of tissue engineering strategies.

Deep phenotypic profiling of neuroactive drugs in larval zebrafish

Behavioral larval zebrafish screens leverage a high-throughput small molecule discovery format to find neuroactive molecules relevant to mammalian physiology. We screen a library of 650 central nervous system active compounds in high replicate to train deep metric learning models on zebrafish behavioral profiles. The machine learning initially exploited subtle artifacts in the phenotypic screen, necessitating a complete experimental re-run with rigorous physical well-wise randomization. These large matched phenotypic screening datasets (initial and well-randomized) provide a unique opportunity to quantify and understand shortcut learning in a full-scale, real-world drug discovery dataset. The final deep metric learning model substantially outperforms correlation distance–the canonical way of computing distances between profiles–and generalizes to an orthogonal dataset of diverse drug-like compounds. We validate predictions by prospective in vitro radio-ligand binding assays against human protein targets, achieving a hit rate of 58% despite crossing species and chemical scaffold boundaries. These neuroactive compounds exhibit diverse chemical scaffolds, demonstrating that zebrafish phenotypic screens combined with metric learning achieve robust scaffold hopping capabilities.

An insights into structural diversity of β-lactam scaffold towards varied medicinal applications: A comprehensive update (2020–2024)

β-Lactams have long been a cornerstone in the treatment of various bacterial infections, largely due to their unique structure–activity relationship with pathogenic bacteria. Significant efforts have been devoted in the literature to the development of novel β-lactam compounds and their subsequent medicinal evaluation. Moreover, the structural diversity in β-lactam derivatives has garnered significant interest in medicinal arena. Therefore, in this review thoroughly discusses the impact of structural diversity on various medicinal applications, which can be achieved through multiple synthetic approaches, including stereoselective reactions, heterocyclic fusion, regioselective modifications, and metal-catalyzed transformations. Additionally, the occurrence of functional groups such as electron-donating or electron-withdrawing groups in structurally diverse β-lactam scaffolds has been explored to assess their medicinal impact. Furthermore, β-lactam compounds have increasingly attracted interest in medicinal chemistry because of their many other remarkable biological activities. Through the analysis of stereoselectivity, heterocyclic motifs, and the impacts of functional groups, we highlight the compounds noteworthy for medicinal applications, including anti-bacterial, anti-fungal, anti-cancer, anti-oxidant, anti-diabetic, anti-viral, anti-tubercular, anti-inflammatory, analgesic and anti-malarial activity. Owing to these captivating pharmacological properties, this review provides a comprehensive update on the varied medicinal applications of β-lactam scaffolds, emphasizing a wide range of examples from 2020 to 2024.

Cascade Cyclization/Annulation of β-Enamino Diketones and o-Phenylenediamine: A Strategy to Access Pyrrole-fused 1,5-Benzodiazepines.

Herein, we introduce an unprecedented cascade reaction for the assembly of pyrrole-fused 1,5-benzodiazepine frameworks. These diverse privileged scaffolds were controllably constructed by intramolecular cyclization of β-enamino diketone, followed by annulation with o-phenylenediamine. The protocol features efficient one-pot cascade cyclization/annulation, performed under simple and mild reaction conditions. The products are obtained in a metal-free manner, in good to excellent yields (65-91%), and represent a fused heterocyclic scaffold that is not yet found in nature.

Diffusion-based generative drug-like molecular editing with chemical natural language

Recently, diffusion models have emerged as a promising paradigm for molecular design and optimization. However, most diffusion-based molecular generative models focus on modeling 2D graphs or 3D geometries, with limited research on molecular sequence diffusion models. The International Union of Pure and Applied Chemistry (IUPAC) names are more akin to chemical natural language than the Simplified Molecular Input Line Entry System (SMILES) for organic compounds. In this work, we apply an IUPAC-guided conditional diffusion model to facilitate molecular editing from chemical natural language to chemical language (SMILES) and explore whether the pre-trained generative performance of diffusion models can be transferred to chemical natural language. We propose DiffIUPAC, a controllable molecular editing diffusion model that converts IUPAC names to SMILES strings. Evaluation results demonstrate that our model outperforms existing methods and successfully captures the semantic rules of both chemical languages. Chemical space and scaffold analysis show that the model can generate similar compounds with diverse scaffolds within the specified constraints. Additionally, to illustrate the model's applicability in drug design, we conducted case studies in functional group editing, analogue design and linker design.