Molecular Scaffold Research Articles

Two-Fold Oxidative Coupling of Furan with Indole Provides Modular Access to a New Class of Tetra-(Hetero)Arylated Furans with Up to Four Different Substituents.

Highly arylated propeller-shaped heteroarenes constitute an intriguing class of molecular scaffolds for material science applications. Among these, tetraarylated furans demonstrate differentiated properties as compared to other similar heterocyclic cores. The synthetic complexity to access tetraarylated furans increases significantly with increasing number of different peripheral aryl groups. There are only a very limited number of methodologies available to access furans with four different (hetero)aryl substituents. Notably, none of these involve direct oxidative coupling on the furan core as the method of choice. Herein, we report the first methodology based on a sequential two-fold oxidative C-C coupling of furans with indoles to access bis(indolyl)furans (BIFs) - a new class of 'extremely congested' tetra-(hetero)arylated furans with up to four different substituents. The reaction is mediated by inexpensive, earth-abundant FeCl3⋅6H2O and displays high efficiency, wide substrate scope, modularity and aqueous compatibility. Moreover, we also present the first validation of the distinct aggregation-caused quenching (ACQ) property of the tetraarylated furans beyond only phenyls as peripheral groups and disclose new mechanistic underpinnings for the same.

Evaluation of Anti-Alzheimer's Potential of Azo-Stilbene-Thioflavin-T derived Multifunctional Molecules: Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity.

Inhibition of amyloid β (Aβ) aggregation and cholinesterase activity are two major therapeutic targets for Alzheimer's disease (AD). Multifunctional Molecules (MFMs) specifically designed to address other contributing factors, such as metal ion induced abnormalities, oxidative stress, toxic Ab aggregates etc. are very much required. Several multifunctional molecules have been developed using different molecular scaffolds. Reported herein is a new series of four MFMs based on ThT, Azo-stilbene and metal ion chelating pockets. The synthesis, characterization, and metal chelation ability for [Cu(II) and Zn(II)] are presented herein. Furthermore, we explored their multifunctionality w.r.t. to their (i) recognition of Aβ aggregates and monomeric form, (ii) utility in modulating the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) ex-vivo staining of amyloid plaques in 5xFAD mice brain sections, (iv) ability to scavenge free radicals and (v) ability to inhibit cholinesterase activity. Molecular docking studies were also performed with Aβ peptides and acetylcholinesterase enzyme to understand the observed inhibitory effect on activity. Overall, the studies presented here establish the multifunctional nature of these molecules and qualify them as promising candidates for furthermore investigation in the quest for finding Alzheimer's disease treatment.

Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics.

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads. A compact parallel synthesizer was built in-house, capable of producing 5 distinct molecules per cycle; 525 reactions could be finished within three months to generate 42 derivatives for a structure-activity relationship (SAR) investigation. Among these, ten derivatives exhibited promising target inhibitory activity (IC50 < 100 nM) including two with antiviral activity (EC50 < 250 nM). The platform, coupled with digital chemical recipe files, offers rapid access to a wide range of peptidomimetics, serving as a valuable reservoir for broad-spectrum antiviral candidates. This automated solid-phase flow synthesis approach expedites the generation of previously difficult complex molecular scaffolds. By integration of SPS-flow synthesis with medicinal chemistry campaign, >10-fold target inhibitory activity was achieved from a small set of derivatives, which indicates the potential to shift the paradigm of drug discovery.

Tryptamine‐Derived Schiff Bases: Potent Antimicrobial Agents and Evaluation of Cytotoxicity, ADME and DNA Binding Properties

Inspired by the fact that the introduction of indole pharmacophore in organic scaffolds could enable interesting pharmacological properties, the series of novel tryptamine‐derived Schiff bases was synthetized. Tryptamine was used as a source of indole pattern, as well as an example of biogenic amines which chemical transformations lead to the compounds with prominent biological activities. The obtained results for antimicrobial activity against a range of bacterial and fungal strains and cytotoxic activities have revealed that Schiff base TSB4 combining the tryptamine and p‐nitro aryl patterns in the structure showed better antifungal activity at low concentrations than standard drug Fluconazole, while compound TSB6 with molecular scaffold composed from tryptamine and quinoline moieties showed certain cytotoxic effect on HCT‐116 cell line with a strongly expressed selectivity about healthy fibroblast cells, MRC‐5. For these two selected compounds, additional ADME analysis and DNA interactions were performed. to obtain better insight into their pharmacokinetics and determination of binding mode for DNA molecules. As results suggested, strong binding of examined compounds to CT‐DNA was observed, while the ADME screening showed that selected compounds possess suitable physicochemical properties for oral bioavailability and druglikeness.

Rumicidins are a family of mammalian host-defense peptides plugging the 70S ribosome exit tunnel

The antimicrobial resistance crisis along with challenges of antimicrobial discovery revealed the vital necessity to develop new antibiotics. Many of the animal proline-rich antimicrobial peptides (PrAMPs) inhibit the process of bacterial translation. Genome projects allowed to identify immune-related genes encoding animal host defense peptides. Here, using genome mining approach, we discovered a family of proline-rich cathelicidins, named rumicidins. The genes encoding these peptides are widespread among ruminant mammals. Biochemical studies indicated that rumicidins effectively inhibited the elongation stage of bacterial translation. The cryo-EM structure of the Escherichia coli 70S ribosome in complex with one of the representatives of the family revealed that the binding site of rumicidins span the ribosomal A-site cleft and the nascent peptide exit tunnel interacting with its constriction point by the conservative Trp23-Phe24 dyad. Bacterial resistance to rumicidins is mediated by knockout of the SbmA transporter or modification of the MacAB-TolC efflux pump. A wide spectrum of antibacterial activity, a high efficacy in the animal infection model, and lack of adverse effects towards human cells in vitro make rumicidins promising molecular scaffolds for development of ribosome-targeting antibiotics.

Enhancing Efficiency and Sustainability: Unleashing the Potential of Continuous Flow in Multicomponent Reactions.

The integration of multicomponent reactions (MCRs), which offer a rapid and efficient approach to synthesize complex molecular scaffolds, with continuous flow platforms is an increasingly recognized strategy in green synthesis. This association enables precise control over reaction parameters, including improved kinetics and selectivity, reduced reaction times, enhanced yields and scalabilities, while aligning with sustainable and green chemistry principles through resource utilization, minimized waste, and reduced environmental impact. This review presents a critical analysis of recent studies covering the MCR-continuous flow association, with a focus on achieving greener and more sustainable synthesis practices.

Synthesis of 2‐Substituted Bicyclo[2.1.1]Hexan‐1‐ols via SmI2‐Mediated Reductive Cyclization Reactions

AbstractThe replacement of benzene rings with saturated bioisosteric counterparts is a key priority in drug discovery programs, and disubstituted bicyclo[2.1.1]hexanes have been recognized as flexible molecular scaffolds that could act as ortho‐substituted benzene bioisosteres. In this study, we outline the synthesis of a wide range of 2‐substituted bicyclo[2.1.1]hexan‐1‐ols, which have the potential to emulate ortho‐phenolic derivatives, via SmI2‐mediated reductive cyclization reactions. The synthetic utility of this methodology was exemplified by the preparation of several saturated analogs of pharmaceutically relevant compounds.

Quadrupolar dinuclear hypervalent tin(iv) compounds with near-infrared emission consisting of Schiff bases based on π-conjugated scaffolds.

Since π-conjugated molecules are commonly used as a scaffold for constructing optoelectronic and functional materials, much effort has been devoted to exploring novel molecular scaffolds for obtaining superior properties. This study focuses on dinuclear hypervalent tin(iv) compounds prepared by the ladderization of Schiff bases using hypervalent tin units. The optical measurements found that introducing hypervalent tin atoms can reinforce the D-π-A system. We synthesized two types of dinuclear hypervalent compounds by simple condensation reactions and observed near-infrared (NIR) emission. Also, depending on the direction of the imine bonds, these molecules had different quadrupolar orientations with D-π-A-π-D and A-π-D-π-A systems followed by negative solvatochromism, which is the unique behavior of quadrupolar-derived absorption. Furthermore, the π-conjugated polymers involving dinuclear compounds showed NIR emission in the wavelength range over 800 nm owing to the distinct expansion of π-conjugation. Our findings could be useful not only for constructing electronic structures with narrow energy gaps but also for designing molecules with unique electronic states and environmental responsiveness.

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis.

With the resurgence of electrosynthesis in organic chemistry, there is a significant increase in the number of routes available for late-stage functionalization (LSF) of drugs. Electrosynthetic methods, which obviate the need for hazardous chemical oxidants or reductants, offer unprecedented control of reactions through the continuous variation of the applied potential and the possibility of combination with photochemical processes. This capability is a substantial advantage for performing electrochemical or photoelectrochemical LSF. Ultimately, these protocols are poised to become a vital component of the medicinal chemist's toolkit. In this review, we discuss electrochemical protocols that have been demonstrated to be applicable for the LSF of pharmaceutical drugs, their derivatives, and natural substrates. We present and analyze representative examples to illustrate the potential of electrochemistry or photoelectrochemistry for the LSF of valuable molecular scaffolds.

Truncated NPY-based NPY(Y1)R-specific radiopeptides: Improved in vivo PET tumor imaging by application of peptidase inhibitors

The neuropeptide Y receptor subtype 1 (NPY(Y1)R) exhibits high expression rates on human breast cancer and is therefore an important target structure for the sensitive and specific visualization and characterization of the disease by Positron Emission Tomography (PET). However, imaging of this receptor type has been of limited success so far due to the low stability of peptide-based NPY-derived NPY(Y1)R-specific radiotracer candidates due to in vivo degradation. Given the challenges in stabilizing these agents, our study sought to explore whether the stability of NPY(Y1)R-specific radiopeptides could be enhanced. We aimed to achieve this by either modifying the peptide structure with various molecular scaffolds or by applying peptidase inhibitors. This evaluation aimed to identify the optimal approach for achieving effective NPY(Y1)R-specific imaging in the following. To validate our approach, we systematically investigated four new truncated 68Ga-labeled analogs of NPY and the reference compound [68Ga]Ga-[Lys4(Nε-DOTA)]BVD15, bearing different molecular scaffolds such as a DOTA or NODA-GA chelator, a 4-APipAc linker, a Bip unit, and an N-terminal Lys(lauryl) group. The four new radiotracers as well as the reference compound were obtained in high chemical and radiochemical yields with molar activities of 33–39 GBq/μmol. The radiopeptides exhibited varying logD7.4 values, ranging from −3.37 ± 0.09 to +0.35 ± 0.11, and showed different levels of stability in human serum and liver microsomes, depending on their molecular structure. Subsequently, the influence of the peptidase inhibitors actinonin, phosphoramidon, captopril and E−64 on the in vitro stability of the radiotracers was investigated. In these studies, only actinonin demonstrated a positive effect on the stability of all radiopeptides. In contrast, phosphoramidon yielded variable results, and neither captopril nor E−64 showed a significant stabilizing effect.Consequently, the effect of actinonin administration on the in vivo PET/CT imaging results of the most promising ligand [68Ga]Ga-[Lys4(Nε-NODA-GA)]BVD15 ([68Ga]Ga-2) was investigated in a T47D tumor-bearing xenograft mouse model, followed by ex vivo biodistribution studies. In these experiments, the administration of 250 μg actinonin resulted in a significantly increased uptake of [68Ga]Ga-2 in the T47D tumor (5.9 ± 1.0 % ID/g (with actinonin) instead of 3.1 ± 0.9 % ID/g (without actinonin) at 2h p.i.), and an increase in tumor-to-muscle ratios from 1.8 to 4.0 upon co-administration of the inhibitor.The results impressively demonstrate the positive influence of actinonin on the in vivo stability of the NPY(Y1)R-specific radiopeptide [68Ga]Ga-2, resulting in an increased tumor accumulation and improved tumor-to-background ratios. These findings thus provide important incentive for further advancement of NPY(Y1)R-specific tumor imaging using PET.

Design, synthesis, in vitro and in vivo trypanosomaticidal efficacy of novel 5-nitroindolylazines

Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (SN), hydrazination and Schiff base condensation reactions, and was evaluated against various Leishmania and Trypanosoma species and strains. Several promising hits portraying leishmanicidal and trypanocidal with in vitro submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine 11 (Tc IC50: 0.08 ± 0.03 μM) and nitrothienylazine 13 (Tc IC50: 0.09 ± 0.01 μM) were evaluated in vivo against Trypanosoma congolense, the causative agent of nagana, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.

Tyramine Derivatives as Versatile Pharmacophores With Potent Biological Properties: Sex Hormone-Binding Globulin Inhibition, Colon Cancer Antimigration, and Antimicrobial Activity.

Guided by the idea that the presence of a heterocyclic aromatic core and tyramine moiety, under the umbrella of a single molecular scaffold could bring interesting biological properties, herein we present synthesis, characterization, with two crystal structures reported, and biological evaluation of some tyramine derivates. Cytotoxic and antimigratory potential was addressed by using a colorectal cancer cell line as a model system. Although possessing no cytotoxic effects, two compounds have shown strong antimigratory potential in low doses, with no effect on healthy MRC-5 cells. Evaluation of their antimicrobial activities suggested prominent antimicrobial activity, where Compound 4 outperformed streptomycin against Escherichia coli and Proteus mirabilis. Hormone-dependent types of cancer, such as prostate, ovary, and breast, are highly dependent on human sex hormone-binding globulin (SHBG) blood levels. A molecular docking study has shown that 1 has high affinity to bind and therefore compete with natural steroids for the SHBG steroid-binding site. DNA-binding study have shown that 4 interacts with CT-DNA in a groove-binding mode. In silico ADME/T study revealed that all compounds have suitable physicochemical properties for oral bioavailability and druglikeness, while toxicity tests for 1, 4, and 6 suggested potential for mutagenicity (4, 6), hepatotoxicity (6), and skin sensation (1).

Improving redox reactions of Spiro-OMeTAD via p-type molecular scaffold to reduce energy loss at Ag-electrode in perovskite solar cells

Improving redox reactions of Spiro-OMeTAD via p-type molecular scaffold to reduce energy loss at Ag-electrode in perovskite solar cells

Ligand-based Pharmacophore Modeling Targeting the Fluoroquinolone Antibiotics to Identify Potential Antimicrobial Compounds

Antibiotic resistance presents a serious challenge to global healthcare, making the discovery of new therapeutic agents crucial. In this study, we used pharmacophore modeling and virtual screening to identify potential lead compounds against drug-resistant bacteria. We developed a shared feature pharmacophore (SFP) map using four antibiotics—Ciprofloxacin, Delafloxacin, Levofloxacin, and Ofloxacin—and generated a drug library of 160,000 compounds from ZINCPharmer based on these features, which included hydrophobic areas, hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), and aromatic moieties (Ar). Through virtual screening, we identified 25 potential drug compounds as hits, with fit scores ranging from 97.85 to 116 and RMSD values from 0.28 to 0.63. These hits were then subjected to molecular docking against the DNA gyrase subunit A protein (PDB ID: 4DDQ), with ciprofloxacin as a control. The top five compounds—ZINC09133461, ZINC03791737, ZINC21983587, ZINC26469742, and ZINC26740199—achieved the highest docking scores, ranging from -7.3 to -7.4kcal/mol and ciprofloxacin -7.3kcal/mol. After evaluating the drug-likeness of these compounds using Lipinski’s rule and analyzing their physicochemical properties, ZINC26740199 emerged as the most promising lead, offering hope in the fight against antibiotic resistance. Furthermore, molecular scaffold analysis revealed key similarities between ZINC26740199 and Ciprofloxacin, particularly in aromatic rings, hydrophobic regions, and hydrogen bond acceptors. These features suggest its potential as an effective antimicrobial agent, though further laboratory studies are needed to confirm its efficacy.

Cyclodextrin-assisted high selectivity of imprinted adsorbents loaded on polyoxometalate@UiO-66 for H2S removal at ambient temperature

The efficient removal of H2S is necessary for clean production and energy safety. However, industrial gases are usually accompanied by CO2 significantly affecting desulfurization effects. Hence, novel imprinted adsorbents (PMo12@UiO-66@H2S-MIP-CDs) were synthesized through surface imprinting technology using cyclodextrins (CDs) as molecular scaffolds and UiO-66 modified by phosphomolybdic acid (PMo12@UiO-66) as a support. Wherein, PMo12@UiO-66@H2S-MIP-β-CD was determined as the optimal adsorbent since β-CD with low solubility is prone to keep its inherent cavity to promote dispersion of imprinted polymers and enrich internal pore channels. H2S capacity of PMo12@UiO-66@H2S-MIP-β-CD (31.67 mg/g) was about 2.4 and 1.7 times that of PMo12@UiO-66 and PMo12@UiO-66@H2S-MIPs, respectively, revealing the remarkable contribution of β-CD as a molecular scaffold to improve desulfurization. The results showed that PMo12@UiO-66@H2S-MIP-β-CD can maintain stable desulfurization efficiency regardless of the presence of CO2 or moisture, and O2 can strengthen the redox reaction between H2S and PMo12 accompanied by the increased reduction degree of Mo6+ in PMo12. After five adsorption-regeneration cycles, PMo12@UiO-66@H2S-MIP-β-CD still exhibited ideal removal efficiency. The excellent desulfurization performance is mainly ascribed to the selective adsorption role of H2S-MIP-β-CD and oxidative removal ability of PMo12. This work provides a valuable reference for the directional design of high-capacity functional adsorbents for room-temperature desulfurization.

Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen.

NLRP3, a crucial member of the NLRP family, plays a pivotal role in immune regulation and inflammatory modulation. Here, we report a potent and specific NLRP3 inhibitor Z48 obtained though docking-based virtual screening and structure-activity relationship studies with an IC50 of 0.26 μM in THP-1 cells and 0.21 μM in mouse bone marrow-derived macrophages. Mechanistic studies indicated that Z48 could bind directly to the NLRP3 protein (KD = 1.05 μM), effectively blocking the assembly and activation of the NLRP3 inflammasome, consequently manifesting anti-inflammatory properties. Crucially, with acceptable mouse pharmacokinetic profiles, Z48 demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, while displaying no significant therapeutic impact on NLRP3KO mice. In conclusion, this study provided a promising NLRP3 inflammasome inhibitor with novel molecular scaffold, poised for further development as a therapeutic candidate in the treatment of inflammatory bowel disease.

Divergent Tandem Acyl Carrier Proteins Necessitate In-Series Polyketide Processing in the Leinamycin Family.

The leinamycin family of polyketides are promising antitumour antibiotics, yet several aspects of their biosynthesis remain elusive. All leinamycin family members bear a sulfur-containing moiety which is essential for the anticancer activity exhibited by leinamycin. The key building blocks required for the incorporation of these functionalities are introduced in the final module of the polyketide synthase (PKS), which elegantly combines β-branching and thiocysteine incorporation to generate a diverse library of sulfur-based molecular scaffolds. Two acyl carrier proteins (ACPs) form a key didomain component of this module, but their amino acid sequence divergence has brought into question the common notion of functional equivalence. Here, we provide unprecedented functional evidence that these tandem ACPs play distinct roles in the final module of polyketide assembly. Using the weishanmycin biosynthetic pathway as a template, the in vitro reconstitution of key polyketide chain extension and β-branching steps in this module has revealed strict functional selectivity for a single ACP. Furthermore, we propose a cryptic transacylation step must occur prior to polyketide off-loading and cyclization. Altogether, these mechanistic investigations suggest that an atypical in-series mechanism underpins sulfur incorporation in the leinamycin family, and provides significant progress towards delineating their late-stage assembly.

Essential Oil Extracted from Lippia sidoides Cham. (Verbenaceae) Induces Cell Cycle Arrest, Apoptosis, and Antimigratory Effects in Melanoma Cells.

Melanoma, the most aggressive form of skin cancer, poses a substantial global health threat with increasing incidence rates. Although novel targeted therapies have improved melanoma treatment, challenges persist due to poor response rates and drug resistance. Plant-derived compounds have been crucial in anticancer drug discovery, with many natural products demonstrating the ability to target molecular pathways involved in tumor development. In this study, the anti-melanoma potential of essential oil extracted from the aerial parts of Lippia sidoides Cham. (EO-LS), composed mainly by the monoterpene thymol (96%), was demonstrated. Obtained results demonstrated that EO-LS disrupted critical cancer hallmarks in A2058 melanoma cells harboring the BRAFV600E mutation. Specifically, EO-LS induced G1-phase cell cycle arrest and apoptosis, as assessed by annexin-V, caspase-3 activity, and TUNEL assays. EO-LS also inhibited cell migration and disrupted the AKT signaling pathway, which is a critical regulator of melanoma progression. Furthermore, a dose-dependent increase in reactive oxygen species (ROS) generation was observed, indicating pro-oxidant properties. These findings highlighted the significant in vitro anticancer properties of EO-LS suggesting its potential as a promising molecular scaffold for developing of novel anti-melanoma candidates.

A Visible-Light-Responsive Fluorescent Diarylethene Having a Betaine Structure.

As a new molecular scaffold of photoswitchable fluorophore, we developed a photochromic diarylethene containing a betaine structure based on pyridinium N-enolate. A facile reaction of a pyridyl-substituted dithienylperfluorocyclopentene derivative with octafluorocyclopentene constructed the betaine structure. The introduction of the betaine moiety provided the diarylethene molecule with bathochromically shifted optical absorption and fluorescing ability, thus enabling the molecule to function as a visible-light-sensitive turn-off mode photoswitchable fluorophore. The molecule in the open-ring form emitted bright blueish green fluorescence. Upon irradiation with 405 nm light, the molecule underwent cyclization isomerization to form the closed-ring isomer and the fluorescence intensity significantly decreased. The turn-off mode fluorescence photoswitching was observed not only in solution but also in polymer films.

Sterically Controlled Lewis Acid−Base Interaction Toward para‐Selective Borylation of Aromatic Aldimines and Benzylamines

AbstractSite‐selective C−H bond functionalization of arenes at the para position remains extremely challenging primarily due to its relative inaccessibility from the catalytic site. As a consequence, it is significantly restricted to limited molecular scaffolds. Herein, we report a method for the para‐C−H borylation of aromatic aldimines and benzylamines using commercially available ligands under iridium catalysis. The established method displays excellent para selectivity for variously substituted aromatic aldimines, benzylamines and bioactive molecules. Based on several control experiments, it is proposed that a Lewis acid−base interaction between the nitrogen and boron functionality guides the para selectivity via a steric shield for the aromatic aldimines, where Bpin acts as a transient directing group. However, the steric shield of the in situ generated N−Bpin moiety controlled the overall selectivity for the para borylation of benzylamines.