Structure-activity Relationship Research Articles

Design, synthesis and biological evaluation of novel benzocoumarin derivatives as potent inhibitors of MAO-B activity

The continued research of novel reversible inhibitors targeting monoamine oxidase (MAO) B remains crucial for effectively symptomatic treatment of Parkinson’s disease. In this study we synthesized and evaluated a new series of 3-aryl benzo[g] and benzo[h] coumarin derivatives as MAO-B inhibitors. Compound A6 has been found to display the most potent inhibitory activity and selectivity against the MAO-B isoform (IC50 = 13 nM and SI = >7693.31 respectively). Inhibition mode of A6 on MAO-B was predicted as mixed reversible inhibition with a Ki value of 3.274 nM. Furthermore, in order to elaborate structure–activity relationships, the binding mode of A6 was investigated by molecular docking simulations.

Electrochemical C-O and C-N Arylation using Alternating Polarity in Flow for Compound Libraries.

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure-activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale-transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C-X arylation (X = NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across > 30 aryl halide scaffolds, diverse amines (including electron-deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C-X arylation compound libraries using flow electrochemistry.

Adjusting the Structure-Activity Relationship of MOFs to Obtain Electrocatalysts with Higher Hydrogen Evolution and Urea Oxidation Performance by Introducing Different Linkers.

Three kinds of metal-organic frameworks possessing analogous structures were prepared by regulating the structure units of organic linkers. MOF/nickel foam electrocatalysts were formed by in situ hydrothermal growth of MOFs on a clean supported substrate nickel foam (NF), and the corresponding composites were prepared. We phosphatated them and obtained the heterojunction catalyst. Different structure units in the ligand have significant influences on the phosphating, resulting in heterogeneous materials that are not quite the same. Among them, heterogeneous materials with Co2P and NiP have the best catalytic performance. We also studied the urea oxidation reaction (UOR) properties of the materials and proved that it is feasible to improve the UOR performance of MOF/NF composites by regulating the structure units in the organic linkers. The results provided an idea for the reasonable selection of organic ligands to construct MOFs to regulate the electrocatalytic performance.

Weak magnetic field for enhanced degradation of sulfamethoxazole by the CoFe2O4/PAA system: Insights into performance and mechanism

In this work, a novel approach coupling a heterogeneous weak magnetic field (WMF) with the CoFe2O4/peroxyacetic acid (PAA) system was employed to enhance the degradation of sulfamethoxazole (SMX). Under the optimized conditions of 50 mT WMF, 0.1 g/L CoFe2O4, 0.2 mM PAA, and initial pH 6.0, a complete degradation of 10 μM SMX was achieved in 25 min, exhibiting a high synergistic coefficient of 1.61. This result indicates a significant synergistic effect among WMF, CoFe2O4, and PAA in effectively degrading SMX. The introduction of WMF did not alter the pH application range of the CoFe2O4/PAA system. Furthermore, the degradation efficiency of SMX by the CoFe2O4/PAA/WMF system was significantly reduced in the presence of humic acid (HA) and bicarbonate ions (HCO3−), while chloride ions (Cl−) exhibited a minor inhibitory effect. Quenching experiments and electron paramagnetic resonance (EPR) analysis reveal that WMF did not alter the types of reactive oxygen species (ROS) generated in the CoFe2O4/PAA system. The degradation of SMX in the CoFe2O4/PAA/WMF system involved both radical (CH3C(O)O∙ and CH3C(O)OO∙) and non-radical (1O2) oxidation pathways, driven by the redox cycling between ≡Co2+/≡Co3+ and PAA, as well as the rapid adsorption and transformation of oxygen (O2) at oxygen vacancies (OV), respectively. The presence of WMF enhanced the utilization of PAA by CoFe2O4 by improving the convection and mass transport in the solution, facilitating the formation of superoxide anion (O2∙−) and supplemented lattice oxygen (O2−) through the directional migration of paramagnetic O2 towards the CoFe2O4 surface, thus significantly promoting ROS formation. Additionally, the degradation pathways of SMX in the CoFe2O4/PAA/WMF system were proposed based on density functional theory (DFT) calculations and the detected transformation products (TPs). The toxicity of SMX was effectively reduced, as verified by predictions from the Ecological Structure-Activity Relationship Model (ECOSAR) procedure. The excellent catalytic performance, reusability, and effective degradation of various organic pollutants demonstrated by the CoFe2O4/PAA/WMF system suggest its potential as a promising strategy for water treatment.

Discovery of glycosidated glycyrrhetinic acid derivatives: Natural product-based soluble epoxide hydrolase inhibitors

There are few reports on soluble epoxide hydrolase (sEH) structure-activity relationship studies using natural product-based scaffolds. In this study, we discovered that C-30 urea derivatives of glycyrrhetinic acid such as 33, rather than C-20/C-3 urea derivatives, possess in vitro sEH inhibitory capabilities. Furthermore, we explored the impact of stereoconfigurations at C-3 and C-18 positions, and glycosidic bonds at the 3-OH on the compound's activity. Consequently, a glycoside of 33, specifically 49Cα containing alpha-oriented mannose, exhibited promising in vivo efficacy in alleviating carrageenan-induced paw edema and acetic acid-induced writhing. Meanwhile, 49Cα demonstrated potential in mitigating acute pancreatitis by modulating the ratios of anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory dihydroxyeicosatrienoic acids (DHETs). The co-crystal structure of sEH in complex with 49Cα revealed that the N-tetrahydropyranylmethylene urea hydrogen bonded with the residues within the sEH tunnel, contrasting with the mannose component that extended beyond the tunnel's confines. Our findings highlight 49Cα (coded LQ-38) as a promising candidate for anti-inflammatory and analgesic effects, and pave the way for the future rational design of triterpenoid-based sEH inhibitors.

Molten-salt-chemistry-assisted synthesis of heterostructured g-C3N4/BiOI nanocomposites with enhanced sunlight absorption properties for efficient solar-to-chemical energy conversion

The g-C3N4 nanosheets coupled BiOI (g-C3N4/BiOI) nanocomposites with unique heterojunction structure and excellent wide-spectrum sunlight absorption properties have been developed via molten-salt-chemistry-assisted strategy. The heterostructured g-C3N4/BiOI shows enhanced solar to the thermal effect, improved electron mobility and carrier lifetime for efficient photocatalytic dye degradation. The engineered g-C3N4/BiOI catalyst exhibits outstanding photocatalytic activity for methyl orange (MO) removal with 100 % degradation conversion and excellent stability under solar light irradiation, which is respectively 2.69 and 1.27 times higher than those of g-C3N4 and BiOI counterparts. The broad scope toward other dyes degraded by g-C3N4/BiOI and the generality of the molten-salt-chemistry-assisted strategy for synthesizing g-C3N4/BiOCl and g-C3N4/BiOBr with considerable photodegradation efficiency are proved. The analysis of kinetic behaviors, electron spin resonance, and nanosecond transient absorption spectra for structure-activity relationship, key intermediate of •O2− species, and excited state lifetime of g-C3N4/BiOI heterojunction material in the photocatalytic MO degradation processes are also demonstrated.

Bakuchiol and their Derivatives: Unveiling its Chemistry, SAR, Pharmacological Marvels and Therapeutic Odyssey

Bakuchiol, a meroterpene natural product found in various plants, exhibits diverse biological activities, notably anticancer properties. Researchers have synthesized numerous analogs targeting different positions, such as alcoholic OH, ethenyl, and isopropylidene groups within bakuchiol, aiming to enlighten potent therapeutic agents with enhanced pharmaceutical characteristics. The review aims to focus on the extensive potential of the bioactive molecule, bakuchiol describing SAR that may lead to the development of a variety of bakuchiol derivatives. Literature survey has been carried out to determine the potential of bakuchiol and its derivatives. This review comprehensively outlines the biosynthesis, isolation, patent, and clinical studies of bakuchiol, and pharmacological potential of bakuchiol derivatives documented to date. Additionally, it explores the structure-activity relationships observed in its derivatives. Collectively, findings from various studies underscore the significant potential of bakuchiol and its derivatives in the development of potent anticancer and other therapeutic agents. Ultimately, this review serves as a valuable resource for researchers interested in both the chemistry and biology of bakuchiol, offering insights into its multifaceted applications and paving the way for further exploration in this field.

Exploring the Role of Titanate Perovskites in the Oxidation of Amines to Imines via Photocatalysis.

Considering that structural differences could affect the photocatalytic efficiency of titanate perovskites, cubic SrTiO3 (STO) and tetragonal CaTiO3 (CTO) were synthesised as models to elucidate the structure-activity relationship. STO and CTO materials were produced through hydrothermal approaches, adjusting parameters such as temperature and pressure to optimise material purity. Among the perovskite photocatalysts, two stand out for their exceptional photocatalytic capacity and crystalline purity: CaTiO3, prepared at 180 ºC for 36 h, and SrTiO3, synthesised at 200 ºC for 24 h. Notably, we explore the selective ability of these materials for the photocatalytic oxidative self-coupling of benzylamine (BZA) to produce N-benzylidenebenzylamine (BZI), with CaTiO3 emerging as the most efficient catalyst for this reaction. The CTO material prepared at 180 ºC for 36 h (CTO180T-36) achieved a peak BZI production of 0.5 mM, with a total conversion of BZA after 7 h of irradiation. This study also emphasises the crucial role of reaction conditions and perovskite morphologies in fine-tuning photocatalytic performance. These findings highlight opportunities for developing efficient and selective photocatalytic processes, holding the compromise for applications in organic synthesis and sustainable green chemistry.

Efficiency and mechanistic insights of photocatalytic degradation and sterilization utilizing g-C3N4/WO3-x Z-scheme heterojunction under full-spectrum light

Designing highly efficient full-spectrum responsive Z-scheme heterojunction for wastewater decontamination and disinfection is urgently essential. Herein, a novel Z-scheme g-C3N4/WO3-x heterojunction was successfully synthesized by a facile wet impregnation method for the highly efficient photocatalytic degradation and sterilization. Benefiting from the accelerated charge separation, broadened light absorption to near infrared region, and appropriate band energy, optimized g-C3N4/WO3-x heterojunction exhibited photocatalytic degradation of 86.3 % and 97.4 % tetracycline in 2 h under visible light and full-spectrum light, respectively. Meanwhile, 6.5-log of Escherichia coli strains could also be inactivated by optimized g-C3N4/WO3-x heterojunction within 45 min and 15 min under visible light and full-spectrum light, respectively. Impressively, it also exhibited desirable anti-interference ability and satisfying photocatalytic degradation capacity with various key experimental parameters. The plausible degradation pathways of TC and the main active species involved in the photocatalysis were investigated based on liquid chromatography-mass spectrometer (LC-MS) and electron paramagnetic resonance (EPR) analysis. Mineralization process of TC was further confirmed by three-dimensional fluorescence spectra (3D EMMs). Besides, Toxicity Estimation Software Tool (T.E.S.T.) and Ecological Structure-Activity Relationships (ECOSAR) program were applied to predict the noxiousness of TC and its potential intermediates. The results suggested that the excitotoxicity of intermediates generally decreased relative to the pristine TC. Finally, we propose a plausible enhancement mechanism of photocatalytic degradation and sterilization. This work sheds a new light on the design of novel full-spectrum responsive Z-scheme heterojunction for environmental remediation.

A spectroscopic study on the Amyloid-βinteraction with clicked peptide-porphyrin conjugates: a vision toward the detection of Aβpeptides in aqueous solution.

Alzheimer's disease (AD) is a multifactorial form of dementia mainly affecting people in the elderly, but no effective cure is available. According to the amyloid hypothesis the aggregation of Amyloid-β (Aβ) into oligomeric toxic species is believed to concur with the onset and progression of the disease heavily. By using a click chemistry approach, we conjugated a suitable designed peptide sequence to a metalloporphyrin moiety to obtain three hybrid peptide systems to be studied for their interact ion with Amyloid-β peptides. The aim is to get new tools for the diagnosis and therapy in AD. The results described in this study, which were obtained through spectroscopic techniques (UV-Vis, CD, Bis-Ans and intrinsic porphyrin Fluorescence), Microfluidics (GCI) and cell biology (MTT, Live cell imaging and flow cytometry), reveal interesting features about the structure-activity relationships connecting these conjugates with the interaction with Aβ, as well as on their potential use as sensing systems. In our opinion the data reported in this paper make the porphyrin-peptide conjugates highly compelling for further exploration as spectroscopic probes to detect Aβ biomarkers in biological fluids.

Larvicidal activity, molecular docking, and molecular dynamics studies of 7-(trifluoromethyl)indolizine derivatives against Anopheles arabiensis.

A novel series of 7-(trifluoromethyl)indolizine derivatives (4a-4n) was synthesized using a 1,3-Dipolar cycloaddition reaction. Structure elucidation of the synthesized compounds was done using various spectroscopic techniques. Compounds were assessed for their larvicidal activity against Anopheles arabiensis. Exposure of Anopheles arabiensis larvae to a series of 7-(trifluoromethyl)indolizine at 4µg/mL for 24 and 48h resulted in moderate to high larval mortality rates. Among them, compounds 4b, 4a, 4g, and 4m exhibited the most promising larvicidal activities, with mortality rates of 94.4%, 93.3%, 80.00%, and 85.6%, respectively, compared to controls, Acetone and Temephos. The structural activity relationship analysis of the evaluated compounds revealed that substitution with halogens or electron-withdrawing groups (CN, F, Cl, Br) at the para position of the benzoyl group is crucial for achieving promising larvicidal activity. Molecular docking studies were carried out involving six potential larvicidal target proteins to predict how the tested compounds might work. Compounds 4a and 4b showed strong binding to the Mosquito Juvenile Hormone-Binding Protein (5V13). Molecular dynamics (MD) simulations confirmed the stability of the protein-ligand complexes over the simulation period, reinforcing the reliability of the docking results. Compounds 4a and 4b also exhibited favourable ADMET profiles, showing high oral bioavailability, good permeability, moderate distribution, low plasma protein binding, sufficient metabolic stability, efficient renal clearance and low toxicity. Given the crucial role of Juvenile Hormone in regulating gene expression and developmental pathways through receptor interactions, compounds 4a and 4b show promise as inhibitors of this protein. Inhibiting this process could hinder larval growth and reproduction, presenting a promising approach for early-stage mosquito larvicidal activity. Therefore, compounds 4a and 4b represent lead candidates for further optimization and the development of new larvicidal agents.

Research on microscopic structure–activity relationship of AP particle–matrix interface in HTPB propellant

Abstract The matrix and particle interface of hydroxyl-terminated polybutadiene (HTPB) propellant is the weakest part of its mechanical properties, making it prone to dewetting damage and destroying the structural integrity of the propellant. This article uses nano-indentation, gas cluster ion beam etching, and X-ray photoelectron spectroscopy experimental analyses to study the physicochemical properties of the interface and subsequently construct a microscopic model for the HTPB matrix and ammonium perchlorate particle interface. The model fully considers the existing forms of curing agent toluene diisocyanate, bonding agent Tris (2-methyl-aziridine) phosphine oxide (MAPO), and the aging products of the propellant in the interface structure. Meanwhile, the physicochemical properties, mechanical properties, and adhesive properties of the interface under different tensile loading conditions were analyzed. The results indicate that the bonding agent MAPO significantly enhances the mechanical and adhesive properties of the interface. The interface is sensitive to changes in temperature and tensile rate, and the aged interface is more fragile.

Construction of One-Dimensional Covalent-Organic Framework Coordinated with Main Group Metals for Selective Electrochemical Synthesis of H2O2.

Covalent-organic frameworks (COFs) are promising electrocatalysts for the selective synthesis of H2O2 through the two-electron oxygen reduction reaction (2e- ORR). However, the design and synthesis of efficient and stable COF-based electrocatalysts is still challenging. In this work, a predesigned 1,10-phenanthroline-based one-dimensional COF (PYTA-PTDE-COF) was constructed to anchor main group metal (In, Sn, and Sb) as electrocatalysts toward 2e- ORR. The catalysts are featured with fully exposed metalated side chains. Structural characterization revealed that PYTA-PTDE-M's (M = In, Sn, and Sb) are all quite similar, except for the coordinated metal ions with the maintenance of good crystallinity. They all exhibited satisfying activity and selectivity toward 2e- ORR under alkaline conditions. Among them, PYTA-PTDE-Sb exhibited the best performance (Eonset is 0.765 V, the H2O2 selectivity is 96%, and the yield rate is 209.2 mmol gcat-1 h-1). Moreover, it also delivered superior stability with almost no attenuation of current density during the long-time test. Theoretical calculations revealed that the Sb metal site in the COFs has the lowest adsorption strength of *OOH, which could be the main reason for its superior selectivity. The PYTA-PTDE-Sb assembled zinc-air battery realizes not only the supply of clean energy but also the production of green chemicals, showing it is highly promising in practical applications. This work offers an example for designing main group metal-coordinated 1D COFs and reveals fundamental structure-activity relationship toward 2e- ORR.

Development of Tetrahydroquinoline-Based Inhibitors for Chronic Pain.

Chronic pain affects a substantial portion of the population, posing a significant health challenge. Current treatments often come with limitations and side effects, necessitating novel therapeutic approaches. Our study focuses on disrupting the Cav3.2-USP5 interaction as a strategy for chronic pain management. Through structure-activity relationship studies of a tetrahydroquinoline (THQ) scaffold, we identified a family of lead molecules that demonstrated potent inhibition of the Cav3.2-USP5 interaction. In vitro pharmacokinetic assessments and in vivo studies support the efficacy and drug-like properties of the lead compounds in mouse models of acute and chronic pain. Dependence on the Cav3.2 channels was validated in Cav3.2 null mice, consistent with the proposed mode of action of these small molecules. These findings provide a novel chronic pain treatment strategy, highlighting the potential of these small molecules for further development.

Discovery of new acetamide derivatives of 5-indole-1,3,4-oxadiazol-2-thiol as inhibitors of HIV-1 Tat-mediated viral transcription.

Human immunodeficiency virus-1 (HIV-1) encodes a transcriptional factor called Tat, which is critical for viral transcription. Tat-mediated transcription is highly ordered apart from the cellular manner; therefore, it is considered a target for developing anti-HIV-1 drugs. However, drugs targeting Tat-mediated viral transcription are not yet available. Our high-throughput screen of a compound library employing a dual-reporter assay identified a 1,3,4-oxadiazole scaffold against Tat and HIV-1 infection. Furthermore, a serial structure-activity relation (SAR) study performed with biological assays found 1,3,4-oxadiazole derivatives (9 and 13) containing indole and acetamide that exhibited potent inhibitory effects on HIV-1 infectivity, with half-maximal effective concentrations (EC50) of 0.17 (9) and 0.24 µM (13), respectively. The prominent derivatives specifically interfered with the viral transcriptional step without targeting other infection step(s) and efficiently inhibited the HIV-1 replication cycle in the T cell lines and peripheral blood mononuclear cells infected with HIV-1. Additionally, compared to the wild type, the compounds exhibited similar potency against anti-retroviral drug-resistant HIV-1 strains. In a series of mode-of-action studies, the compounds inhibited the ejection of histone H3 for facilitating viral transcription on the long-terminal repeat (LTR) promoter. Furthermore, SAHA (a histone deacetylase inhibitor) treatment abolished the compound potency, revealing that the compounds can possibly target Tat-regulated epigenetic modulation of LTR to inhibit viral transcription. Overall, our screening identified novel 1,3,4-oxadiazole compounds that inhibited HIV-1 Tat, and subsequent SAR-based optimization led to the derivatives 9 and 13 development that could be a promising scaffold for developing a new class of therapeutic agents for HIV-1 infection.

Oxidation Potential of 2,6-Dimethyl-1,4-dihydropyridine Derivatives Estimated by Structure Descriptors

Linear relationships, expressing the electrochemical properties of molecules as functions of structure, give insight into the associated electrochemical process and are a tool for prediction. Many biological activities rely on water-based dissociation, making electrochemical properties a bridge between structure and activity. Motivated by a previous study, a replica is made here on a different dataset in order to validate/invalidate the previously reported results. There are several methods for obtaining structure-based descriptors. Some of the methods have been devised to account for molecular topology, some to account for molecular geometry, and others to account for both. Two methods are involved here to derive structure-based descriptors and further obtain structure–property relationships (FMPI and ChPE). In order to express structure descriptors, both FMPI and ChPE express first the topology of the molecule, using the heavy atoms identity matrix and the heavy atoms adjacency matrix, both square symmetric matrices in the belief that symmetry is one major factor of molecular stability. A set of 2,6-dimethyl-1,4-dihydropyridine derivatives with oxidation peak potentials and coulometrically determined number of electrons experimental data is subjected to the search for structure–activity relationships. Even if the 2,6-dimethyl-1,4-dihydropyridine is a symmetric compound (of Cs point group), their derivatives are generally not symmetric (9 out of 24 are asymmetric). The dataset is subjected to descriptive and inferential statistics in order to filter out the most relevant structure–activity relationship. The geometry is built using three levels of theory (one from molecular mechanics and two others from density functionals, of which one accounts for the interaction with water as solvent). One challenge of picking one out of two reported measured values is dealt with by calculating the likelihood associated with the two choices. Relevant structure–activity models are extracted and discussed. The use of in vivo (in water, SM8 model) models in geometry optimization (from MMFF94 and B3LYP and to M06 + Water SM8) results in a precision gain, but this is, in most of the cases, not statistically significant, and this can be considered a negative result.

Synthesis of para‐Carboxamidostilbene Derivatives as Antihyperglycemia Agents and Their In Silico ADMET and Molecular Docking Studies

AbstractIn this project, para‐carboxamidostilbene derivatives were synthesized using the Heck coupling reaction, confirmed through various analytical techniques such as FT‐IR, HRMS, and NMR analyses, and tested in vitro to evaluate their α‐amylase inhibitory activity. In silico molecular docking was employed to model the binding interactions of compounds with α‐amylase. Pharmacokinetic properties (ADME) and drug‐likeness were also examined. Structure activity relationship (SAR) analysis was conducted to establish the relationship between the chemical structure and α‐amylase inhibitory activity. The synthesized compounds exhibited significant α‐amylase inhibitory activity with IC50 values ranging from 15.0 to 37.5 µM in comparison with acarbose (IC50 = 30.2 ± 1.9 µM). Among them, compounds 6d–6f and 7c–7f demonstrated promising inhibitory activity. Furthermore, molecular docking studies revealed strong interactions between the studied molecules and the α‐amylase binding pocket. The drug‐likeness prediction results indicated that all synthesized compounds adhered to Lipinski's rule of five, suggesting their suitability as drug‐like molecules. Additionally, the assessment of ADMET properties indicated favorable absorption profiles, particularly in terms of human intestinal absorption (HIA). Overall, this study successfully identified several para‐carboxamidostilbene derivatives as potential α‐amylase inhibitors for the treatment of T2DM.

Single-Stranded Hairpin Loop RNAs (loopmeRNAs) Potently Induce Gene Silencing through the RNA Interference Pathway.

Synthetic small interfering RNAs conjugated to trivalent N-acetylgalactosamine (GalNAc) are clinically validated drugs for treatment of liver diseases. Incorporation of phosphorothioate linkages and ribose modifications are necessary for stability, potency, and duration of pharmacology. Although multiple alternative siRNA designs such as Dicer-substrate RNA, shRNA, and circular RNA have been evaluated in vitro and in preclinical studies with some success, clinical applications of these designs are limited as it is difficult to incorporate chemical modifications in these designs. An alternative siRNA design that can incorporate chemical modifications through straightforward synthesis without compromising potency will significantly advance the field. Here, we report a facile synthesis of GalNAc ligand-containing single-stranded loop hairpin RNAs (loopmeRNAs) with clinically relevant chemical modifications. We evaluated the efficiency of novel loopmeRNA designs in vivo and correlated their structure-activity relationship with the support of in vitro metabolism data. Sequences and chemical modifications in the loop region of the loopmeRNA design were optimized for maximal potency. Our studies demonstrate that loopmeRNAs can efficiently silence expression of target genes with comparable efficacy to conventional double-stranded siRNAs but reduced environmental and regulatory burdens.

Synthetic Routes to 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amines: Cross-Coupling and Challenges in SEM-Deprotection

7-Azaindoles are compounds of considerable medicinal interest. During development of the structure–activity relationship for inhibitors of the colony stimulated factor 1 receptor tyrosine kinase (CSF1R), a specific 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine was needed. Two different synthetic strategies were evaluated, in which the order of the key C-C and C-N cross-coupling steps differed. The best route relied on a chemoselective Suzuki–Miyaura cross-coupling at C-2 on a 2-iodo-4-chloropyrrolopyridine intermediate, and subsequently a Buchwald–Hartwig amination with a secondary amine at C-4. Masking of hydroxyl and pyrroles proved essential to succeed with the latter transformation. The final trimethylsilylethoxymethyl (SEM) deprotection step was challenging, as release of formaldehyde gave rise to different side products, most interestingly a tricyclic eight-membered 7-azaindole. The target 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine (compound 3c) proved to be 20-fold less potent than the reference inhibitor, confirming the importance of the N-3 in the pyrrolopyrimidine parent compound for efficient CSF1R inhibition.

Biocompatible Flash Chemiluminescent Assay Enabled by Sterically Hindered Spiro-Strained-Oxetanyl-1,2-Dioxetane.

Chemiluminescence is the emission of light that occurs as a result of a chemical reaction. Depending on the rate of chemiexcitation, light emission can occur as a long-lasting,glow-type reaction or a rapid, highly intense flash-type reaction. Assays using a flash-type mode of action provide enhanced detection sensitivity compared to those using a glow-type mode. Recently, our group discovered that applying spiro-strain to 1,2-dioxetanes significantly increases their chemiexcitation rate. However, further examination of the structure-activity relationships revealed that the spiro-strain severely compromises the chemical stability of the 1,2-dioxetanes. We hypothesized that a combination of spiro-strain, steric hindrance, and an electron-withdrawing effect, will result in a chemically stable spiro-strained dioxetane with an accelerated chemiexcitation rate. Indeed, spiro-fused tetramethyl-oxetanyl exhibited a 128-fold faster chemiexcitation rate compared to adamantyl while maintaining similar chemical stability, with a half-life of over 400 hours in PBS 7.4 buffer at room temperature. Turn-on probes composed of tetramethyl-oxetanyl spiro-dioxetane exhibited significantly improved chemical stability in bacterial and mammalian cell media compared to previously developed dioxetane probes fused to a cyclobutyl unit. The superior chemical stability enables a tetramethyl-oxetanyl dioxetane probe to detect β-galactosidase activity with enhanced sensitivity in E. coliassays and leucine aminopeptidase activity in cancer cells.