2-substituted Derivatives Research Articles

Design, Synthesis and Anti-Inflammatory Evaluation of 3-Substituted 5-Amidobenzoate Derivatives as Novel P2Y14 Receptor Antagonists via Structure-Guided Molecular Hybridization.

The P2Y14R is activated by UDP and UDP glucose and is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y14R antagonists and the crystallographic overlap study between PPTN and compound IV, a series of 3-substituted 5-amidobenzoate derivatives were designed, synthesized, and identified as promising P2Y14R antagonists. The optimal compound 45 (methyl 3-(1H-benzo[d]imidazol-2-yl)-5-(2-(p-tolyl) acetamido)benzoate, IC50 = 0.70 ± 0.01 nM) showed a strong binding ability to P2Y14R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In the LPS-induced acute lung injury model, compound 45 demonstrated significant anti-inflammatory efficacy, effectively mitigating the pulmonary infiltration of immune cells and inflammatory response through suppressing the NLRP3 signaling pathway. Thus, 45 with potent P2Y14R antagonistic activity, in vitro and vivo efficacy, and favorable druggability can be a strategy for treating acute lung injury and can be optimized in further studies.

Development of a Buchwald-Hartwig Amination for an Accelerated Library Synthesis of Cereblon Binders.

In recent years, targeted protein degradation (TPD) has emerged as a powerful therapeutic modality utilizing both heterobifunctional ligand-directed degraders (LDDs) and molecular glues (e.g., CELMoDs) to recruit E3 ligases for inducing polyubiquitination and subsequent proteasomal degradation of target proteins. The immunomodulatory drugs lenalidomide and pomalidomide bind to cereblon (CRBN), a substrate receptor of the CRL4A E3 ligase complex, to initiate degradation of neosubstrates critical for cell survival. Recently, nonlenalidomide or pomalidomide CRBN binders, known as alternate glutarimides, have gained popularity, offering potential degraders with varying physicochemical properties. Specifically, 3-substituted indazole derivatives have emerged as potent CRBN binders. We developed conditions for the direct cross-coupling of unprotected glutarimides with amines, streamlining the synthesis of alternative CRBN binders. This manuscript describes the rapid synthesis of 30 CRBN binders, their characterization as potential degraders and a cryo-EM structure of the CRBN/DDB1 with a representative compound (6).

One Step Synthesis of 4,6,8-Trimethoxyazulenes - as Building Block for 2-Functionalized Azulenes.

Here we present a simple gold-catalyzed one-pot reaction of easily available diarylbutadiynes, with trimethoxybenzene as solvent and reactant to synthesize 4,6,8-trimethoxyazulenes. The methoxy substituents, which render the azulene very electron-rich, enable a change of azulenes typical regioselectivity for electrophilic substitutions, which enables facile electrophilic 2-substitution with iodine, bromine, chlorine, selenium or sulfur. Especially the 2-haloazulenes which can usually only be obtained through lengthy multistep syntheses are valuable building blocks for the synthesis of 2-substituted azulene derivatives.

L-Amino acid ester as a biomimetic reducing agent for the reduction of unsaturated CC bonds.

The first example of an efficient protocol for the reduction of disubstituted methyleneindolinones, isoindigos and tetrasubstituted olefins for the synthesis of 3-substituted 2-oxindoles, dihydroisoindigos and tetrasubstituted ethane derivatives using an L-amino acid ester as an attractive biomimetic reducing agent has been developed. This new protocol has the advantages of mild reaction conditions without the need for any metal catalysts, a broad substrate scope (31 examples), excellent yields (90-98%) and good functional group tolerance, providing an operationally simple and practically useful methodology for reductive reactions. The L-amino acid derivative, which is cheap, nontoxic and easy to handle, serves as a new biomimetic reducing agent for use in organic chemistry, providing a novel and promising approach for future applications in reductive reactions.

In vitro and in vivo Investigations of 4-Substituted 2-Phenylquinazoline derivatives as multipotent ligands for the treatment of Alzheimer's disease.

The pathology of Alzheimer's disease (AD) is complex due to its multifactorial nature and single targeting drugs proved inefficient. A series of novel 4-N-substituted-2-phenylquinazoline derivatives was designed and synthesized as potential multi-target directed ligands (MTDLs) through dual inhibition of AChE and MAO-B enzymes along with Aβ42 aggregation inhibition for the treatment of AD. Two compounds in the series, VAV-8 and VAV-19 were found to be the most potent inhibitors of both AChE and MAO-B enzymes and moderate inhibitor of Aβ42, with good thermodynamic stability at the binding pocket of the enzymes. Both the ligands showed moderate ROS inhibition and neuroprotection potential and found to be permeable to the blood-brain barrier. Furthermore, VAV-8 was subjected to toxicity evaluation and in vivo investigation using a zebrafish model. In adult zebrafish, VAV-8 (5μM, and 10μM) was found to be effective in reducing cognitive deterioration, neurodegeneration, and oxidative stress induced by scopolamine. Thus, these quinazoline derivatives have the potential to be developed as MTDLs for the treatment of Alzheimer's disease.

Deep eutectic solvent as a green catalyst for the one-pot multicomponent synthesis of 2-substituted benzothiazole derivatives.

The need for diverse essential chemicals and resources has markedly risen alongside the advancement of civilization. Regrettably, many toxic solvents used in chemical laboratories and industrial settings pose significant risks to the health of researchers and intensify environmental pollution. Deep eutectic solvents (DESs), serving as an alternative to ionic liquids, provide superior environmental benefits and have garnered significant interest in chemical research. DESs have garnered increasing interest in the field of chemistry for their use as catalysts and solvents. Benzothiazole is an organic molecule with a heterocyclic nucleus (thiazole) that possesses a wide range of biological activities. In this study, we established [CholineCl][Imidazole]2 as an efficient catalyst for the one-pot multicomponent synthesis of 2-substituted benzothiazole derivatives using conventional heating under solvent-free conditions. Its reactivity remains stable with a maximum yield of 78% for 2-phenylbenzo[d]thiazole, and using a solvent that is both environmentally safe and compatible with the reusability of the [CholineCl][Imidazole]2 catalyst, the reaction time can be effectively decreased.

Synthesis of 3-Substituted Indoles by Yonemitsu Three-Component Reactions Accelerated in Microdroplet/Thin Film.

3-Substituted indoles are an important framework of many drugs, agricultural chemicals, functional materials, and bioactive compounds. Malononitrile-based three-component Yonemitsu reactions are attractive choices for the synthesis of 3-substituted indole derivatives but suffered from long reaction time and harsh conditions (e.g., elevated temperature and special catalysts/solvents) in conventional conversions. In this study, we developed a metal-free, efficient, mild, and wide microdroplet/thin-film method to construct 18 3-substituted indoles from various substituted aromatic aldehydes and indoles with good reaction yields (42-69%) and fantastic reaction acceleration (1.32 × 103 rate acceleration factor relative to the bulk reaction). By spraying 0.8 mol L-1 reactants at 300 μL min-1, the rate of the microdroplet/thin film product was scaled up to 1.72 g h-1. Overall, the microdroplet/thin-film method offered several advantages including high efficiency, mild conditions, wide scope, and gram-scale ability, making it attractive for synthesizing 3-substituted indoles under the requirements of sustainable chemistry.

Photoinduced Regioselective Decarbonylative and Decarboxylative C-O Bond Functionalizations: Approach toward Chemoselective Scissions of Isatoic Anhydride and Unraveling the Enroutes through Control Experiments and DFT Studies.

Distinctive, green, innovative, and well-organized photoinduced (metal- or photocatalyst-free) regioselective decarbonylative and decarboxylative C-O bond functionalization protocols to access aryl 2-aminobenzoates and 2-substituted benzoxazinone derivatives in excellent yields have been devised. These are achieved through the chemoselective scission of isatoic anhydride with ketones, diaryliodonium triflate, nitroalkene, phthalazinone, and phenol derivatives, which, in turn, served as the representative "electrophilic and nucleophilic" coupling partners. Control experiments and DFT calculations reveal that electrophilic radical-bearing coupling partners specifically follow the decarbonylation pathway, while nucleophilic radical-bearing conjugates facilitate the decarboxylation process. Thus, the devised methods represent the chemoselective fragmentation of isatoic anhydride, which occurs due to the electronic nature of the coupling partners. Again, the regioselective C-O/O-C bond formation is also a novel outcome of this methodology. We have also devised a green method for synthesizing 2-aminobenzoate-subtituted paracetamol through a decarboxylation route. A fluorescence quenching study indicates that phenyl 2-aminobenzoate specifically detects Fe(II) ions, exhibiting no reactivity toward various other metal ions. Additionally, transition-metal-catalyzed C-H bond functionalization of 2-substituted benzoxazinone with phenyl vinyl sulfone was performed at ease with significant yields, which appreciated the strategy developed by us.

Nano-Catalytic Synthesis of 5-Substituted 1H Tetrazole Derivatives and Biological Applications

This review explores the innovative use of nano-catalysts in the synthesis of 5-substituted 1H-tetrazole derivatives, highlighting their significant biological applications. The novel methodologies discussed demonstrate enhanced efficiency and selectivity in the production of these compounds. Key findings include the optimization of reaction conditions and the discovery of new catalytic pathways that improve yield and reduce reaction time. The synthesized tetrazole derivatives exhibit strong potential as therapeutic agents due to their biological activity. This work provides a comprehensive overview of the state-of-the-art techniques in nano-catalytic synthesis, emphasizing their practical applications in medicinal chemistry and materials science.

Synthesis, crystal structure, spectroscopic characterization, DFT calculations, Hirshfeld surface analysis, biological activity studies, molecular docking investigation, and ADMET properties evaluation of a novel 3-substituted coumarin derivative

In this paper, the title compound was synthesized by nucleophilic substitution and Schiff base reaction from 4-Hydroxycoumarin as the starting material. 2-({1-[(3E)-2,4-dioxo-3,4-dihydro-2H-chromen-3-ylidene]ethyl}amino)benzoic acid was designed and synthesized, and the structure was characterized by spectroscopic techniques including UV–vis, FT-IR, 1H NMR, 13C NMR and MS. The single crystal structure of the target molecule was confirmed by X-ray diffraction and showed intermolecular O-H…O, C-H…O hydrogen bonding which was the most important factor in the crystal stacking interaction. The geometrical parameters, molecular electrostatic potential (MEP), and frontier molecular orbital analysis (FMOs) of the molecule are also presented to reveal the physicochemical properties of the investigated compound. In addition, Hirshfeld surface analysis of the title molecule by using crystal information file, a significant contribution (33.6%) to the crystal packing comes from O…H/H…O contacts. Molecular docking study showed that compound has significant binding affinity (ΔG = -54.98 kcal/mol). Additionally, the title compound exhibited MIC values of 4.04, 32.33, and 8.08 μg·mL−1 against S. parauberis, S.aureus, L.garvieae, and E.piscicida, respectively. The results presented herein demonstrate the compound's remarkable efficacy in effectively inhibiting bacterial growth, thereby providing a valuable reference for the biosynthesis of coumarin derivatives and facilitating further exploration of their medicinal potential.

The synthesis and antileukemic activity of 5-substituted thiazolyl urea derivatives

A series of novel 5-substituted thiazolyl urea derivatives were synthesized and evaluated for their efficacy as antileukemic agents against two human leukemic cell lines (THP-1 and MV-4-11). Results showed that the activities of the investigated compounds were quite sensitive to the positions and properties of the aromatic substituents. Among these compounds, compound 12k showed the highest activity with IC50 values of 29 ± 0.3 nM for THP-1 cells and 98 ± 10 nM for MV-4-11 cells.

In Silico and In Vitro Studies of the Biological Activity of 5-Substituted Derivatives of N1-Carboxymethyl-5-Fluorouracil: Potential 5-Fluorouracil Prodrugs

In Silico and In Vitro Studies of the Biological Activity of 5-Substituted Derivatives of N1-Carboxymethyl-5-Fluorouracil: Potential 5-Fluorouracil Prodrugs

Investigation of the ability of 3-((4-chloro-6-methyl pyrimidin-2-yl)amino) isobenzofuran-1(3H)-one to bind to double-stranded deoxyribonucleic acid.

Phthalides represent a notable category of secondary metabolites that are prevalent in various plant species, certain fungi, and liverworts. The significant pharmacological properties of these compounds have led to the synthesis of a novel phthalide derivative. The current study focuses on investigating the binding interactions of a newly synthesized 3-substituted phthalide derivative, specifically 3-((4-chloro-6-methyl pyrimidine-2-yl)amino) isobenzofuran-1(3H)-one (Z11), with double-stranded deoxyribonucleic acid (dsDNA). Research in the pharmaceutical and biological fields aimed at developing more potent DNA-binding agents must take into account the mechanisms by which these newly synthesized compounds interact with DNA. This investigation seeks to explore the binding dynamics between dsDNA and our compound through a variety of analytical techniques, such as electrochemistry, UV spectroscopy, fluorescence spectroscopy, and thermal denaturation. The binding constant (Kb) of Z11 with DNA was determined using both spectroscopic and voltammetric approaches. The research revealed that Z11 employs a groove binding mechanism to associate with dsDNA. To further explore the interactions between Z11 and dsDNA, the study utilized density functional theory (DFT) calculations, molecular docking, and molecular dynamics simulations. These analyses aimed to ascertain the potential for a stable complex formation between Z11 and dsDNA. The results indicate that Z11 is situated within the minor groove of the dsDNA, demonstrating the ability to establish a stable complex. Furthermore, the findings imply that both π-alkyl interactions and hydrogen bonding play significant roles in the stabilization of this complex.

Total Synthesis of (-)-Aspidospermidine via an Enantioselective Palladium-Catalyzed Allylic Substitution Strategy.

A total synthesis of (-)-aspidospermidine via an enantioselective Pd-catalyzed allylic substitution strategy is reported. This represents the first application of a Pd-catalyzed allylic substitution with a 3-substituted indole derivative in the synthesis of Aspidosperma alkaloids. In our synthetic route, the allylic substitution reaction was the stereo defining step. The pentacyclic framework was then constructed in a fully diastereoselective sequence. This culminated in the shortest enantioselective synthesis of aspidospermidine reported to date, in seven linear steps.

Sustainable aqueous-mediated one-pot synthesis of 2-hydroxy-5-oxo-5,6,7,8-tetrahydro-4H-chromene and coumarin derivatives using taurine as the green bioorganic catalyst

In this study, two taurine-catalyzed, aqueous-mediated methodologies were reported for the synthesis of 4-aryl-2-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydro-4H-chromen-5-one (3a-j) and 3-substituted coumarin derivatives (3′a-f) under reflux conditions. These methodologies entail the use of substituted aromatic aldehydes, diethyl malonate, and dimedone as reagents for the sustainable synthesis of 2-hydroxy-tetrahydro-4H-chromene derivatives via the Knoevenagel-Michael cascade, as well as the use of substituted salicylaldehyde with diethyl malonate or ethyl 3-oxobutanoate for the efficient synthesis of coumarin derivatives via the Knoevenagel-transesterification reaction. These strategies emphasize environmental sustainability and are designed as one-pot processes, ensuring simplicity and convenience. The methods deliver high yields and are cost-effective, significantly reducing reaction times, enhancing step efficiency, and are successful at the multigram level. Notably, the taurine catalyst demonstrates exceptional reusability, maintaining its activity for up to five cycles without notable degradation. The catalyst is easily recoverable through filtration, and the overall procedure is streamlined, requiring no additional purification steps. These attributes collectively contribute to the green chemistry paradigm by minimizing waste and energy consumption, thus offering a practical and efficient approach to the synthesis of these important organic compounds.

Synthesis, structure, and solution chemistry of mixed-ligand oxidovanadium(IV) complexes incorporating ONO donor hydrazone ligands

Four mixed-ligand oxidovanadium(IV) complexes, [VIVO(L1-4)(phen)], 1-4, incorporating tridentate dibasic ONO donor hydrazone ligands (H2L1-4, general abbreviation H2L) derived from the condensation of 2-picolinyl hydrazide with 2-hydroxy acetophenone and its 5-substituted derivatives as primary ligands and 1,10-phenanthroline (phen) as auxiliary ligand have been synthesized in excellent yields. The complexes were characterized by elemental analyses, magnetic susceptibility measurements, and various spectral (e.g. IR, UV–Vis and EPR) studies. The molecular structure of one of the four complexes has been determined by single-crystal X-ray diffractometry. In 1, the hydrazone ligand is meridionally disposed of, coordinating through one enolic-O, one phenolic-O, and one imine-N. The other basal position is occupied by one pyridine-N of the phen moiety. The axial positions are occupied by one oxido-O atom and the other pyridine-N atom of the phen moiety. The complexes are paramagnetic with one unpaired electron (μeff ≈ 1.73 BM), suggesting no interaction with the neighboring molecules and are EPR active. The complexes display two d-d transitions, one near 725 and the other near 840 nm due to d xy → d xz , d yz and d xy → d x 2 − y 2 transitions, respectively. The other d-d transition associated with d xy → d z 2 transition was not observed as it falls in the UV region, which is masked by highly intense intra-ligand transitions. The complexes display one-electron oxidation peaks in the +0.75 to +0.89 V vs. Ag/AgCl region in the CH3CN solution that show a linear relationship with the Hammett parameter (σ) of the substituents in the aryloxy ring.

Anti-inflammatory Activity of 1-Substituted Glyoxal β-Carboline Derivatives

The anti-inflammatory properties of β-carbolines have been widely studied, highlighting their potential in treating inflammatory disorders. This research investigates the anti-inflammatory activity of selected 1-substituted glyoxal β-carboline derivatives, achieved through a one-step conversion of 5-hydroxy-L-tryptophan with activated glyoxal, without forming tetrahydro-β-carboline (THβC) intermediates. These derivatives (4e-g) were synthesized successfully without requiring expensive metal catalysts, prolonged reaction times, or stringent reaction conditions, and yielded moderate amounts. Our findings indicate that all the derivatives significantly inhibit xanthine oxidase (XO) activity, leading to a reduction in reactive oxygen species (ROS) and free radicals. This inhibition disrupts the inflammatory cascade and attenuates the inflammatory response.

HCO-RLF: Hybrid classification optimization using recurrent learning and fuzzy for COVID-19 detection on CT images

COVID-19 infection detection through initial lesion classification provides early diagnosis and prevents breathing difficulties. Detecting the infectious part of the lungs using computerized tomography (CT) images has become an instantaneous detection method. In this article, a Hybrid Classification Optimization (HCO) using Recurrent Leaning and Fuzzy (RLF) is proposed. The neural network classifies infected and non-infected regions using pixel distributions and their variations. This is performed by identifying missing features and training the recurrent network using regional differences. Based on the feature availability, recurrent learning classifies the region through the input dataset and recurrent training correlation. The fuzzy predicts missing features through substituted derivatives obtained between wide ranges of variations. In this process, the maximum fuzzy derivatives for feature substitution are used for infected region prediction. The least fuzzy derivatives are prevented from the training layer to reduce false rates in region classification. This joint process improves the training consistency to leverage the detection and region classification accuracies. The proposed HCO-RLF improves detection and classification accuracy, and precision by 11.96 %, 9.98 %, and 13.42 % for the varying classification rates. Besides, the results are obtained in comparison with the existing DR-MIL, DSAE, and BS-FSA methods discussed later in the article.

Acute toxicity of salicylic acid and its derivatives on the diatom Phaeodactylum tricornutum: Physico-Biochemical and transcriptomic insights

Salicylate pollutants (SAs) poses a serious threat to marine ecosystems as emerging contaminants. However, the toxic effects of SAs on marine phytoplankton, as well as the potential mechanisms and their ecological risks linked with them, are remain largely unknown. In this study, we aimed to evaluate the toxic effects of salicylic acid (SA) and its 5-substituted derivatives (5-sSA) on the marine diatom Phaeodactylum tricornutum, as well as the potential molecular mechanism involved in the toxicity. Physiological assays conducted on P. tricornutum revealed significant changes in photosynthetic pigments, chlorophyll fluorescence parameters, and antioxidant enzyme activities. The results showed that exposure of P. tricornutum to SAs caused a significant decline in chlorophyll contents and damage to the photosystem II (PSII) core resulting in the decline of photosynthesis. Although the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were enhanced, oxidative damage occurred. Transcriptome analysis showed that a large number of differentially expresses genes (DEGs) were significantly enriched in metabolic pathways such as porphyrin metabolism, terpenoid backbone biosynthesis, and carbon fixation in photosynthetic organisms after SA and 5-BrSA treatments. In addition, key genes in transcriptomic metabolic pathways were further analyzed and validated using weighted correlation network analysis (WGCNA) and real-time fluorescence quantitative PCR (qPCR). Considering the above results, SAs mainly inhibit the processes of photosynthesis by repressing the expression of genes involved in secondary metabolite synthesis and photosynthetic carbon sequestration pathways, thus exerting toxic effects on algal cells. The results of the study will provide key data for understanding the ecological risk and toxicity mechanisms of SA pollutants.

Synergic Effects of Ordered Mesoporous Bifunctional Ionic Liquid: A Recyclable Catalyst to Access Chemoselective N-Protected Indoline-2,3-dione Analogous

SBA-15 and organic ionic liquid were incorporated in a post-grafting technique for generating a bifunctional ionic liquid embedded mesoporous SBA-15. The prepared heterogeneous catalyst was employed for the first time to synthesize N-alkylated indoline-2,3-dione at mild conditions to afford excellent yields in a short reaction time. The synthesized DABCOIL@SBA-15 catalyst was meticulously characterized by various techniques, such as FT-IR, solid-state 13C NMR, solid-state 29Si NMR, small-angle X-ray diffraction (XRD), and N2 adsorption–desorption. Further, the morphological behavior of the catalyst was studied by SEM and TEM. The thermal stability and number of active sites were determined by thermogravimetric analysis (TGA). The Hammett equation was used to analyze the synergetic effect of the catalyst and substituent effects on the N-alkylated products of 5-substituted isatin derivatives, which resulted in a negative slope. This negative slope indicates a positive charge in the transition state. Notably, the DABCOIL@SBA-15 catalyst demonstrated its practicality by being reused for seven cycles with consistently high catalytic activity.