2-substituted Derivatives Research Articles

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.

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.

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.

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.

Synthesis and antiproliferative activity of 7-substituted amide estradiol derivatives

Synthesis and antiproliferative activity of 7-substituted amide estradiol derivatives

Coumarin-Based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors.

A series of 7-substituted coumarin derivatives have been characterized as pan-aldo-keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7-hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3 a possessed IC50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits 'drug-like' metabolic stability and half-life in human and mouse liver microsomes and plasma. Compound 3 a was employed as a chemical tool to determine pan-AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan-AKR1C inhibitors, 3 a demonstrated no radiation sensitization effect in a radiation-resistant prostate cancer cell line model. Pan-AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT-737, daunorubicin or dexamethasone, in two patient-derived T-cell ALL and pre-B-cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT-737 and daunorubicin in the T-cell ALL cell line model. Thus, the inhibitory profile required to enhance chemotherapeutic cytotoxicity in leukemia may be AKR1C isoform and drug specific.

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.

Substituent Effect in Salicylaldehyde 2-Furoic Acid Hydrazones: Theoretical and Experimental Insights into DNA/BSA Affinity Modulation, Antimicrobial and Antioxidant Activity

The biological properties of five aroylhydrazones derived from salicylaldehyde and its 5-substituted derivatives with 2-furoic acid hydrazide were thoroughly investigated. NMR analysis confirmed the predominant existence of the aroylhydrazones in the keto-amine form in aqueous solution. Geometries of these compounds were optimized using density functional theory (DFT) calculations with the B3LYP hybrid functional, while ADMET analysis predicted their pharmacokinetic and toxicological properties. Substituent effects on the interactions between the salicyl aroylhydrazones and BSA and DNA were elucidated through experimental and molecular docking studies, revealing the bromo-substituted hydrazone as the most potent binder to both biomolecular targets. Experimental results aligned well with theoretical predictions, indicating that salicyl hydrazones predominantly act as DNA groove binders. Thermodynamic analysis suggested that the hydrazones predominantly interact with BSA through hydrogen bonding and van der Waals forces. Moreover, antioxidant potential assessment using DPPH, ABTS, FRAP, and metal chelating assays demonstrated the potent antioxidant power of nitro and hydroxy-substituted derivatives. Additionally, the antimicrobial properties of hydrazone against Gram-positive and Gram-negative bacteria, as well as fungi, were thoroughly explored, highlighting the nitro derivative as the most prominent candidate with broad-spectrum antimicrobial potential.

Investigation into the Sonodynamic Activity of Three Newly Synthesized Derivatives of Ciprofloxacin.

Sonosensitizers play a crucial role in the efficacy of sonodynamic antitumor therapy (SDT) and sonodynamic antimicrobial chemotherapy (SACT), highlighting the necessity for the development of new compounds with good sonodynamic activity. In this study, three novel 3-substituted ciprofloxacin derivatives (CIPD1, CIPD2, and CIPD3) were designed and synthesized. Their sonodynamic activities were evaluated by assessing the damage to bovine serum albumin (BSA) and Escherichia coli (E. coli). Furthermore, the potential mechanism underlying their sonodynamic damage activities was investigated by detecting reactive oxygen species (ROS) under ultrasound irradiation (US). The results demonstrated that all three derivatives exhibited enhanced sonodynamic damage to BSA and E. coli under US, with CIPD1 and CIPD2 showing superior effectiveness compared to CIP. Both the concentrations of derivatives and the duration of ultrasound irradiation were found to significantly impact their sonodynamic effects. All three CIP derivates could be activated to produce ROS following ultrasound irradiation, primarily consisting of 1O2 and ·OH. The levels of ROS production were positively correlated with their sonodynamic activities, potentially explaining the mechanism underlying their sonodynamic damage activities.

Synthesis of novel 4-substituted isatin Schiff base derivatives as potential autophagy inducers and evaluation of their antitumour activity.

Induction of autophagic death in cancer cells is one of the promising strategies for the development of anti-cancer therapeutics. In the present study, we designed and synthesized a series of isatin Schiff base derivatives containing thioether structures. After discovering the highly active target compound H13 (IC50 = 4.83μM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC50 of 69.01μM, indicating a sufficient therapeutic window. In addition, to provide reference for subsequent studies, a model was successfully constructed by Sybyl software. Preliminary mechanistic studies suggested that H13-induced apoptosis may be closely related to ROS accumulation and mitochondrial dysfunction. Subsequent studies revealed that H13 inhibited cell proliferation by inducing cellular autophagy mainly through blocking signal of the PI3K/AKT/mTOR pathway. Altogether, these results suggested that H13 was potentially valuable as a lead compound.

Unexplored catalytic potency of a magnetic CoFe2O4/Ni-BDC MOF composite for the one-pot sustainable synthesis of 5-substituted 1-H tetrazoles

Within the domain of materials science and engineering, significant progress has led to the emergence of innovative materials based on magnetic MOFs, positioning them as promising candidates in the field of catalysis. This research aims to elaborate on the development of a finely tailored magnetic MOF composite; Ni-BDC (Nickel benzene-1,4-dicarboxylate) microflakes which was synthesized through a straightforward in-situ solvothermal approach. Extensive investigations into the structural properties of the resultant hybrid composite were carried out using various characterization techniques encompassing X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller (BET) analysis, atomic absorption spectroscopy (AAS), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric analysis (TGA) and vibrating sample magnetometry (VSM). The developed material demonstrated remarkable efficiency in expediting the synthesis of a diverse array of pharmaceutically active 5-substituted 1H-tetrazole derivatives through a multicomponent coupling reaction involving substituted aldehydes, malononitrile, and sodium azide as key components. A noteworthy feature of this approach is its adherence to environmentally friendly reaction conditions, thus making it superior in comparison to previously established methodologies. Furthermore, a plausible mechanistic pathway has been proposed to elucidate the impressive performance of the developed catalytic system in the targeted reaction. It is anticipated that the current research will not only contribute to the purposeful designing of advanced magnetic MOF-based architectures but will also play a pivotal role in promoting sustainable practices in industrial processes, addressing pressing environmental and economic concerns.

Exploring the Therapeutic Potential of Benzoxazolone Derivatives on the Circadian Clock: An In Silico and Hypothetical Approach

Objective: Pain conditions exhibit variations linked to circadian rhythms. Circadian rhythms, regulated by clock proteins, impact melatonin levels and immune functions. Melatonin, structurally similar to indomethacin, a non-steroidal anti-inflammatory drug, serves as an alternative in pain-related conditions. Literature suggests a correlation between melatonin-dependent regulation of circadian rhythm and reductions in pain complaints. 2(3<i>H</i>)-Benzoxazolone, known for its anti-inflammatory and analgesic properties, is a promising scaffold for drug design. In this study, pharmacophore analysis focused on benzoxazolone derivatives, evaluating their impact on clock proteins, and providing insights into potential chronotherapeutic implications. Methods: Molecular docking and dynamics simulations were conducted on CLOCK:BMAL1, PER1, PER2, CRY1, and CRY2 clock proteins using benzoxazolone and its 5-substituted derivatives. Molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations were employed to analyze binding free energies. Benzoxazolone derivatives, especially 5-nitro-2-benzoxazolone and 5-fluoro-2-benzoxazolone, exhibited elevated binding affinities on clock proteins compared to melatonin and indomethacin, the reference molecules. The interaction profiles and stability of complexes were maintained throughout the simulations. Results: The results suggest a regulatory impact on CRY proteins, emphasizing their role in circadian rhythm and pain modulation. In addition, the benzoxazolone ring and its derivatives, structurally resembling the core structure of melatonin and indomethacin, demonstrate promising affinities on clock proteins. Conclusion: These findings provide preliminary data and hypothetically propose benzoxazolone derivatives as potential candidates for dual functionality in analgesic activity and circadian rhythm regulation, warranting further in vitro and clinical investigations.