Search

Imidazo[1,2-a] pyridines are privileged heterocycles with diverse applications in medicinal chemistry; however, the catalytic asymmetric synthesis of these heterocyclic structures remains underexplored. Herein, we present an efficient and modular approach for the atroposelective synthesis of axially chiral imidazo[1,2-a] pyridines via an asymmetric multicomponent reaction. By utilizing a chiral phosphoric acid catalyst, the Groebke-Blackburn-Bienaymé reaction involving various 6-aryl-2-aminopyridines, aldehydes, and isocyanides gave access to a wide range of imidazo[1,2-a] pyridine atropoisomers with high to excellent yields and enantioselectivities. Extensive control experiments underscored the pivotal role of the remote hydrogen bonding donor on the substrates in achieving high stereoselectivity for these reactions. The versatile derivatizations of these atropisomeric products, especially their role as an analog of NOBINs and their facile conversion into unique 6,6-spirocyclic products, further emphasize the merits of this methodology. [ABSTRACT FROM AUTHOR]

Imidazo[1,2-a]pyridines and especially their amide derivatives exhibit a wide range of favourable pharmacological properties. In this work, Pd-catalysed carbonylation was used for the first time for the introduction of the carboxamide moiety into positions 6 or 8. A recyclable Pd catalyst, with palladium immobilised on a supported ionic liquid phase decorated with pyridinium ions, was used efficiently for the conversion of 6- or 8-iodo derivatives to the products. In the case of 6-iodo derivatives, a competing mono- and double carbonylation could be observed in the reactions of aliphatic amines as nucleophiles, but under the proper choice of reaction conditions, good-to-excellent selectivities could be achieved towards either the corresponding amides or α-ketomides. The heterogeneous catalyst showed excellent recyclability and low Pd-leaching. [ABSTRACT FROM AUTHOR]

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups. [ABSTRACT FROM AUTHOR]

The document "Organosulfur and Organoselenium Chemistry" published in the journal Molecules highlights the importance of sulfur and selenium-containing compounds in various fields such as pharmaceuticals, materials, natural products, and food. The special issue contains contributions from scientists worldwide, showcasing the global reach of organosulfur and organoselenium chemistry. The articles cover topics like the synthesis of biarylsulfoxides, thioacetals, thionated perylenediimides, and the regioselective selenation of indoles, among others. The research presented in this special issue aims to benefit scientists, researchers, and graduate students in organic chemistry, material chemistry, chemical biology, and computational chemistry. [Extracted from the article]

Pharmacotherapy protocols used in cancer treatment are far from curative for many patients due to reasons such as drug-related toxicity and decreased effectiveness of the drug. Multidrug resistance is a defense mechanism developed by the cancer cell against different drug groups or drug combinations. One of the most important reasons is the increase in the efficiency or number of ABC transporters that ensure drug removal from the cell. Imidazopyridines, which are incorporated into the structure of many biomolecules, have been produced under laboratory conditions for many years. Imidazopyridines are effective anticancer agents that can kill cancer cells in various ways. In this review, we presented a detailed summary of studies in which imidazopyridines were used to overcome multidrug resistance by targeting ABC transporters in cancer cells. For this purpose, we collectively evaluated the synthesis strategies and laboratory results of the agents synthesized and used as drugs and the compounds whose clinical trials have not yet started. The introduction of several imidazopyridine derivatives as prescription drugs reflects the potential of these molecules. We think that agents that can provide targeted therapy will be used more frequently in the clinic and will improve treatment success. [ABSTRACT FROM AUTHOR]

Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules. [ABSTRACT FROM AUTHOR]

Introduction: Imidazo[1,2- a ]pyridine derivatives with diverse pharmacological properties and curcumin, as a potential natural anti-inflammatory compound, are promising compounds for cancer treatment. This study aimed to synthesize a novel imidazo[1,2- a ]pyridine derivative, (MIA), and evaluate its anti-inflammatory activity and effects on nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways, and their target genes, alone and in combination with curcumin, in MDA-MB-231 and SKOV3 cell lines. Methods: We evaluated the interaction between imidazo[1,2- a ]pyridine ligand, curcumin, and NF-κB p50 protein, using molecular docking studies. MTT assay was used to investigate the impacts of compounds on cell viability. To evaluate the NF-κB DNA binding activity and the level of inflammatory cytokines in response to the compounds, ELISA-based methods were performed. In addition, quantitative polymerase chain reaction (qPCR) and western blotting were carried out to analyze the expression of genes and investigate NF-κB and STAT3 signaling pathways. Results: Molecular docking studies showed that MIA docked into the NF-κB p50 subunit, and curcumin augmented its binding. The MTT assay results indicated that MIA and its combination with curcumin reduced cell viability. According to the results of the ELISA-based methods, MIA lowered the levels of inflammatory cytokines and suppressed NF-κB activity. In addition, real-time PCR and Griess test results showed that the expression of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) genes, and nitrite production were reduced by MIA. Furthermore, the western blotting analysis demonstrated that MIA increased the expression of inhibitory κB (IκBα) and B-cell lymphoma 2 (Bcl-2)-associated X proteins (BAX), and suppressed the STAT3 phosphorylation, and Bcl-2 expression. Our findings revealed that curcumin had a potentiating role and enhanced all the anti-inflammatory effects of MIA. Conclusion: This study indicated that the anti-inflammatory activity of MIA is exerted by suppressing the NF-κB and STAT3 signaling pathways in MDA-MB-231 and SKOV3 cancer cell lines. [ABSTRACT FROM AUTHOR]

Disubstituted isothiazolo[4,3-b]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-b]pyridines remain elusive, a strategy was established to prepare this chemotype, starting from 2,4-dichloro-3-nitropyridine. Selective C-4 arylation using ligand-free Suzuki-Miyaura coupling and palladium-catalyzed aminocarbonylation functioned as key steps in the synthesis. The 3-N-morpholinyl-7-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine was completely devoid of GAK affinity, in contrast to its 3,5- and 3,6-disubstituted congeners. Molecular modeling was applied to rationalize its inactivity as a GAK ligand. [ABSTRACT FROM AUTHOR]

Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 48 imidazo [1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an IC50 value of 1.0 µM. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound's metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding. [ABSTRACT FROM AUTHOR]

Hydrogen peroxide (H2O2), a significant member of reactive oxygen species, plays a crucial role in oxidative stress and cell signaling. Abnormal levels of H2O2 in the body can induce damage or even impair body function, leading to the development of certain diseases. Therefore, real-time monitoring of H2O2 in living cells is very important. In this work, the aggregation-induced emission fluorescence probe 2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) oxy) phenyl) imidazo [1,2-a] pyridine (B2) was designed and synthesized, which enables the long-term tracing of H2O2 in living cells. The addition of H2O2 to probe B2 results in a dramatic fluorescence enhancement around 500 nm. Notably, B2 can visualize both exogenous and endogenous H2O2 in living cells. The synthesis method for B2 is simple, has a high yield, and utilizes readily available materials. It exhibits advantages such as low toxicity, photostability, and good biocompatibility. Consequently, the developed fluorescent probe in this study has great potential as a reliable tool for determining H2O2 in living cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine mammary cancer (CMC) is the most prevalent neoplasm in intact female dogs, with approximately 50% of these cases diagnosed as malignant. Various chemotherapeutic agents have been applied in CMC treatment, but these agents come with notable disadvantages and limited information on efficacy. The benzo[6,7]oxepino[3,2-b] pyridine (BZOP) derivative, 2-((2-methylpyridin-3-yl)oxy)benzaldehyde (MPOBA), exhibited potent anticancer activity against a human colorectal cancer cell line. However, the anticancer effects and molecular mechanisms of MPOBA on CMC have not been elucidated. This study investigated the effects of MPOBA on proliferation, migration, and apoptosis and investigated its potential mechanism in two CMC cell lines, REM134 canine mammary carcinoma and CMGT071020 canine mammary tubulopapillary carcinoma. Furthermore, an in vitro cytotoxicity test was also evaluated in the Madin–Darby canine kidney (MDCK) cell line. The results revealed that MPOBA significantly inhibited proliferation and migration and induced apoptosis in CMC cell lines. In addition, MPOBA showed lower cytotoxicity in MDCK cells. According to the gene expression analysis, the mRNA expression levels of TP53 tumor suppressor (TP53), Bcl-2 associated X (BAX), and B-cell lymphoma-2 (BCL-2) in both CMC cells were significantly altered in the treatment groups compared to the control. These results suggested that MPOBA may have induced apoptosis in both CMC cell lines. This effect may be mediated through the downregulation of BCL-2 and upregulation of BAX gene expressions. These findings indicated that MPOBA may serve as an emerging candidate agent for CMC treatment. However, mRNA expression levels may not be directly proportional to protein expression levels. Therefore, additional studies, including apoptosis-related protein analysis and apoptosis marker assays, are required to confirm the major apoptosis signaling pathway regulated by MPOBA. CMC is the most frequently diagnosed cancer and one of the leading causes of death in non-spayed female dogs. Exploring novel therapeutic agents is necessary to increase the survival rate of dogs with CMC. MPOBA is a BZOP derivative that has a significant anticancer effect in a human cell line. The main goal of this study was to investigate the anticancer properties of MPOBA against two CMC cell lines (REM134 and CMGT071020) using a 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, a wound healing assay, a transwell migration assay, an Annexin V-FITC apoptosis assay with a flow cytometry analysis, a mRNA expression analysis using quantitative real-time PCR (qRT-PCR), and an immunohistochemistry (IHC). According to the accumulated studies, MPOBA caused significant concentration- and time-dependent reductions in cell proliferation and cell migration and induced apoptosis in both CMC cell lines. In gene expression analysis, nine canine genes, including TP53, BCL-2, BAX, epidermal growth factor receptor (EGFR), snail transcription factor (SNAIL), snail-related zinc-finger transcription factor (SLUG), TWIST, E-cadherin, and N-cadherin, were investigated. The mRNA expression results revealed that MPOBA induced upregulation of TP53 and overexpression of the pro-apoptotic gene BAX, together with an inhibition of BCL-2. Moreover, MPOBA also suppressed the mRNA expression levels of SNAIL, EGFR, and N-cadherin and induced upregulation of E-cadherin, crucial genes related to the epithelial-to-mesenchymal transition (EMT). However, there was no significant difference in the IHC results of the expression patterns of vimentin (VT) and cytokeratin (CK) between MPOBA-treated and control CMC cells. In conclusion, the results of the present study suggested that MPOBA exhibited significant anticancer activity by inducing apoptosis in both CMCs via upregulation of TP53 and BAX and downregulation of BCL-2 relative mRNA expression. MPOBA may prove to be a potential candidate drug to be further investigated as a therapeutic agent for CMC. [ABSTRACT FROM AUTHOR]

In the present work, we developed an experimental class for undergraduate students concerning the linear synthesis of 2-phenylimidazo[1,2-α]pyridine through mechanochemical techniques. This approach aims to conceptualize the green chemistry principles through a safe, robust, atom-economic, energy-efficient, and solvent-free method for preparing these classes of compounds by manual grinding and vortex mixing. The methodology was easily applied in experimental classes for chemistry students and could be easily expanded to other courses such as pharmacy and biotechnology.

Phosgene is a highly concealed and highly toxic gas that seriously threatens human health and public security. Therefore, the detection of phosgene is of great significance to world security. Herein, a new type of fluorescent probe based on 2-(2-aminophenyl) imidazo [1,5-a] pyridine is reported for the rapid detection of phosgene. The probe itself only emits a faint green fluorescence, while phosgene allows it to produce a strong blue fluorescence. During the recognition process, phosgene interacts simultaneously with both amino site and imidazole moiety in the probe molecule, resulting in a four-ring-fused rigid structure with high fluorescence quantum yield. The probe not only has the characteristics of high efficiency, high sensitivity (detection limit 2.68 nM), and high selectivity, but also has remarkable spectral changes. Finally, a portable test strip is used to detect phosgene in the gas phase, and the fluorescent color change of the test strip can be easily observed. The most exciting thing is that the portable test strip with the probe PMPY-NH2 can produce a strong fluorescence response to 1 ppm of phosgene, which is far lower than the level of phosgene that seriously threatens to human health. [ABSTRACT FROM AUTHOR]

Two series of novel imidazo[1,2-a]pyridine-2-carbohydrazide derivatives have been designed, synthesized, and evaluated for cytotoxic activity. Target compounds were designed in two series: aryl hydrazone derivatives that were devoid of triazole moiety (7a-e) and aryl triazole bearing group (11a-e). In vitro cytotoxicity screening was carried out using MTT assay against three human cancer cells including breast cancer (MCF-7), colon cancer (HT-29), and leukemia (K562) cell lines as well as a non-cancer cell line (Vero). Compound 7d bearing 4-bromophenyl pendant from aryl hydrazone series exhibited the highest cytotoxic potential with IC50 values of 22.6 µM and 13.4 µM against MCF-7 and HT-29 cells, respectively, while it was not toxic towards non-cancer cells up to the concentration of 100 µM. Cell cycle analysis revealed that 7d increased the number of MCF-7 cells in the G0/G1 phase and also induced apoptosis in these cells as revealed by Hoechst 33,258 staining. The molecular mechanism contributing to the anti-proliferative effect of the most potent compound was investigated in silico using Super Pred software and introduced PDGFRA as a plausible target for 7d. Molecular docking and molecular dynamic studies demonstrated Lys627 and Asp836 as key residues interacting with the active compound. Overall, 7d could serve as a suitable candidate for further modifications as a lead anticancer structure. [ABSTRACT FROM AUTHOR]

Hot-water-soluble starch (HWSS) was used as a powerful cementing material to produce nano-size conglomerates of talc and magnetite nanoparticles. Coordination of HWSS hydroxyl groups to iron atoms at surface of magnetite leads to grafting and encapsulation of its nanoparticles. The resulting nano-complex showed a higher loading capacity on talc than pristine magnetite nanoparticles. Only a minute amount of HWSS was detected in the fabricated nano-composite Talc\HWSS@Fe3O4. XPS study suggests a considerable interaction between HWSS and Fe3O4 nanoparticles, upon which some of the Fe+3 atoms on surface of Fe3O4 are reduced into Fe+2 atoms. ATR FT-IR spectra of the nano-composite revealed significant delamination of talc sheets on interaction with HWSS-coated Fe3O4 nanoparticles. The nano-composite displayed an efficient catalytic activity in the synthesis of new imidazo[1,2-c]quinazoline derivatives via Grobke–Blackburn–Bienaymé three-component reaction of 4-aminoquinazoline, arylaldehydes and isocyanide. The efficiency of the method was exemplified by synthesizing 7 new products in fairly high yields (68–83%) within short reaction times (24–30 min) using a catalytic amount of the catalyst under solvent-free condition at 120 °C. Clean and fast synthesis of the products and convenient separation of the robust nano-catalyst are the prominent advantages of the present method. The nano-catalyst was properly characterized. [ABSTRACT FROM AUTHOR]

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3Kα and a panel of PI3Kα-addicted cancer cells. Among them, compound 35 was identified as a PI3Kα inhibitor with nanomolar potency as well as acceptable antiproliferative activity. Flow cytometry analysis confirmed 35 induced cell cycle arrest and apoptosis in T47D cells. In addition, it also showed desirable in vitro ADME properties. The design, synthesis, and SAR exploration of 35 are described within. [ABSTRACT FROM AUTHOR]

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases. [ABSTRACT FROM AUTHOR]

Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx cancer (HEP2), lung cancer (H460), colon cancers (HCT116 and Caco2), and hypopharyngeal cancer (FADU), and normal Vero cell lines were used. Compounds 8 and 14 displayed outstanding effects on the investigated cell lines and were further tested for their antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, and Vero cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), and nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection and cell cycle DNA index using the HEPG-2 cell line were established on both compounds as well. Furthermore, compounds 8 and 14 were assessed for their EGFR kinase (Wild and T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, and SAR studies were carried out for the investigated candidates. [ABSTRACT FROM AUTHOR]

• Enhance oil and gas well flow assurance. • Oil and gas pipelines need to be protected from corrosion. • Using pyridine derivatives as corrosion inhibitors. • The study focuses on the synthesis of amphiphilic inhibitors (SAOBR, SADBR, SAHBR) and their inhibition properties on carbon steel. • Molecular orbital energies of the inhibitors were calculated to confirm their practical inhibition properties. • The study used molecular dynamics simulation (MDS) technique to achieve equilibrium of the simulated system. • The inhibition efficiency of the synthesized amphiphilic inhibitors was quantified using the formula % η E =(1 −) X 100. • The study found that SAHBR has the best inhibitory activity for carbon steel compared to SADBR and SAOBR. • The study also found that the presence of inhibitors resulted in higher relaxation time values compared to those found in HCl solution. • The study provides a detailed methodology for determining the corrosion rate and mass loss of the metal surface. • The study concludes that the synthesized amphiphilic inhibitors have practical applications in inhibiting corrosion of carbon steel. Acidizing, which is essential in crude oil wells, improves oil/gas flow by injecting acid chemicals. HCl is frequently used to increase production. Add inhibitor chemicals to reduce acid stimulation and metal corrosion. Oil and gas well corrosion is successfully inhibited by amphiphilic amino pyridine derivatives. In this study, three cationic amphiphilic amino pyridine derivative inhibitors were synthesized and evaluated by FT-IR and 1H NMR analysis. These inhibitors exhibit cost-effective, eco-friendly, and highly effective inhibition reactivity for corrosion prevention. The surface activity was evaluated at 250,400 and 60 °C in 1 mol HCl, where CMC values increase and surface tension decreases as temperature increases. The corrosion inhibition efficacy (%η w) was determined using gravimetric methods at various temperatures of 250,550, and 70 °C which revealed that SAHBR has a higher efficacy (94.5% at 25 °C, 92.3% at 55 °C and 91.1% at 70 °C) than SADBR (92.9% at 25 °C, 90.5% at 55 °C and 88.4% at 70 °C) and SAOBR (91.6% at 25 °C, 89.7% at 55 °C and 87.0% at 70 °C) for 400 ppm dose. Also, the inhibition efficacy (%η p) which determined through potentiodynamic polarization technique which display SAHBR is 95.90% higher than SADBR is 93.90% and SAOBR is 89.90% at 25 °C for 400 ppm dose and electrochemical impedance spectroscopy (EIS) practice which parade the inhibition efficacy (%η E) of the synthesized inhibitors where SAHBR is 91.7% higher than SADBR is 89.0% and SAOBR is 87.3% at 25 °C for 400 ppm dose. Density Functional Theory (DFT) computed quantum chemistry parameters using B3LYP level, 6-311G+ (d, p) basis sets. Calculations included EHOMO, ELUMO energies, energy gap (ΔE), softness (σ), chemical hardness (η), electrophilicity (ω), electronegativity (X), and electron transfer (ΔN) to validate amphiphilic inhibitors' inhibition properties. Molecular Dynamics Simulation (MDS) ensured system equilibrium. [ABSTRACT FROM AUTHOR]

In this paper, we report an eco-friendly approach for the C(sp2)–H bond selenylation of imidazopyridines and other N-heteroarenes as well as simple arenes at ambient temperature. This new protocol consists of the reaction between (N-hetero)-arenes and the diorganyl-diselenides and trichloroisocyanuric acid (TCCA)-ethanol reagent system. In a short reaction time, the desired selenylated products were obtained regioselectively in good yields, with tolerance for a wide range of functional groups. [ABSTRACT FROM AUTHOR]

A facile and efficient method has been developed for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted Friedel–Crafts reaction of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines. This strategy could be applied to the direct C(sp2)-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines and afford a series of novel difluoromethylated carbinols in good to satisfactory yields with 29 examples. Furthermore, gram-scale and synthetic transformation experiments have also been achieved, demonstrating its potential applicable value in organic synthesis. This green protocol has several advantages, including being transition metal- and oxidant-free, being carried out at room temperature, having high efficiency, and having a wide substrate scope. [ABSTRACT FROM AUTHOR]

Diabesity is a major global health concern, and ghrelin O-acyltransferase (GOAT) acts as an important target for the development of new inhibitors of this disease. The present work highlights a detailed QSAR study using QSARINS software, which provides an excellent model equation using descriptors. Here, the best model equation developed has two variables, namely MLFER_E and XlogP, with statistical parameters R2 = 0.8433, LOF = 0.0793, CCCtr = 0.915, Q2LOO = 0.8303, Q2LMO = 0.8275, CCCcv = 0.9081, R2ext = 0.7712, and CCCext = 0.8668. A higher correlation of the key structural fragments with activity is validated by the developed QSAR model. Furthermore, molecular docking helped us identify the binding interactions. Thirty four new molecules with better predicted biological activity (pIC50) were designed. The binding energy of four compounds have shown higher binding activity into the membrane protein (PDB Id: 6BUG). Molecular dynamics simulation has established the stability of the protein-ligand complex over 100 ns. DFT and ADME-toxicity analyses also confirmed their drug-like properties. Based on our findings, we report that these new oxadiazolo pyridine derivatives lead to the development of potent candidates for further development. METTL3-mediated HOTAIRM1 promotes vasculogenic mimicry in glioma via regulating IGFBP2 expression. METTL3 expression is high in glioma cells and tissues that stabilize and enhance HOTAIRM1 expression. This HOTAIRM1 then interacts with IGFBP2 which in turn promotes glioma cell malignancy and vasculogenic mimicry (VM) formation, thus providing a new direction for glioma therapy [ABSTRACT FROM AUTHOR]

Azacarbazoles have attracted significant interest due to their valuable properties, such as anti-pathogenic and antitumor activity. In this study, a series of structurally related tricyclic benzo[4,5]- and tertacyclic naphtho[2′,1′:4,5]imidazo[1,2-c]pyrimidinone derivatives with one or two positively charged tethers were synthesized and evaluated for anti-proliferative activity. Lead tetracyclic derivative 5b with two amino-bearing arms inhibited the metabolic activity of A549 lung adenocarcinoma cells with a CC50 value of 3.6 μM, with remarkable selectivity (SI = 17.3) over VA13 immortalized fibroblasts. Cell-cycle assays revealed that 5b triggers G2/M arrest without signs of apoptosis. A study of its interaction with various DNA G4s and duplexes followed by dual luciferase and intercalator displacement assays suggests that intercalation, rather than the modulation of G4-regulated oncogene expression, might contribute to the observed activity. Finally, a water-soluble salt of 5b was shown to cause no acute toxic effects, changes in mice behavior, or any decrease in body weight after a 72 h treatment at concentrations up to 20 mg/kg. Thus, 5b is a promising candidate for studies in vivo; however, further investigations are needed to elucidate its molecular target(s). [ABSTRACT FROM AUTHOR]

Over 30 compounds, including para-, meta-, and ortho-phenylenediboronic acids, ortho-substituted phenylboronic acids, benzenetriboronic acids, di- and triboronated thiophenes, and pyridine derivatives were investigated as potential β-lactamase inhibitors. The highest activity against KPC-type carbapenemases was found for ortho-phenylenediboronic acid 3a, which at the concentration of 8/4 mg/L reduced carbapenems' MICs up to 16/8-fold, respectively. Checkerboard assays revealed strong synergy between carbapenems and 3a with the fractional inhibitory concentrations indices of 0.1–0.32. The nitrocefin hydrolysis test and the whole cell assay with E. coli DH5α transformant carrying blaKPC-3 proved KPC enzyme being its molecular target. para-Phenylenediboronic acids efficiently potentiated carbapenems against KPC-producers and ceftazidime against AmpC-producers, whereas meta-phenylenediboronic acids enhanced only ceftazidime activity against the latter ones. Finally, the statistical analysis confirmed that ortho-phenylenediboronic acids act synergistically with carbapenems significantly stronger than other groups. Since the obtained phenylenediboronic compounds are not toxic to MRC-5 human fibroblasts at the tested concentrations, they can be considered promising scaffolds for the future development of novel KPC/AmpC inhibitors. The complexation of KPC-2 with the most representative isomeric phenylenediboronic acids 1a, 2a, and 3a was modeled by quantum mechanics/molecular mechanics calculations. Compound 3a reached the most effective configuration enabling covalent binding to the catalytic Ser70 residue. [ABSTRACT FROM AUTHOR]

The present study was devoted to the investigation of the effect of NO2 and OH groups on the structure of two imidazopyridines, namely: (E)-N-(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-1-(4-nitrophenyl)methanimine (Imid1) and (E)-4-(((7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)imino)methyl)phenol (Imid2) on the corrosion inhibition efficiency of steel in an acidic medium, to remediate mild steel in hydrochloric acid. The evaluation of this activity was revealed using several experimental techniques such as weight loss measurements (WL), potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS), UV–visible spectroscopy study, surface characterization by SEM, as well as the impact of temperature and concentration on the inhibition efficiency for two inhibitors. The results obtained from these techniques show that the inhibition efficiency is reduced by the effect of the nitro electron-withdrawing group (NO2) in the Imid1 molecule, but increased by the presence of the donor group (-OH) in the Imid2 molecule. The comparison of the results obtained by UV–visible spectroscopy of the inhibited and uninhibited electrolyte provided evidence for the formation of an Fe-ligand complex of two imidazopyridine molecules in 1 M HCl. Surface morphological studies by SEM revealed a uniform surface in the presence of Imid1-2, in contrast to a destroyed surface in the absence of the inhibitors. Finally, the results of DFT and MDS simulations are in good agreement with the experimental data and showed that the obtained order of the inhibition efficiency is always respected (Imid2 > Imid1). [ABSTRACT FROM AUTHOR]

A series of novel 2,6-diphenyl substituted imidazo[4,5-b]pyridines was designed and synthesized using optimized Suzuki cross coupling to evaluate their biological activity in vitro. The conditions of the Suzuki coupling were evaluated and optimized using a model reaction. To study the influence of the substituents on the biological activity, we prepared N-unsubstituted and N-methyl substituted imidazo[4,5-b]pyridines with different substituents at the para position on the phenyl ring placed at position 6 on the heterocyclic scaffold. Antiproliferative activity was determined on diverse human cancer cell lines, and the selectivity of compounds with promising antiproliferative activity was determined on normal peripheral blood mononuclear cells (PBMC). Pronounced antiproliferative activity was observed for p-hydroxy substituted derivatives 13 and 19, both displaying strong activity against most of the tested cell lines (IC50 1.45–4.25 μM). The unsubstituted N-methyl derivative 19 proved to be the most active derivative. There was a dose-dependent accumulation of G2/M arrested cells in several cancer cell lines after exposure to compound 19, implying a cell cycle-phase-specific mechanism of action. Additionally, the novel series of derivatives was evaluated for antiviral activity against a broad panel of viruses, yet the majority of tested compounds did not show antiviral activity. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is a childhood cancer, commonly treated with drugs, such as etoposide (ETO), whose efficacy is limited by the onset of resistance. Here, aiming at identifying new treatments for chemo-resistant NB, the effects of two synthesized imidazo-pyrazoles (IMPs) (4G and 4I) were investigated on ETO-sensitive (HTLA-230) and ETO-resistant (HTLA-ER) NB cells, detecting 4I as the more promising compound, that demonstrated IC50 values lower than those of ETO on HTLA ER. Therefore, to further improve the activity of 4I, we developed 4I-loaded palmitic acid (PA) and polystyrene-based (P5) cationic nanoparticles (P5PA-4I NPs) with high drug loading (21%) and encapsulation efficiency (97%), by a single oil-in-water emulsification technique. Biocompatible PA was adopted as an emulsion stabilizer, while synthesized P5 acted as an encapsulating agent, solubilizer and hydrophilic–lipophilic balance (HLB) improver. Optic microscopy and cytofluorimetric analyses were performed to investigate the micromorphology, size and complexity distributions of P5PA-4I NPs, which were also structurally characterized by chemometric-assisted Fourier transform infrared spectroscopy (FTIR). Potentiometric titrations allowed us to estimate the milliequivalents of PA and basic nitrogen atoms present in NPs. P5PA-4I NPs afforded dispersions in water with excellent buffer capacity, essential to escape lysosomal degradation and promote long residence time inside cells. They were chemically stable in an aqueous medium for at least 40 days, while in dynamic light scattering (DLS) analyses, P5PA-4I showed a mean hydrodynamic diameter of 541 nm, small polydispersity (0.194), and low positive zeta potentials (+8.39 mV), assuring low haemolytic toxicity. Biological experiments on NB cells, demonstrated that P5PA-4I NPs induced ROS-dependent cytotoxic effects significantly higher than those of pristine 4I, showing a major efficacy compared to ETO in reducing cell viability in HTLA-ER cells. Collectively, this 4I-based nano-formulation could represent a new promising macromolecular platform to develop a new delivery system able to increase the cytotoxicity of the anticancer drugs. [ABSTRACT FROM AUTHOR]

Emerging and re-emerging viruses periodically cause outbreaks and epidemics around the world, which ultimately lead to global events such as the COVID-19 pandemic. Thus, the urgent need for new antiviral drugs is obvious. Over more than a century of antiviral development, nucleoside analogs have proven to be promising agents against diversified DNA and RNA viruses. Here, we present the synthesis and evaluation of the antiviral activity of nucleoside analogs and their deglycosylated derivatives based on a hydroxybenzo[4,5]imidazo[1,2-c]pyrimidin-1(2H)-one scaffold. The antiviral activity was evaluated against a panel of structurally and phylogenetically diverse RNA and DNA viruses. The leader compound showed micromolar activity against representatives of the family Coronaviridae, including SARS-CoV-2, as well as against respiratory syncytial virus in a submicromolar range without noticeable toxicity for the host cells. Surprisingly, methylation of the aromatic hydroxyl group of the leader compound resulted in micromolar activity against the varicella-zoster virus without any significant impact on cell viability. The leader compound was shown to be a weak inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase. It also inhibited biocondensate formation important for SARS-CoV-2 replication. The active compounds may be considered as a good starting point for further structure optimization and mechanistic and preclinical studies. [ABSTRACT FROM AUTHOR]

The present study was undertaken to investigate the effect of harvest time on the bioactive properties of Echinacea pallida and to determine the antioxidant effect of its extract in vegetable oils. E. pallida was harvested in June, 2009, June, 2010 and August. 2010. Total phenolic content and antioxidant activity analyses of the plant extracts obtained with three different solvents were carried out using spectrophotometric methods. It was determined that harvest time and solvent type had significant effects on bioactive properties. In addition, the effect of E. pallida extract on the oxidative stability of vegetable oils was determined by the rancimat method. The extract (2000 ppm) obtained by ethanol (100%) showed similar oxidative stability on sunflower and canola oils compared to BHA (100 ppm). The GC-MS results revealed various volatile compounds such as bornyl acetate, caryophyllene E, musk ambrette, germacrene D, a-muurolol, musk ambrette, imidazo (1,2-a) pyrimidine, 1-pyrrolidino-1-cyclohexene, 2,3,5,6-tetrahydro-1H-pyrrolizine, pyrazine, and benzenaminium. [ABSTRACT FROM AUTHOR]

α-Glucosidase inhibition is an approved treatment for type 2 diabetes mellitus (T2DM). In an attempt to develop novel anti-α-glucosidase agents, two series of substituted imidazo[1,2-c]quinazolines, namely 6a–c and 11a–o, were synthesized using a simple, straightforward synthetic routes. These compounds were thoroughly characterized by IR, 1H and 13C NMR spectroscopy, as well as mass spectrometry and elemental analysis. Subsequently, the inhibitory activities of these compounds were evaluated against Saccharomyces cerevisiae α-glucosidase. In present study, acarbose was utilized as a positive control. These imidazoquinazolines exhibited excellent to great inhibitory potencies with IC50 values ranging from 12.44 ± 0.38 μM to 308.33 ± 0.06 μM, which were several times more potent than standard drug with IC50 value of 750.0 ± 1.5 μM. Representatively, compound 11j showed remarkable anti-α-glucosidase potency with IC50 = 12.44 ± 0.38 μM, which was 60.3 times more potent than positive control acarbose. To explore the potential inhibition mechanism, further evaluations including kinetic analysis, circular dichroism, fluorescence spectroscopy, and thermodynamic profile were carried out for the most potent compound 11j. Moreover, molecular docking studies and in silico ADME prediction for all imidazoquinazolines 6a–c and 11a–o were performed to reveal their important binding interactions, as well as their physicochemical and drug-likeness properties, respectively. [ABSTRACT FROM AUTHOR]

Imidazo[1,2-a]pyrimidine derivatives bearing imine groups (3a-e) were successfully synthesized in moderate to good yields using microwave-assisted heating. Corresponding amine derivatives (4a-e) were also obtained by the reduction reaction of the imine derivatives (3a-e). All synthesized products were characterized by FT-IR, ¹H NMR, 13C NMR, and LC-MS spectroscopic techniques. In silico ADMET, Lipinski, and drug-likeness studies of the compounds were conducted and all were found to be suitable drug candidates. The cytotoxicity of the potential drug molecules was screened against the breast cancer cell lines MCF-7 and MDA-MB-231 and the healthy model HUVEC by the sulforhodamine B method. According to the antiproliferative studies, compounds 3d and 4d showed remarkable inhibition of MCF-7 cells with IC50 values of 43.4 and 39.0 μM and of MDA-MB-231 cells with IC50 values of 35.9 and 35.1 μM, respectively. In particular, compound 3d selectively inhibited the proliferation of MCF-7 1.6-fold and MDA-MB-231 2.0-fold relative to healthy cells. Moreover, the apoptotic mechanism studies indicated that compound 4d induced apoptosis by moderately increasing the ratio of Bax/Bcl-2 genes. Imidazo[1,2-a]pyrimidine derivative 3d, a promising cytotoxic agent, may be helpful in the discovery of new and more efficient anticancer agents for breast cancer treatment. [ABSTRACT FROM AUTHOR]

3-Amino-2-arylcarboxamido-thieno[2-3-b]pyridines have been previously described as having potent anti-proliferative activity against MDA-MB-231 and HCT116 cancer cell lines. The mechanism by which these molecules prevent cancer cell growth is proposed to be through interfering with phospholipid metabolism via inhibition of PI-PLC, along with other cellular processes. Previously, 5-cinnamyl derivatives of these thieno[2-3-b]pyridines have been shown to have enhanced anti-proliferative activity compared to compounds lacking this moiety, indicating a tethered aromatic ring is important for this western region of the pharmacophore. Herein, we report the synthesis and biological evaluation of a library of 40 novel thieno[2-3-b]pyridine analogues containing shorter benzoyl or secondary benzyl alcohol tethers at the 5-position, in addition to various substituents on the two phenyl rings present on the molecule. Compounds bearing alcohol functionality had improved efficacy compared to their benzoyl counterparts, in addition to a 2-methyl-3-halogen substitution on the 2-arylcarboxamide ring being important for maximising anti-proliferative activity. The most potent molecules 7h and 7i demonstrated IC50 concentrations of 25–50 nM against HCT116 and MDA-MB-231 cells, a similar level of activity as previous thienopyridine compounds bearing cinnamyl moieties, suggesting that these novel derivatives with shorter tethers were able to maintain potent anti-proliferative activity, while allowing for a more concise synthesis. [ABSTRACT FROM AUTHOR]

The design of colchicine site ligands on tubulin has proven to be a successful strategy to develop potent antiproliferative drugs against cancer cells. However, the structural requirements of the binding site endow the ligands with low aqueous solubility. In this work, the benzothiazole scaffold is used to design, synthesize, and evaluate a new family of colchicine site ligands exhibiting high water solubility. The compounds exerted antiproliferative activity against several human cancer cell lines, due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HEK-293 cells, as evidenced by MTT and LDH assays. The most potent derivatives, containing a pyridine moiety and ethylurea or formamide functionalities, displayed IC50 values in the nanomolar range even in the difficult-to-treat glioblastoma cells. Flow cytometry experiments on HeLa, MCF7, and U87MG cells showed that they arrest the cell cycle at the G2/M phases at an early time point (24 h), followed by apoptotic cell death 72 h after the treatment. Tubulin binding was confirmed by microtubule network disruption observed via confocal microscopy. Docking studies support favorable interaction of the synthesized ligands at the colchicine binding site. These results validate the proposed strategy to develop potent anticancer colchicine ligands with improved water solubility. [ABSTRACT FROM AUTHOR]

Urease enzyme is a known therapeutic drug target for treatment of Helicobacter pylori infection due to its role in settlement and growth in gastric mucosa. In this study, we designed a new series of sulfonates and sulfamates bearing imidazo[2,1-b]thiazole scaffold that exhibit a potent inhibitory activity of urease enzyme. The most potent compound 2c inhibited urease with an IC50 value of 2.94 ± 0.05 μM, which is 8-fold more potent than the thiourea positive control (IC50 = 22.3 ± 0.031 μM). Enzyme kinetics study showed that compound 2c is a competitive inhibitor of urease. Molecular modeling studies of the most potent inhibitors in the urease active site suggested multiple binding interactions with different amino acid residues. Phenotypic screening of the developed compounds against H. pylori delivered molecules of that possess high potency (1a, 1d, 1h, 2d, and 2f) in comparison to the positive control, acetohydroxamic acid. Additional studies to investigate the selectivity of these compounds against AGS gastric cell line and E. coli were performed. Permeability of the most promising derivatives (1a, 1d, 1h, 2d, and 2f) in Caco-2 cell line, was investigated. As a result, compound 1d presented itself as a lead drug candidate since it exhibited a promising inhibition against urease with an IC50 of 3.09 ± 0.07 μM, MIC value against H. pylori of 0.031 ± 0.011 mM, and SI against AGS of 6.05. Interestingly, compound 1d did not show activity against urease-negative E. coli and exhibited a low permeability in Caco-2 cells which supports the potential use of this compound for GIT infection without systemic effect. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) causes one of the most dangerous diseases—acquired immunodeficiency syndrome (AIDS). An estimated about 40 million people are currently living with HIV worldwide, most of whom are already on antiretroviral therapy. This makes the development of effective drugs to combat this virus very relevant. Currently, one of the dynamically developing areas of organic and medicinal chemistry is the synthesis and identification of new compounds capable of inhibiting HIV-1 integrase—one of the HIV enzymes. A significant number of studies on this topic are published annually. Many compounds inhibiting integrase incorporate pyridine core. Therefore, this review is an analysis of the literature on the methods for the synthesis of pyridine-containing HIV-1 integrase inhibitors since 2003 to the present. [ABSTRACT FROM AUTHOR]

The microwave-assisted reaction of 2-nitroimidazole with 3-bromophenacyl bromide in the presence of potassium carbonate as a base and dimethylformamide as a solvent afforded 2-(3-bromophenyl)imidazo[2,1-b]oxazole. The formation of this compound was explained via a domino mechanism comprising an initial N-alkylation reaction of the imidazole substrate, followed by the base-promoted deprotonation of the position adjacent to the carbonyl to give an enolate anion that finally cyclizes via an intramolecular SNAr reaction, with the loss of the nitro group as potassium nitrite. Then, the proposed 1-(3-bromophenacyl)-2-nitroimidazole intermediate could be isolated by reducing the reaction time and was shown to be a precursor of the imidazo[2,1-b]oxazole final product. [ABSTRACT FROM AUTHOR]

Context: At present, sulfonamides and their metal complexes have received a new impetus for development. Of particular interest is the study of molecular and crystal structures, which takes into account weak non-valent interactions. Despite the low energy of such interactions, in many cases, they act collectively, and the sum of their actions can play a significant role. As a result, the spectrum of medical and biological activity of new metal complexes is expanded. In this regard, the synthesis and study of the molecular and crystal structure of sulfonamides and their metal complexes is of undoubted relevance. In this work, we studied non-valent intra- and intermolecular interactions in ligands of sulfonamide-substituted imidazo[2,1-b]thiazoles and their previously unknown complexes with CuCl2. The performed analysis of the data obtained by X-ray diffraction analysis made it possible to establish the intramolecular π-stacking interaction in imidazothiazole ligands, which is retained in their complexes with CuCl2. Within the framework of QTAIM topological analysis of electron density and DORI analysis, stereoelectronic and topological structures were studied. In the complexes, tetral, chalcogen, and pnycogen new interligand non-valent interactions were established. The energies of all established types of non-valent interactions have been calculated, and their comparative evaluation has been made. Methods: X-ray data of new arylsulfonylamino-substituted derivatives of imidazo[2,1-b]thiazoles and their metal complexes with CuCl2 have been studied. To determine the theoretical prerequisites for the occurrence of π-stacking in the molecules under study, the QTAIM method was used in the framework of the DFT/B3LYP/6–311 + G(d) calculation using the GAUSSIAN 09 program. In addition, the DORI electron density region overlap indicator and the Multiwfn program were used to analyze non-valent interactions. [ABSTRACT FROM AUTHOR]

5-bromopyridine-2,3-diamine reacted with benzaldehyde to afford the corresponding 6-Bromo-2-phenyl-3H-imidazo[4,5-b]pyridine (1). The reaction of the latter compound (1) with a series of halogenated derivatives under conditions of phase transfer catalysis solid–liquid (CTP) allows the isolation of the expected regioisomers compounds (2–8). The alkylation reaction of (1) gives, each time, two regioisomers, N3 and N4; in the case of ethyl bromoactate, the reaction gives, at the same time, the three N1, N3 and N4 regioisomers. The structures of synthesized compounds were elucidated on the basis of different spectral data (1H NMR, 13C NMR), X-Ray diffraction and theoretical study using the DFT method, and confirmed for each compound. Hirshfeld surface analysis was used to determine the intermolecular interactions responsible for the stabilization of the molecule. Density functional theory was used to optimize the compounds, and the HOMO-LUMO energy gap was calculated, which was used to examine the inter/intra molecular charge transfer. The molecular electrostatic potential map was calculated to investigate the reactive sites that were present in the molecule. In order to determine the potential mode of interactions with DHFR active sites, the three N1, N3 and N4 regioisomers were further subjected to molecular docking study. The results confirmed that these analogs adopted numerous important interactions, with the amino acid of the enzyme being targeted. Thus, the most docking efficient molecules, 2 and 4, were tested in vitro for their antibacterial activity against Gram-positive bacteria (Bacillus cereus) and Gram-negative bacteria (Escherichia coli). Gram-positive bacteria were more sensitive to the action of these compounds compared to the Gram-negative, which were much more resistant. [ABSTRACT FROM AUTHOR]

The purpose of this work was to prepare new isatin- and monothiomalondiamide-based indole derivatives, as well as to study the properties of the new compounds. The four-component reaction of 5-R-isatins (R = H, CH3), malononitrile, monothiomalonamide (3-amino-3-thioxo- propanamide) and triethylamine in hot EtOH yields a mixture of isomeric triethylammonium 6′-amino-3′-(aminocarbonyl)-5′-cyano-2-oxo-1,2-dihydro-1′H- and 6′-amino-3′-(aminocarbonyl)- 5′-cyano-2-oxo-1,2-dihydro-3′H-spiro[indole-3,4′-pyridine]-2′-thiolates. The reactivity and structure of the products was studied. We found that oxidation of spiro[indole-3,4′-pyridine]-2′-thiolates with DMSO-HCl system produced only acidification products, diastereomeric 6′-amino-5′-cyano-5-methyl-2-oxo-2′-thioxo-1,2,2′,3′-tetrahydro-1′H-spiro-[indole-3,4′-pyridine]- 3′-carboxamides, instead of the expected isothiazolopyridines. The alkylation of the prepared spiro[indole-3,4′-pyridine]-2′-thiolates upon treatment with N-aryl α-chloroacetamides and α-bromoacetophenones proceeds in a regioselective way at the sulfur atom. In the case of α-bromoacetophenones, ring-chain tautomerism was observed for the S-alkylation products. According to NMR data, the compounds consist of a mixture of stereoisomers of 2′-amino-6′-[(2-aryl-2-oxoethyl)thio]-3′-cyano-2-oxo-1′H-spiro[indoline-3,4′-pyridine]-5′-carboxamides and 5′-amino-3′-aryl-6′-cyano-3′-hydroxy-2-oxo-2′,3′-dihydrospiro[indoline-3,7′-thiazolo[3,2-a]pyridine]-8′-carboxamides in various ratios. The structure of the synthesized compounds was confirmed by IR spectroscopy, HRMS, 1H and 13C DEPTQ NMR studies and the results of 2D NMR experiments (1H-13C HSQC, 1H-13C HMBC). Molecular docking studies were performed to investigate suitable binding modes of some new compounds with respect to the transcriptional regulator protein PqsR of Pseudomonas aeruginosa. The docking studies revealed that the compounds have affinity for the bacterial regulator protein PqsR of Pseudomonas aeruginosa with a binding energy in the range of −5.8 to −8.2 kcal/mol. In addition, one of the new compounds, 2′-amino-3′-cyano-5-methyl-2-oxo-6′-{[2-oxo-2-(p-tolylamino)ethyl]thio}-1′H-spiro-[indoline-3,4′-pyridine]-5′-carboxamide, showed in vitro moderate antibacterial effect against Pseudomonas aeruginosa and good antioxidant properties in a test with 1,1-diphenyl-2-picrylhydrazyl radical. Finally, three of the new compounds were recognized as moderately active herbicide safeners with respect to herbicide 2,4-D in the laboratory experiments on sunflower seedlings. [ABSTRACT FROM AUTHOR]

Heme and nonheme dimanganese catalases are widely distributed in living organisms to participate in antioxidant defenses that protect biological systems from oxidative stress. The key step in these processes is the disproportionation of H2O2 to O2 and water, which can be interpreted via two different mechanisms, namely via the formation of high-valent oxoiron(IV) and peroxodimanganese(III) or diiron(III) intermediates. In order to better understand the mechanism of this important process, we have chosen such synthetic model compounds that can be used to map the nature of the catalytically active species and the factors influencing their activities. Our previously reported μ-1,2-peroxo-diiron(III)-containing biomimics are good candidates, as both proposed reactive intermediates (FeIVO and FeIII2(μ-O2)) can be derived from them. Based on this, we have investigated and compared five heterobidentate-ligand-containing model systems including the previously reported and fully characterized [FeII(L1−4)3]2+ (L1 = 2-(2′-pyridyl)-1H-benzimidazole, L2 = 2-(2′-pyridyl)-N-methyl-benzimidazole, L3 = 2-(4-thiazolyl)-1H-benzimidazole and L4 = 2-(4′-methyl-2′-pyridyl)-1H-benzimidazole) and the novel [FeII(L5)3]2+ (L5 = 2-(1H-1,2,4-triazol-3-yl)-pyridine) precursor complexes with their spectroscopically characterized μ-1,2-peroxo-diiron(III) intermediates. Based on the reaction kinetic measurements and previous computational studies, it can be said that the disproportionation reaction of H2O2 can be interpreted through the formation of an electrophilic oxoiron(IV) intermediate that can be derived from the homolysis of the O–O bond of the forming μ-1,2-peroxo-diiron(III) complexes. We also found that the disproportionation rate of the H2O2 shows a linear correlation with the FeIII/FeII redox potential (in the range of 804 mV-1039 mV vs. SCE) of the catalysts controlled by the modification of the ligand environment. Furthermore, it is important to note that the two most active catalysts with L3 and L5 ligands have a high-spin electronic configuration. [ABSTRACT FROM AUTHOR]

A series of multistep synthesis protocols was adopted to synthesize substituted imidazopyridines (IMPs) (SM-IMP-01 to SM-IMP-13, and DA-01-05). All substituted IMPs were then characterized using standard spectroscopic techniques such as 1H-NMR, 13C-NMR, elemental analyses, and mass spectrometry. Our both in vitro qualitative and quantitative results for antibacterial analysis, against Klebsiella pneumoniae ATCC 4352 and Bacillus subtilis ATCC 6051 suggested that all compounds essentially exhibited activity against selected strains of bacteria. Our DFT analyses suggested that the compounds of the SM-IMP-01–SM-IMP-13 series have HOMO/LUMO gaps within 4.43–4.69 eV, whereas the compounds of the DA-01–DA-05 series have smaller values of the HOMO/LUMO gaps, 3.24–4.17 eV. The lowest value of the global hardness and the highest value of the global softness, 2.215 and 0.226 eV, respectively, characterize the compound SM-IMP-02; thus, it is the most reactive compound in the imidazopyridine carboxamide series (except hydrazide series). This compound also depicted lesser MIC values against Klebsiella pneumoniae ATCC 4352 and Bacillus subtilis ATCC 6051 as 4.8 µg/mL, each. In terms of another series, hydrazide DA-05 depicted strong antimicrobial actions (MIC: 4.8 µg/mL against both bacterial strains) and also had the lowest energy gap (3.24 eV), higher softness (0.309 eV), and lesser hardness (1.62 eV). Overall, when we compare qualitative and quantitative antimicrobial results, it is been very clear that compounds with dibromo substitutions on imidazopyridine (IMP) rings would act as better antimicrobial agents than those with -H at the eighth position on the IMP ring. Furthermore, substituents of higher electronegativities would tend to enhance the biological activities of dibromo-IMP compounds. DFT properties were also well comparable to this trend and overall, we can say that the electronic behavior of compounds under investigation has key roles in their bioactivities. [ABSTRACT FROM AUTHOR]

A small library of 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one derivatives was prepared in good to excellent yields, involving a Ag2CO3/TFA-catalyzed intramolecular oxacyclization of N-Boc-2-alkynylbenzimidazole substrates. In all experiments, the 6-endo-dig cyclization was exclusively achieved since the possible 5-exo-dig heterocycle was not observed, indicating the high regioselectivity of this process. The scope and limitations of the silver catalyzed 6-endo-dig cyclization of N-Boc-2-alkynylbenzimidazoles as substrates, bearing various substituents, were investigated. While ZnCl2 has shown limits for alkynes with an aromatic substituent, Ag2CO3/TFA demonstrated its effectiveness and compatibility regardless of the nature of the starting alkyne (aliphatic, aromatic or heteroaromatic), providing a practical regioselective access to structurally diverse 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones in good yields. Moreover, the rationalization of oxacyclization selectivity in favor of 6-endo-dig over 5-exo-dig was explained by a complementary computational study. [ABSTRACT FROM AUTHOR]

Indolizine-carbaldehydes with the easily modifiable carbaldehyde group are important synthetic targets as versatile precursors for distinct indolizines. However, the efficient one-pot construction of trisubstituted indolizine-2-carbaldehydes represents a long-standing challenge. Herein, we report an unprecedented recyclable stereoauxiliary aminocatalytic approach via aminosugars derived from biomass, which enable the efficient one-pot synthesis of desired trisubstituted indolizine-2-carbaldehydes via [3+2] annulations of acyl pyridines and α,β-unsaturated aldehyde. Compared to the steric shielding effect from α-anomer, a stereoauxiliary effect favored by β-anomer of D-glucosamine is supported by control experiments. Furthermore, polymeric chitosan containing predominantly β-D-anhydroglucosamine units also shows excellent catalytic performance in aqueous solutions for the conversion of various substrates, large-scale synthesis and catalytic cycling experiments. Thus, our approach advances the existing methodologies by providing a rich library of indolizine-2-aldehydes. In addition, it delivers an efficient protocol for a set of late-stage diversification and targeted modifications of bioactive molecules or drugs, as showcased with 1,2,3-trisubstituted indolizine-2-carbaldehydes. Indolizine-2-carbaldehydes are important precursors for indolizine synthesis, however, their efficient construction remains challenging. Here, a recyclable stereoauxiliary aminocatalyzed strategy for one-pot synthesis of 1,2,3-trisubstituted indolizine-2-carbaldehydes is reported, via [3+2] annulations of acyl pyridines and α,β-unsaturated aldehydes. [ABSTRACT FROM AUTHOR]

Herein, two novel ruthenium(II) complexes coupled by erianin via a flexible carbon chain, [Ru(phen)2(L1-(CH2)4-erianin)](ClO4)2 (L1 = 2-(2-(tri-fluoromethyphenyl))-imidazo [4,5f][1–10]phenanthroline (1) and [Ru(phen)2(L2-(CH2)4-eria)](ClO4)2 (L2 = 2-(4-(tri-fluoromethyphenyl))-imidazo [4,5f][1,10]phenanthroline (2), have been synthesized and investigated as a potential G-quadruplex(G4) DNA stabilizer. Both complexes, especially 2, can bind to c-myc G4 DNA with high affinity by electronic spectra, and the binding constant calculated for 1 and 2 is about 15.1 and 2.05 × 107 M−1, respectively. This was further confirmed by the increase in fluorescence intensity for both complexes. Moreover, the positive band at 265 nm in the CD spectra of c-myc G4 DNA decreased treated with 2, indicating that 2 may bind to c-myc G4 DNA through extern groove binding mode. Furthermore, fluorescence resonance energy transfer (FRET) assay indicated that the melting point of c-myc G4 DNA treated with 1 and 2 increased 15.5 and 16.5 °C, respectively. Finally, molecular docking showed that 1 can bind to c-myc G4 DNA in the extern groove formed by base pairs G7–G9 and G22–A24, and 2 inserts into the small groove of c-myc G4 DNA formed by base pairs T19–A24. In summary, these ruthenium(II) complexes, especially 2, can be developed as potential c-myc G4 DNA stabilizers and will be exploited as potential anticancer agents in the future. [ABSTRACT FROM AUTHOR]

Available pyrrolylalkynones with tetrahydroindolyl, cycloalkanopyrrolyl, and dihydrobenzo[g]indolyl moieties, acylethynylcycloalka[b]pyrroles, are readily annulated with Δ1-pyrrolines (MeCN/THF, 70 °C, 8 h) to afford a series of novel pyrrolo[1′,2′:2,3]imidazo[1,5-a]indoles and cyclohepta[4,5]pyrrolo[1,2-c]pyrrolo[1,2-a]imidazoles functionalized with an acylethenyl group in up to an 81% yield. This original synthetic approach contributes to the arsenal of chemical methods promoting drug discovery. Photophysical studies show that some of the synthesized compounds, e.g., benzo[g]pyrroloimidazoindoles, are prospective candidates for TADF emitters of OLED. [ABSTRACT FROM AUTHOR]

The present communication elaborates the synthesis of 1,2,3-triazoles using click chemistry and their antibacterial studies. Structures of the synthesized compounds have been assessed by infra-red, NMR and mass spectroscopic methods. The title compounds have been screened for their antibacterial, antibiofilm and time kill studies. The molecules 5f, 5b, 5e, 5c and 3b have shown excellent activity and remaining compounds have also been found to exhibit moderate activity against the test organisms employed. [ABSTRACT FROM AUTHOR]

The organic–inorganic lead halide hybrids comprising semiconducting perovskite components and organic modules have proven to be promising candidates for optoelectronic applications. The modulation of the inorganic components as optical centres by diverse organic cationic templates is under intense investigation. Herein, we successfully prepared new one-dimensional lead halide hybrid perovskites [L1]2n[Pb2Cl6]n∞·nH2O (1) and [PbBr2(L2)]n∞·0.5nH2O (2), and the dimeric complex [PbBr2(L3)]2 (3) in water media. In 1, 2-(2-hydroxyethyl)-2H-imidazo[1,5-a]pyridinium cation [L1]+ resulted from the oxidative condensation–cyclization between formaldehyde, ethanolamine and 2-pyridinecarbaldehyde (2-PCA); the polydentate Schiff base ligands L2 and L3 formed in the in situ condensation of 2-PCA and ethanolamine or ethylenediamine, respectively. The lead chloride hybrid 1 contains the previously unreported type of a [Pb2Cl6]∞ double chain constructed from three-edge- and five-edge-sharing PbCl6 octahedra, and cations forming π-bonded stacks aligned along the inorganic wires. In the crystal of 2, pairs of the double-side organically decorated [PbBr2(L2)]∞ chains built of corner-sharing PbBr3N2O octahedra arrange hydrophilic channels to host water molecules. In the solid state, the identically stacked dimers of 3 form columns parallel to the ab plane with the Pb2Br4 moieties in the column being strictly coplanar. Hirshfeld surface analysis was used to rationalize the packing patterns through hydrogen bonds of O−H···O/Cl and C−H···O/Cl types with the involvement of OH groups of [L1]+, L2 and water molecules in 1 and 2, as well as C–H∙∙∙Br hydrogen bonding in 2 and 3. The QTAIM analysis of non-covalent interactions in 1–3 was performed. According to the analysis of the solid-state UV–visible reflectance spectra by a Tauc plot, the optical band gap values of 1, 2 and 3 as direct gap semiconductors were estimated to be 3.36, 3.13 and 2.96 eV, respectively. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel imidazo[1,2- a ]pyridine derivatives were synthesized and characterized. • The compounds were evaluated against HIV-1 and HIV-2 in vitro. • Molecular docking and dynamics simulations showed stable interactions. • ADME predictions suggested acceptable pharmacokinetic profiles. Given the ease of synthetic accessibility and the promising biological profile demonstrated by both imidazo[1,2- a ]pyridine and Chalcone derivatives, a series of Chalcone-based imidazo[1,2- a ]pyridine derivatives were synthesized and characterized using 1H NMR, 13C NMR, Mass Spectrometry and FTIR techniques. Density functional theory (DFT) was employed to investigate the structural and electronic properties, providing insights into potential reactive sites. The synthesized compounds were evaluated in vitro for their antiviral properties against human immunodeficiency virus type-1 (HIV-1) and human immunodeficiency virus type-2 (HIV-2) in MT-4 cells. Furthermore, Molecular docking studies show strong binding affinities with HIV-1 reverse transcriptase and HIV-2 protease. To further understand the dynamic behavior and stability of these interactions, molecular dynamics (MD) simulations were conducted. The MD results indicated stable binding conformations of the ligands within the active sites, with low RMSD and RMSF values throughout the simulation, confirming the robustness of these interactions. ADME predictions suggested acceptable pharmacokinetic profiles, though solubility remains a limitation for these compounds. Although the in vitro antiviral activity was limited, the combination of in vitro and in silico approaches provided valuable insights, guiding further structural optimization to improve bioavailability and enhance the therapeutic potential of these derivatives. [ABSTRACT FROM AUTHOR]

An efficient method for the synthesis of pyrazolo [4,3-b]pyridines has been developed on the basis of readily available 2-chloro-3-nitropyridines via a sequence of SNAr and modified Japp–Klingemann reactions. The method offers a number of advantages including utilization of stable arenediazonium tosylates, operational simplicity as well as combining the azo-coupling, deacylation and pyrazole ring annulation steps in a one-pot manner. An unusual rearrangement (C-N-migration of the acetyl group) was observed and a plausible mechanism was proposed based on the isolated intermediates and NMR experiments. In addition, the developed protocol was successfully applied to the synthesis of 1-arylindazoles combining the Japp–Klingemann reaction and cyclization of the resulting hydrazone as a one-pot procedure. [ABSTRACT FROM AUTHOR]

A series of cyano- and amidino-substituted imidazo[4,5-b]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound 10, which contained an unsubstituted amidino group, and compound 14, which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC50 0.4 and 0.7 μM, respectively). All tested compounds lacked antibacterial activity, with the exception of compound 14, which showed moderate activity against E. coli (MIC 32 μM). Bromo-substituted derivative 7, which contained an unsubstituted phenyl ring (EC50 21 μM), and para-cyano-substituted derivative 17 (EC50 58 μM) showed selective but moderate activity against respiratory syncytial virus (RSV). [ABSTRACT FROM AUTHOR]