Pyridine Analogues Research Articles

Molecular hybridization-based design, PASE three-component synthesis, antiproliferative activity and molecular modelling studies of N,N-dimethylaminophenyl substituted 5H-chromeno[2,3-b]pyridine analogs

A series of N,N-dimethylaminophenyl substituted 5H-chromeno[2,3-b]pyridine derivatives were designed using molecular-hybridization strategy and synthesised using a pot, atom and step economy (PASE) approach. The synthesis involves the one-pot three component reaction of salicyaldehydes, 3-(dimethylamino)phenol and 2-aminopropene-1,1,3-tricarbonitrile catalyzed by triethylamine as a catalyst in ethanol at reflux. This methodology has many beneficial features, including a broad substrate range, easy work up, non-column chromatographic separation, and high product yield. All newly synthesized compounds were screened for their antiproliferative activity towards several human cancer cell lines such as PC3 (prostate), MDA-MB-231 (breast cancer), MIA Paca-2 (pancreatic), HEK293 (hypotriploid) and CHO (Chinese hamster ovary). The SAR identified the compounds 4e and 4k as the most potent analogs in the series, while 4c and 4d demonstrated moderate antitumoral activities. Molecular docking studies revealed that the lead compounds selectively occupy the colchicines binding site of tubulin. Molecular dynamics simulation results supported anticancer efficacy of the synthesized compounds with high molecular stability in binding pocket of heterodimer.

Oxidation studies of isomeric lutidins under liquid phase ozonation conditions

The reaction of isomeric lutidines with ozone in acetic acid solution was investigated. The composition of final and intermediate products was established. Kinetic studies of the interaction of isomeric lutidines with ozone in acetic acid solution were studied, with a possible reaction mechanism proposed. The influence of methyl groups on the ozonation of pyridine analogues was studied.

Recent developments of imidazo[1,2-a]pyridine analogues as antituberculosis agents.

Over the past 2000 years, tuberculosis (TB) has killed more people than any other infectious disease. In 2021, TB claimed 1.6 million lives worldwide, making it the second leading cause of death from an infectious disease after COVID-19. Unfortunately, TB drug discovery research was neglected in the last few decades of the twentieth century. Recently, the World Health Organization has taken the initiative to develop new TB drugs. Imidazopyridine, an important fused bicyclic 5,6 heterocycle has been recognized as a "drug prejudice" scaffold for its wide range of applications in medicinal chemistry. A few examples of imidazo[1,2-a]pyridine exhibit significant activity against multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Here, we critically review anti-TB compounds of the imidazo[1,2-a]pyridine class by discussing their development based on the structure-activity relationship, mode-of-action, and various scaffold hopping strategies over the last decade, which is identified as a renaissance era of TB drug discovery research.

Spectroscopic characterization and the reactivity of a high valent (L)Cu(III) species supported by a proline-based pseudopeptide.

Inspired by copper-based metalloenzymes, we aim to incorporate amino acids into our ligands to facilitate active copper intermediates that serve as functional and structural models for these enzymes. Herein, we report the synthesis of a Cu(II) complex with a C2 symmetric proline-based pseudopeptide LH2 (N,N'-(ethane-1,2-diyl)bis(pyrrolidine-2-carboxamide)), which is capable of supporting an [(L)Cu(III)]+ (3) intermediate in MeOH : CH3CN (1 : 20) at -30 °C. From comparative studies with the pyridine analog Cu(II) complex, it was demonstrated that the incorporation of amino acid in the ligand framework decreased the Cu(III)/Cu(II) redox potential significantly to react readily with mCPBA and CAN. The newly generated [(L)Cu(III)]+ can promote hydrogen atom abstraction reactions with phenolic substrates.

Diheme cytochromes: Effect of mixed-axial ligation on the electronic structure and electrochemical properties with cobalt porphyrin dimer

A series of six-coordinate diCo(III) porphyrin dimers, as synthetic analogues of diheme cytochromes, have been reported here having bis(imidazole), bis(pyridine) and mixed thiophenolate−pyridine/imidazole axial ligands. In the X-ray structures of bis(imidazole) and bis(pyridine) complexes, the axial ligands are in perpendicular orientation while they are parallelly oriented in their monomeric analog. The porphyrin rings are also highly ruffle-distorted in dimer but planar in monomer which reflect the effect of intramolecular interaction between two Co(porphyrin) units in dimers. In the X-ray structure of diCo(III) thiophenolate−pyridine mixed-ligated complex, the axial Co-S and Co–N(py) distances are 2.256(1) and 2.063(2) Å, respectively. The Co–N(py) distance of 2.063(2) Å is much longer than the distances of 1.961(3) and 1.972(3) Å observed in bis(pyridine) complex and the Co-S distance is larger than Co–N(py) in the mixed ligated complex which results in a displacement of Co by 0.15 Å towards the pyridine ligand from the mean porphyrin plane. Indeed, this is the first X-ray structure of a metalloporphyrin with mixed thiophenolate−pyridine axial ligands. The effect of mixed-axial ligation is demonstrated by a blue-shift of the Soret band in the UV–visible spectroscopy and also a positive shift of the Co(III)/Co(II) redox couple as compared to their bis(pyridine) analogue. The redox potentials are shifted to a large negative value just upon replacing the metal from iron to cobalt. The present investigation emphasizes the role of axial ligation, metal ions, and also the effect of heme-heme interaction in controlling the spectral and electrochemical properties.

Theoretical and experimental study of new deep eutectic solvents for extraction of perfluorinated iodoalkanes

There is a lack of attention and reporting in aspects of the neutral/nonionic perfluoroalkyl substances (PFASs) and corresponding treatment mechanisms. Herein, new function-oriented deep eutectic solvents (DESs) with pyridine moiety were designed for perfluorinated iodoalkanes extraction from the oil phase. The effect of hydrogen bond acceptor (HBA) functional groups on the effectiveness of targets retrieval was investigated. Moreover, different structural, quantum-chemical, solvatochromic, and statistical thermodynamics parameters were conducted, calculated, and correlated to the distribution coefficients of the studied DESs. Results showed that functional groups of HBAs significantly affected the extraction effectiveness of eutectic mixtures. The pyridine ring-based DESs with the CO group possessed the highest extraction efficiencies among the studied groups. To some extent, the extraction performances of the DES were substantially affected by the electrostatic potential extrema of the donor halogen atom and pyridine analogues. For targets with relatively short alkyl chain length, the topological indices had a positive relationship with the treatment efficacy of the DESs, and the quantum-chemical parameters of these solvents had a strong negative relationship with them. For targets with long alkyl chain length, the solvatochromic parameters of DES had a great influence on the distribution coefficients and also on the selectivity of these solvents. Furthermore, the halogen and hydrogen bonds presented cooperativity, clarifying via quantum-chemistry calculations. The synergism mechanism between them is beneficial to the extraction of perfluorinated iodoalkanes. Besides shedding light on the structure–property-performance relationships of the DESs, these findings also provided novel insights into the directional design and selection of DESs.

Synthesis and high sensitivity Al3+ recognition of fluorescent probe molecule based on pincer bis‐N‐heterocyclic carbene

Two bis-(Nitrogen-Heterocyclic Carbene, NHC) derivatives, 1, 3-bis[1-(quinolin-8-yl)-imidazolium-3-yl)]-benzene bis-hexafluorophosphate (2a), 2, 5-bis[1-(quinolin-8-yl)-imidazolium-3-yl)]-pyridine bis-hexafluorophosphate (2b), were synthesized, and characterized by 1H NMR and 13C NMR spectra and X-ray single crystal diffraction. The bis-NHC 2a was demonstrated as an excellent fluorescence chemo-sensor molecule for selectively recognition of Al3+ ion in aqueous-organic media. Its pyridine analogue molecule 2b haven't selectivity recognition character to metal ions with the fluorescence enhancement for most metal ions. A 1:1 binding ratio and strong supramolecular interaction between Al3+ ion and the carbonic hydrogen and quinoline nitrogen were suggested by Job's plot analysis and 1HNMR spectroscopy titrations of Al3+ ion and 2a. The detection limit for Al3+ ion was calculated to be 0.32 µM. The practical application in tap water samples has been evaluated, which reveals the potential applications of bis-NHC 2a in complicated environments.

Synthesis, biological evaluation and molecular docking of new triphenylamine-linked pyridine, thiazole and pyrazole analogues as anticancer agents

A new series of pyridine, thiazole, and pyrazole analogues were synthesized. The pyridone analogues 4a-e were synthesized by treating N-aryl-2-cyano-3-(4-(diphenylamino)phenyl)acrylamides 3a-e with malononitrile. Many 4-arylidene-thiazolidin-5-one analogues 6a-d were obtained by Knoevenagel reactions of 4-(diphenylamino)benzaldehyde (1) with their corresponding thiazolidin-5-one derivatives 5a-d. The structural elucidation of the products was proven by the collections of spectroscopic methods such as IR, 1H NMR, 13C NMR, and MS data. Their anti-cancer activity was examined against two cell lines, MDA-MB-231 (mammary carcinomas) and A-549 (lung cancer). Compared with cisplatin as a reference standard drug, 6-amino-4-(4-(diphenylamino)phenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3,5-dicarbonitrile (4b) and 6-amino-4-(4-(diphenylamino)phenyl)-1-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4e) exhibited better efficiency against the A-549 cell line, with IC50 = 0.00803 and 0.0095 μM, respectively. Also, these compounds 4b and 4e showed the most potency among the examined compounds against MDA-MB-231 with IC50 = 0.0103 and 0.0147 μM, respectively. The newly synthesized compounds were docked inside the active sites of the selected proteins and were found to demonstrate proper binding. 2-Cyano-2-(4,4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)-N-(p-tolyl)acetamide (6c) offered the highest binding affinity (− 8.1868 kcal/mol) when docked into (PDB ID:2ITO), in addition to 2-cyano-N-(4-(diethylamino)phenyl)-2-(4-(4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)acetamide (6a) gave the highest energy score (− 9.3507 kcal/mol) with (PDB ID:2A4L).

Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis.

Small molecules with nitrogen-containing scaffolds have gained much attention due to their biological importance in the development of new anticancer agents. The present paper reports the synthesis of a library of new dihydropyridine and pyridine analogs with diverse pharmacophores. All compounds were tested against the human tissue nonspecific alkaline phosphatase (h-TNAP) enzyme. Most of the compounds showed excellent enzyme inhibition against h-TNAP, having IC50 values ranging from 0.49 ± 0.025 to 8.8 ± 0.53 µM, which is multi-fold higher than that of the standard inhibitor (levamisole = 22.65 ± 1.60 µM) of the h-TNAP enzyme. Furthermore, an MTT assay was carried out to evaluate cytotoxicity against the HeLa and MCF-7 cancer cell lines. Among the analogs, the most potent dihydropyridine-based compound 4d was selected to investigate pro-apoptotic behavior. The further analysis demonstrated that compound 4d played a significant role in inducing apoptosis through multiple mechanisms, including overproduction of reactive oxygen species, mitochondrial dysfunction, DNA damaging, and arrest of the cell cycle at the G1 phase by inhibiting CDK4/6. The apoptosis-inducing effect of compound 4d was studied through staining agents, microscopic, and flow cytometry techniques. Detailed structure–activity relationship (SAR) and molecular docking studies were carried out to identify the core structural features responsible for inhibiting the enzymatic activity of the h-TNAP enzyme. Moreover, fluorescence emission studies corroborated the binding interaction of compound 4d with DNA through a fluorescence titration experiment.

Hybrid imidazo[1,2-a]pyridine analogs as potent ATX inhibitors with concrete in vivo antifibrosis effect.

In recent years, small-molecule inhibitors targeting the autotaxin (ATX)/lysophosphatidic acid axis gradually brought excellent disease management benefits. Herein, a series of imidazo[1,2-a]pyridine compounds (1-11) were designed as ATX inhibitors through a hybrid strategy by combining the imidazo[1,2-a]pyridine skeleton in GLPG1690 and the benzyl carbamate moiety in PF-8380. As indicated by FS-3-based enzymatic assay, the carbamate derivatives revealed moderate to satisfying ATX inhibitory potency (IC50 = 23-343 nM). Subsequently, the carbamate linker was altered to a urea moiety (12-19) with the aim of retaining ATX inhibition and improving the druglikeness profile. The binding mode analysis all over the modification process well rationalized the leading activity of urea derivatives in an enzymatic assay. Following further structural optimization, the diethanolamine derivative 19 exerted an amazing inhibitory activity (IC50 = 3.98 nM) similar to the positive control GLPG1690 (IC50 = 3.72 nM) and PF-8380 (IC50 = 4.23 nM). Accordingly, 19 was tested directly for in vivo antifibrotic effects through a bleomycin model (H&E staining), in which 19 effectively alleviated lung structural damage and fibrosis at an oral dose of 20 and 60 mg/kg. Collectively, 19qualified as a promising ATX inhibitor for potential application in fibrosis-relevant disease treatment.

Synthesis of novel pyridine and pyrimidine thioglycoside phosphoramidates for the treatment of COVID-19 and influenza A viruses

A novel series of pyridine, cytosine, and uracil thioglycoside analogs (4a–i, 9a,b, and 13a,b, respectively) and their corresponding phosphoramidates (6a–I, 10a,b, and 14a,b, respectively) were synthesized and assessed for their antiviral inhibitory activities in a dual-pathogen screening protocol against SARS-CoV-2 and influenza A virus (IAV). MTT cytotoxicity (TC50) and plaque reduction assays were used to explore inhibition and cytotoxicity percentage values for H5N1 influenza virus strain and the half-maximal cytotoxic concentration (CC50) and inhibitory concentration (IC50) for SARS-CoV-2 virus. Most of the tested compounds demonstrated dose-dependent inhibition behavior. Both cytosine thioglycoside phosphoramidates 10a and 10b exhibited the most potent profiles with 83% and 86% inhibition at 0.25 µM concentration against H5N1 and IC50 values of 12.16 µM, 14.9 µM against SARS-CoV-2, respectively. Moreover, compounds 10a and 10b have been shown to have the highest selectivity index (SI) among all the tested compounds against SARS-CoV-2 with 28.2 and 26.9 values, respectively.

Novel pyridine and pyrimidine derivatives as promising anticancer agents: A review

Pyridines and pyrimidines are the class of heterocyclic nitrogenous compounds having plethora of applications in anticancer drug development. These synthetic sources serve as the potent class of compounds in treatment of breast cancer, myeloid leukemia, pancreatic cancer, liver cancer and idiopathic respiratory fibrosis etc. The present review enumerates the results of studies published during past three years (2019–2021) on pyridine and pyrimidine analogues with their respective anticancer properties characterized in vitro or through in silico studies and illustrates their potential in development of anticancer agents. Recent advances on pyridine and pyrimidine analogues mentioned in this review add to the appealing opportunities for cancer therapy.

In silico selectivity modeling of pyridine and pyrimidine based CYP11B1 and CYP11B2 inhibitors: A case study

Designof selective drug candidates for highly structural similar targets is a challenging task for researchers. The main objective of this study was to explore the selectivity modeling of pyridine and pyrimidine scaffold towards the highly homologous targets CYP11B1 and CYP11B2 enzymes by in silico (Molecular docking and QSAR) approaches. In this regard, a big dataset (n = 228) of CYP11B1 and CYP11B2 inhibitors were gathered and classified based on heterocyclic ring and the exhaustive analysis was carried out for pyridine and pyrimidinescaffolds. The LibDock algorithm was used to explore the binding pattern, screening, and identify the structural feature responsible for the selectivity of the ligands towards the studied targets. Finally, QSAR analysis was done to explore the correlation between various binding parameters and structural features responsible for the inhibitory activity and selectivity of the ligands in a quantitative way. The docking and QSAR analysis clearly revealed and distinguished the importance of structural features, functional groups attached for CYP11B2 and CYP11B1 selectivity for pyridine and pyrimidine analogs. Additionally, the docking analysis highlighted the differentiating amino acids residues for selectivity for ligands for each of the enzymes. The results obtained from this research work will be helpful in designing the selective CYP11B1/CYP11B2 inhibitors.

Discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridines as potent and selective SST5 agonists for the treatment of congenital hyperinsulinism

SST5 receptor activation potently inhibits insulin secretion from pancreatic β-cells, and an orally available nonpeptide selective SST5 agonist may be used to effectively manage the blood glucose levels of congenital HI patients to avoid severe hypoglycemia. Our medicinal chemistry efforts have led to the discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridine analogs as potent SST5 agonists. This class of molecules exhibits excellent human SST5 potency and selectivity against SST1, SST2, SST3 and SST4 receptors. Leading compound 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl-5-fluorobenzonitrile (28, CRN02481) showed limited off-target activity and good pharmacokinetic profiles in both male Sprague Dawley rats and Beagle dogs to advance into further preclinical evaluations.

4-Aminobenzotriazole (ABTA) as a Removable Directing Group for Palladium-Catalyzed Aerobic Oxidative C-H Olefination.

4-Aminobenzotriazole (ABTA) was applied as an effective removable directing group (DG) in Pd-catalyzed C-H activation for the first time. Compared with the widely applied pyridine and quinoline analogs, ABTA showed significantly improved reactivity, achieving aerobic oxidative C-H olefination in excellent yields (up to 95% vs <50% with other reported DGs under identical conditions). Using this new strategy, macrocyclization was achieved to give cyclic peptides in good yields with easy ABTA removal under mild conditions, highlighting the promising potential of this new DG.

Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.

Self-Assembled Catalytic Nanoreactors from Molecular Brushes by Utilizing Postpolymerization Modification for Catalyst Attachment

Polymer-based catalytic nanoreactors, with the characteristics of easy preparation, good dispersion, and facile modulation of molecular structures, have been widely applied for various organic transformations. Usually, polymeric nanoreactors are fabricated via the self-assembly of amphiphilic copolymers in water, while the disassembly and instability of the relevant nanoreactors often compromise their potential applicability. Molecular brushes (MBs), as a kind of polymer with high-density grafted side chains on the linear polymer main chain, can be rapidly self-assembled into highly ordered nanostructures even at low concentrations. This study reports the fabrication of catalytic nanoreactors from molecular brushes of poly[norbornene–poly(bromoethyl methacrylate-co-methyl methacrylate)]-co-poly[norbornene polyethylene glycol monomethyl ether] (P[NB-(BEMA-co-MMA)]-co-P[NB-PEG]). The amphiphilic molecular brush was synthesized by combining reversible addition–fragmentation chain transfer (RAFT) polymerization and ring-opening metathesis polymerization (ROMP) techniques. Homogeneous catalysts, such as triethylenediamine and 4-(dimethylamino)pyridine analogues, were introduced by nucleophilic substitution with alkyl bromide on the side chain of molecular brushes. Furthermore, micellar catalytic nanoreactors were fabricated via self-assembly in deionized water. The resulted nanoreactors display high catalytic activities toward the Knoevenagel condensation reaction and acylation reaction of alcohol in water, respectively. This contribution describes a general method for constructing highly efficient molecular brush-based catalytic nanoreactors utilizing postpolymerization modification (PPM) for aqueous catalysis.

Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues.

Based on the molecular hybridization strategy, thirty-four imidazo[1,2-a]pyridine amides (IPAs) and imidazo[1,2-a]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated in vitro for anti-tubercular activity using the microplate Alamar Blue assay against Mycobacterium tuberculosis H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05-≤100 μg mL-1. Among these derivatives, IPA-6 (MIC 0.05 μg mL-1), IPA-9 (MIC 0.4 μg mL-1), and IPS-1 (MIC 0.4 μg mL-1) displayed excellent anti-TB activity, whereas compounds IPA-5, IPA-7 and IPS-16 showed good anti-TB activity (MIC 0.8-3.12 μg mL-1). The most active compounds with MIC of <3.125 μg mL-1 were screened against human embryonic kidney cells to check their cytotoxicity to normal cells. It was observed that these compounds were nontoxic (SI value ≥66). The ADMET characteristics of the final compounds were also predicted in silico. Further, using the Glide module of Schrodinger software, a molecular docking study of IPA-6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB 4TZK). Finally, molecular dynamics simulations were performed for 100 ns to elucidate the stability, conformation, and intermolecular interactions of the co-crystal ligand and significantly active compound IPA-6 on the selected target protein. IPA-6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 μg mL-1).

A novel triruthenium nitrosyl bearing a quinolinic ligand: a comparison of its spectroscopic behavior with its pyridine analogues

A comparative analysis of ruthenium nitrosyl spectroscopic data helps unravel the electronic character of the unit {RuNO}6[RuIIIRuIIIO].

Redox Activity of Iron Diazine-Diimine Carbonyl and Dinitrogen Complexes: A Comparative Study of the Influence of the Heterocyclic Ring.

A detailed investigation of the electronic structure of diazinediimine iron complexes and their comparison with the pyridine analogues reveals subtle but important differences, imparted by the supporting heterocycle. In the case of LFe(CO)2 complexes (L = pyrazine- and pyrimidinediimine), the characterization of three available redox states confirmed that whereas the nature of the electron-transfer processes is similar, the differences in π-acidity of the supporting heterocycle significantly affect the redox potentials. The reduction of LFe(CO)2 can yield either a ligand-centered radical (for L = pyrimidine) or a C-C-bonded dimer (for L = pyrazine), supported by a dearomatized core. In the latter case, the C-C bond can be reversibly cleaved oxidatively. Compared to the carbonyl analogues, employing weak-field N2 ligands triggers changes in electronic structure for the neutral and reduced LFe(N2) complexes (L = pyrimidinediimine). En route to the synthesis of the nitrogen complexes, the square-planar LFeCl (L = pyrimidinediimine) was isolated. The monoradical character of the supporting chelate triggers the asymmetric distribution of electron density around the heterocycle.