Series Of Pyridine Derivatives Research Articles

Novel biologically active pyridine derivatives: Synthesis, structure characterization, in vitro antimicrobial evaluation and structure-activity relationship

The rate of microbial resistance has continued to rise significantly as the availability of new antibiotics has declined. A new series of pyridine and thienopyridine derivatives were designed, synthesized and tested as antimicrobial agents. The reaction of 4-bromo acetophenone and vetraldehyde (3,4-dimethoxy benzaldehyde) in ethanol and sodium hydroxide solution afforded the corresponding chalcone which was used as a suitable precursor to prepare a new series of pyridine derivatives. The treatment of the latter chalcone with 2-cyanothioacetamide afforded the corresponding pyridinethione which was used as a precursor to synthesize the targeted thienopyridine derivatives in good to excellent yield by the reaction with 2-chloro-N-arylacetamide derivatives, α-haloketones, methyl iodide or chloroacetonitrile in one or two steps. The structure of the synthesized compounds was confirmed chemically by their preparations with other pathways and their spectral data. The newly synthesized pyridine and thienopyridine derivatives exhibited good to strong antimicrobial activity against microbial strains E. coli, B. mycoides and C. albicans. With maximal antimicrobial activity against B. mycoides (33 mm) and C. albicans (29 mm), respectively, compounds 12a and 15 demonstrated the highest inhibition zone. Compound 12a prevented the growth of E. coli, at MIC level of 0.0195 mg/mL, and B. mycoides and C. albicans at MIC level below than 0.0048 mg/mL, respectively. Additionally, compound 15 prevented the visible growth of E. coli, B. mycoides, and C. albicans at MIC values of >0.0048, 0.0098, and 0.039 mg/mL, respectively. The relation between the chemical structure of the synthesized pyridine and thienopyridine compounds and their antimicrobial properties was discussed in the SAR study.

Synthesis And Anti-Fungal Activity of N'-(3-Bromophenyl)-2-{[5-(4-Methylpyridine-3-Yl)-1,3,4-Oxadiazol-2-Yl] Sulfanyl} Acetohydrazides Derivatives

A series of Pyridine derivatives were prepared and evaluated for, antibacterial and antifungal activities. The title compounds were prepared by condensation of substituted aromatic aldehydes with N'-(3-bromophenyl)-2-{[5-(4-methylpyridine-3-yl)-1,3,4-oxadiazol-2-yl] sulfanyl} acetohydrazides. The structures of all these compounds were confirmed by their spectral studies. Among synthesized compounds (DK-IB, DK-IC, DK-IG, and DK-IH) have shown good anti-fungal activity and Anti-Microbial Activity (500 µg mL-1) when compared to reference drugs Ketoconazole (25µg mL-1) and Chloramphenicol (25 µg mL-1). In this study, few derivatives showed a broad spectrum of antimicrobial activity at low concentrations. The MICs (Minimum inhibitory concentration) of some compounds are 8-16µg mL-1.

Rational design of novel pyridine-based drugs candidates for lymphoma therapy

Research efforts to develop an effective drug for lymphoma with minimal side effects are still very slow. To aid the discovery of new lymphoma drug, we led an extensive in silico computational study based on pharmacophore QSAR modeling, DFT, Molecular Docking, ADME-Tox, biophysical simulation approaches such as Molecular Dynamics analysis (MD) and comprehensive MM-GBSA free binding energy computations on a novel series of pyridine derivatives as promising MALT1 allosteric inhibitors (PDB code: 4I1R). The developed QSAR models demonstrated a strong correlation between the 2D/3D structural properties of pyridine derivatives and their biological inhibitory activity against MALT1 protease enzymatic activity. Based on detailed structural characterizations provided by the QSAR modeling, the biological inhibitory activity of four novel small molecules derived from the template molecule S40 (pIC50 = 8.00) was improved. Based on the molecular modeling and computer-aided drug design approaches used in this work, the lead novel compounds C2 (pIC50 > 8, BE = -9.4 kcal/mol, ΔGbind = -58.15 kcal/mol) and C3 (pIC50 > 8, BE = -8.7 kcal/mol, ΔGbind = -51.31 kcal/mol) were identified as optimal candidate allosteric inhibitors for MALT1 compared to the synthesized templates molecules S40 and Thioridazine. Finally, biophysical simulations demonstrated the high stability of the modeled ligands C2 and C3 inside the active pocket of the MALT1 protease in aqueous conditions throughout the 100 ns trajectory of the MD simulations. Thus, small designed hit compounds C2 and C3 can be used as valid references for design new drugs for lymphoma therapy by targeting MALT1 protease enzymatic activity.

Efficient synthesis and biological evaluation of some new series of pyridine derivatives: Promising and potent new class of anticancer agents

AbstractIn an attempt to develop potent anticancer agents, we have synthesized some substituted pyridine derivatives. Alkylation of the pyridine‐3‐carbonitrile 1a by chloroacetonitrile or methyl iodide and ethyl iodide produced the O‐alkylated nicotinonitrile derivatives (2–4), respectively. The reaction of nicotinonitrile 1a with acetic anhydride furnished the N‐acetyl derivative 5. In addition, the reaction of 1a with concentrated sulfuric acid yielded compound 6 whereas its reaction with chloroacetone gave the corresponding 2‐alkoxy‐pyridine derivative 7 which then refluxed with sodium methoxide to give compound 8. Furthermore, alkylation of 1a‐c with methyl bromoacetate and ethyl bromoacetate produced the corresponding methyl, ethyl ester derivatives 9, 10a–c, respectively. The reaction of ethyl ester 10c with a solution of sodium hydroxide in ethanol afforded the corresponding acid derivative 11. Hydrazinolysis was carried out by the reaction of ethyl ester 10a,c with hydrazine hydrate to afford the desired acetohydrazide derivative 12a,c which was used as a key intermediate for the synthesis of substituted pyridine derivatives 13–19. Chlorination of 1a with phosphorus oxychloride afforded the 2‐chloro derivative 20 which react with excess of hydrazine hydrate to yield compound 21. All synthesized compounds were characterized using IR, NMR, mass spectra, and elemental analysis. Their cytotoxic activity was evaluated against three different cancer cell lines, including breast (MCF‐7), colon (HCT‐116), and ovarian (SKOV3) cancers as well as human normal cells EA.hy 926 (human endothelial somatic cell hybrid). In general, compounds 3, 4, 5, 9, 12a, 12b, 13, 14, 15, 16, 18, 19, 21 exhibited high cytotoxicity against cancer cell lines. Besides that, the large number of synthesized compounds exhibited moderate anticancer activities.

Dye-sensitized photoanode decorated with pyridine additives for efficient solar water oxidation

Splitting water into hydrogen and oxygen by dye-sensitized photoelectrochemical cell (DSPEC) is a promising approach to solar fuels production. In this study, a series of pyridine derivatives as surface additives were modified on a molecular chromophore and water oxidation catalyst co-loaded TiO2 photoanode, TiO2|RuP, 1 (RuP = Ru(4,4′-(PO3H2)2-2,2′-bipyridine)(2,2′-bipyridine)2, 1 = Ru(bda)(L)2, (bda = 2,2′-bipyridine-6,6′-dicarboxylate, L = 10-(pyridin-4-yloxy)decyl)phosphonic acid). The addition of pyridine additives was found to result in up to 42% increase in photocurrent. Under simulated sun-light irradiation, TiO2|RuP, 1, P1 (P1 = 4-Hydroxypyridine) produced a photocurrent density of 1 mA/cm2 at a bias of 0.4 V vs. NHE in acetate buffer. Moreover, the observed photocurrents are correlated with the electron-donating ability of the substituent groups on pyridine ring. Transient absorption measurements and electrochemical impedance spectroscopy revealed that surface-bound pyridine can effectively retard the back-electron transfer from the TiO2 conduction band to the oxidized dye, which is a major process responsible for energy loss in DSPECs.

Synthesis of Novel Pyridine Bearing Biologically Active Imidiazolyl, Pyrazolyl, Oxa/thiadiazolyl and Urea Derivatives as Promising Anticancer Agents.

A novel series of pyridine containing 1,3,4-oxa/thiadiazol derivatives 4a,b, pyrazole derivatives 5-7, thiazole derivatives 9a,b and 17a-c, urea derivatives 12a-c, imidiazole derivative 16, imidazo[1,2-a]pyridine derivatives 18a, b, tetrazole 19, pyrane 20 and pyridine derivatives 21 has been synthesized. This research aims to synthesize 6-(Trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl] amino} nicotinohydrazide 2 and 6-(trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl]amino} pyridin-3-carboaldhyde 15 as key intermediate for the synthesis of novel pyridine derivatives bearing different heterocyclic rings in order to study the additive effect of this ring toward tumor cell lines. 6-(Trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl]amino} nicotinohydrazide 2 was synthesized in a series of synthetic steps and was used as key intermediate for the synthesis of compounds 3-(1,3,4- oxa/thiadiazol-2-yl)-6-(trifluoromethyl)-N-(3- trifluoromethyl) phenyl) pyridin-2-amine 4a,b, (3,5-dimethyl- 1H-pyrazol-1-yl derivatives) [6-(trifluoromethyl)-2-{[3- trifluoromethyl) phenyl] amino} pyridin-3- yl]methanone 5a,b, 6-8, 9a,b and 12a-c. Also, 6-(trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl]amino} pyridin-3-carboaldhyde (15) was used as a key intermediate for the synthesis of novel series of pyridine derivatives with different heterocyclic ring (16-21). Structures of the newly synthesized compounds were established by elemental analysis and spectral data. All the synthesized compounds were screened for their in vitro anticancer activity against liver cancer (HepG2), human colon cancer (HT-29) and human breast adenocarcinoma cell lines (MCF-7). All the synthesized compounds were investigated for their in vitro antitumor activity. Compounds 4b, 9a,b and 19 showed higher antitumor activity than the doxorubicin. Interestingly, pyridine with pfluorophenyl urea 12a demonstrated the most potent antitumor activity. The activity of these compounds is strongly dependent on the basic skeleton of the molecules and the nature of the heterocyclic ring attached to the pyridine moiety.

Four Keggin-based compounds constructed by a series of pyridine derivatives: synthesis, and electrochemical, photocatalytic and fluorescence sensing properties

Four compounds based on Keggin anions and AgI ions were obtained, the photocatalytic and electrochemical properties were studied. Compound 4 can act as a Hg2+ fluorescence sensor.

SYNTHESIS OF β-( o -HYDROXYBENZYL)PYRIDINES BY THREE-COMPONENT CONDENSATION OF AMMONIA, CARBONYL-SUBSTITUTED 4 Н -CHROMENES, AND СН ACIDS

A series of pyridine derivatives containing a 2-hydroxybenzyl or (2-hydroxynaphthalen-1-yl)methyl substituent were obtained by treating carbonyl-substituted 4Н-chromenes and 1Н-benzo[f]chromenes with ammonia and 1,3-dicarbonyl compounds or aromatic ketones as a result of the carbo-Michael reaction, chromane ring opening, and cyclodehydration.

Synthesis of β-(о-hydroxybenzyl)pyridines by three-component condensation of ammonia, carbonyl-substituted 4Н-chromenes, and СН acids

A series of pyridine derivatives containing a 2-hydroxybenzyl or (2-hydroxynaphthalen-1-yl)methyl substituent were obtained by treating carbonyl-substituted 4Н-chromenes and 1Н-benzo[f]chromenes with ammonia and 1,3-dicarbonyl compounds or aromatic ketones as a result of the carbo-Michael reaction, chromane ring opening, and cyclodehydration.

Role of Synergistic C–H···N and C–H···O H-Bonding Interactions in Self-Assemblies of a Phthalocyanine Derivative and Several Pyridine Derivatives

Phthalocyanine (Pc)-based fused derivatives are widely used materials in many nanotechnology fields, such as photovoltaic devices, pigments, and sensors, because of their excellent physical and chemical properties. It has been proven that most Pc molecules can self-assemble with ligands by the metal–ligand coordination interaction or π–π stacking interaction, yet little is known about the supramolecular packing of H-bonded Pc derivatives. Herein, we report the self-assembly of rylene-annulated Pc (ZnPcPDI4) with a series of pyridine derivatives at the solid/liquid interface via synergistic C–H···N and C–H···O H-bonding interactions. We use scanning tunneling microscopy combined with theoretical simulations to demonstrate the interactions in the self-assembled process. The intermolecular binding modes of Pcs with ligands and their thermodynamics stability are revealed by the combination of density functional theory and molecular dynamics simulations with the modified force field parameters. This study prov...

New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation

A new series of pyridine derivatives with carbamic or amidic function has been designed and synthesized to act as cholinesterase inhibitors. The synthesized compounds were tested toward EeAChE and hAChE and toward eqBChE and hBChE. The carbamate 8 was the most potent hAChE inhibitor (IC50 = 0.153 ± 0.016 μM) while the carbamate 11 was the most potent inhibitor of hBChE (IC50 = 0.828 ± 0.067 μM). A molecular docking study indicated that the carbamate 8 was able to bind AChE by interacting with both CAS and PAS, in agreement with the mixed inhibition mechanism. Furthermore, the carbamates 8, 9 and 11 were able to inhibit Aβ42 self-aggregation and possessed quite low toxicity against human astrocytoma T67 and HeLa cell lines, being the carbamate 8 the less toxic compound on both cell lines.

Surface modification of graphene oxide by pyridine derivatives for copper(II) adsorption from aqueous solutions

Abstract Graphene oxide (GO) was covalently modified by series of pyridine derivatives with SOCl2 activation method for adsorption of Cu(II) for the first time. The effects of pyridine derivatives structure, adsorption thermodynamics, kinetics and adsorbents reusability were investigated. The adsorption capacity of modified GO is related to the number of pyridine groups, and substituent position. The maximum adsorption capacity of 4′-carboxy-2,2′:6′,2″-terpyridine modified GO (GO-CTPy) reaches 119.6 mg g−1, which is much higher than that of other modified GO. The adsorption can be well described by the Langmuir isotherm model and pseudo-second-order kinetic model. GO-CTPy exhibited excellent regeneration and reusability.

Synthesis and structure–activity relationship of 2,6-disubstituted pyridine derivatives as inhibitors of β-amyloid-42 aggregation

It is assumed that amyloid-β aggregation is a crucial event in the pathogenesis of Alzheimer’s disease. Novel 2,6-disubstituted pyridine derivatives were designed to interact with the β-sheet conformation of Aβ via donor–acceptor–donor hydrogen bond formation. A series of pyridine derivatives were synthesized and tested regarding their potential to inhibit the aggregation of Aβ. The 2,6-diaminopyridine moiety was identified as a key component to inhibit Aβ aggregation. Overall, compounds having three 2,6-disubstituted pyridine units separated by at least one C2- or C3-linker displayed the most potent inhibition of Aβ aggregation.

Novel Pyrazolo[3,4-b]pyridine Derivatives: Synthesis, Characterization, Antimicrobial and Antiproliferative Profile.

Three novel series of pyridine derivatives, namely Schiff's bases, 4-thiazolidinones and azetidin-2-ones bearing pyrazolo[3,4-b]pyridine moiety, have been synthesized. The chemical structures of the synthesized compounds were characterized. The compounds were tested for their antimicrobial activity using the agar well diffusion and broth macrodilution methods. The compounds were also evaluated for their antiproliferative activity using the sulforhodamine B (SRB) assay. The majority of the tested compounds exhibited slight to high antimicrobial activity against the test microorganisms with minimum inhibitory concentrations (MICs) of 0.12-62.5 µg/mL when compared to that of 3 standard antimicrobial agents (Ampicillin, 0.007-0.03 µg/mL; Gentamicin; 0.015-0.24 µg/mL; and Amphotericin B, 0.03-0.98 µg/mL). Compound (7b) was found to be nearly as active as the standard antimicrobial drug Amphotericin B against Fusarium oxysporum fungal strain with MIC of 0.98 µg/mL. Some of the test compounds showed remarkable cytotoxic activities against Hep G2 (hepatocellular carcinoma) cells (IC50=0.0158-71.3 µM) in comparison to the standard anticancer drug doxorubicin (IC50=0.008 µM). Among the compounds tested, (5), (6a), (6b), (7b), and (10) exhibited antiproliferative potency (IC50=0.0001-0.0211 µM) that was found to be better than that of doxorubicin (IC50=0.099 µM) against MCF7 (breast adenocarcinoma) cells. In particular, (7b) displayed the highest significant antiproliferative efficacy against both Hep G2 and MCF7 cell lines showing IC50 values of 0.0158 µM and 0.0001 µM, respectively. Our findings suggest that the synthesized compounds may be promising candidates as novel antimicrobial and antiproliferative agents.

Pyridine C-region analogs of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

A series of pyridine derivatives in the C-region of N-((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as to multiple hTRPV1 activators. It demonstrated strong analgesic activity in the formalin test in mice with full efficacy and it blocked capsaicin-induced hypothermia in vivo.

α2-adrenoceptor antagonists: synthesis, pharmacological evaluation, and molecular modeling investigation of pyridinoguanidine, pyridino-2-aminoimidazoline and their derivatives.

We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the α2-adrenoceptor. Furthermore, the compounds exert their effects at the α2-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the α2A- and α2C-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor.

Synthesis, biological evaluation and molecular modeling of novel series of pyridine derivatives as anticancer, anti-inflammatory and analgesic agents

This paper presents a combined synthesis; characterization, computational and biological activity studies of novel series of pyridines heterocyclic compounds. The compounds have been characterized by elemental analyses and spectral like IR, 1H NMR, 13C NMR and MS studies.Michael addition of substituted-2-methoxycarbonylacetanilide 2a,b on the α-substituted cinnamonitriles 3a–d gave the corresponding 2-pyridone derivatives 5–10. Structures of the titled compounds cited in this article were elucidated by spectrometric data (IR, 1H NMR, 13C NMR and MS). The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from the calculation of molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, HOMO and LUMO energy. Various in vitro antitumor as well as in vivo anti-inflammatory and analgesic activities of the synthesized compounds were investigated. Evaluation of anti-inflammatory activity of test compounds was performed using carrageenan induced paw edema in rats. All the tested compounds showed moderate to good activity. The SAR results indicate that all compounds showed moderate to good activity, among these 7 and 10 compounds having –N(CH3)2 group are most effective.

Synthesis and Characterization of Mesogen-Jacketed Liquid Crystalline Polymers through Hydrogen-Bonding

In an attempt to construct mesogen-jacketed liquid crystalline polymers through noncovalent interactions, poly(2-vinylbenzene-1,4-dioic acid) and five series of pyridine derivatives were synthesized as hydrogen-bonding donor and acceptors, respectively. The structures of the compounds were confirmed by 1H NMR, FT-IR, and gel permeation chromatography. A series of complexes with the same degree of polymerization and polydispersity were obtained by mixing the hydrogen-bonding donor and acceptors. The hydrogen-bonds were confirmed by FT-IR spectra. We found that the rigidity and structures of pyridine derivatives and the strength of the hydrogen-bonding all influenced the liquid crystalline behaviors of the resulting complexes. Smectic A and columnar nematic phases were observed in complexes PPANCx and PPANNEC, respectively.

Pyridine Directed Assembly of Di-O-Alkyl-tris-p-Carboxylatocalix[4]arenes

Crystallization of four di-O-alkyl-tris-p-carboxylatocalix[4]arenes from a series of pyridine derivatives has been carried out to investigate the effect of introducing alkyl groups around the pyridine guest/template. Where single crystals were obtained, for 12 of 24 possible structures, in all but one case the calixarenes assemble with the pyridine derivative into hydrogen-bonded head-to-head dimers within extended bilayer or nanotubular arrays.

Pyridine Directed Assembly of Tetra-O-Alkyl p-Carboxylatocalix[4]arenes

A crystallization study of four tetra-O-alkyl p-carboxylatocalix[4]arenes from a series of pyridine derivatives has been carried out to investigate the effects of varying the length of the calixarene lower-rim alkyl group introduced, and the introduction of alkyl groups around the pyridine guest/template. Analysis of 11 of 24 possible sets of single crystals formed shows trends in self-assembly based on the availability of the calixarene cavity for guest/template inclusion, either Py···CO2H or CO2H···CO2H synthons, and dominance of one synthon over the other depending on the position of alkyl groups around the pyridine ring.