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Bioorganic & Medicinal Chemistry Sep 2012A set of 16 previously synthesized aryl-aminopyridine and aryl-aminoquinoline derivatives have been evaluated for cytotoxic activity against three cancer cell lines...
A set of 16 previously synthesized aryl-aminopyridine and aryl-aminoquinoline derivatives have been evaluated for cytotoxic activity against three cancer cell lines (human cervical cancer-HeLa; human chronic myeloid leukemia-K562; human melanoma-Fem-x) and two types of normal peripheral blood mononuclear cells, with and without phytohemaglutinin (PBMC-PHA; PBMC+PHA). Twelve of the studied compounds showed moderate cytotoxicity, with selectivity against K562 but not the remaining two cancer cell lines. Four compounds were not active in cytotoxicity assays, presumably due to high predicted lipophilicity and low solubility. To rationalize the observed cytotoxic effects, structure-based virtual screening was carried out against a pool of potential targets constructed using the inverse docking program Tarfisdock and bibliographical references. The putative targets were identified on the basis of the best correlation between docking scores and in vitro cytotoxicity. It is proposed that the mechanism of action of the studied aminopyridines involves the disruption of signaling pathways and cancer cell cycle through the inhibition of cyclin-dependent kinases and several tyrosine kinases, namely Bcr-Abl kinase and KIT receptor kinase. The obtained results can guide further structural modifications of the studied compounds aimed at developing selective agents targeting proteins involved in cancer cell survival and proliferation.
Topics: Aminopyridines; Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 22841617
DOI: 10.1016/j.bmc.2012.06.051 -
Journal of Medicinal Chemistry Jun 1998The structure of the noncovalent complex of human alpha-thrombin with a nonpeptide inhibitor containing a central phenyl scaffold,...
The structure of the noncovalent complex of human alpha-thrombin with a nonpeptide inhibitor containing a central phenyl scaffold, N-[2-[5-methyl-3-(2-chlorophenylsulfonyloxy)phenoxy]ethyl]-N- methyl-4 -aminopyridine (1), has been determined to 2.20 A resolution. In addition, the thrombin-bound structures of two distinct amino acid-based inhibitors (3 and 4) containing different aminopyridine-derived guanidine mimetics have been determined. Each compound occupies the same region of the active site and projects an aminopyridine, a central hydrophobic group, and an aryl group, into the S1, S2, and aryl subsites on thrombin. Nonpeptide 1 forms only one direct intermolecular hydrogen bond to the thrombin active site and forms no hydrogen bonds to ordered molecules of solvent. Close contacts are observed between main-chain carbonyl groups on thrombin and the edges of the central phenyl and aminopyridine rings and the sulfonyl group of 1 such that atoms carrying opposite partial charges are juxtaposed. Aminopyridine groups in 3 and 4 also form close contacts with the edges of carbonyl groups on thrombin and are flexibly accommodated in the S1 subsite. Superposition of the bound conformations of 1 and D-Phe-Pro-amidobutylguanidine (2) revealed that the central phenyl scaffold of 1 substitutes for the peptide main chain of 2.
Topics: Aminopyridines; Binding Sites; Crystallography, X-Ray; Dipeptides; Enzyme Inhibitors; Guanidines; Humans; Models, Molecular; Molecular Conformation; Molecular Mimicry; Protein Conformation; Thrombin
PubMed: 9622548
DOI: 10.1021/jm970796l -
Biophysical Chemistry Jun 2001This work presents a theoretical analysis of the molecular determinants responsible for the pharmacological activity (K(+) channel blocking) of aminopyridines. Thus, DFT...
This work presents a theoretical analysis of the molecular determinants responsible for the pharmacological activity (K(+) channel blocking) of aminopyridines. Thus, DFT theory at the B3LYP/cc-pVDZ level is applied to a series of active compounds: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. The two forms present in the biological environment, neutral and cationic (protonated), are considered in vacuum as well as in aqueous solution. The results show pyramidal and planar structures for the neutral and cationic forms, respectively. An analysis of the topology of the electron density show that an increase in conjugation between the pyridine ring and the amine group is responsible for the observed planarity of the protonated forms. By computing the Laplacian of the charge density we found the pyridine nitrogen to be the preferred protonation site, as a consequence of a much higher curvature of the charge density field. Also, from three-dimensional (3D) isoLaplacian diagrams a common reactivity pattern is only found in the charged forms. This reactivity pattern implies that interaction with the biological receptor site is mediated by electrostatic interactions and hydrogen bonding. Development of a physical-mathematical model allows identification of the specific relationship of the pharmacological activity index with the affinity for the receptor and the protonation ability.
Topics: Aminopyridines; Models, Chemical; Potassium Channel Blockers; Static Electricity
PubMed: 11403883
DOI: 10.1016/s0301-4622(01)00151-x -
Organic Letters May 2014An efficient synthesis of 11H-pyrido[2,1-b]quinazolin-11-one through palladium-catalyzed C(sp(2))-H pyridocarbonylation of N-aryl-2-aminopyridines has been developed....
An efficient synthesis of 11H-pyrido[2,1-b]quinazolin-11-one through palladium-catalyzed C(sp(2))-H pyridocarbonylation of N-aryl-2-aminopyridines has been developed. The pyridyl group acts as an intramolecular nucleophile for the first time in C-H carbonylation reactions.
Topics: Aminopyridines; Catalysis; Cyclization; Molecular Structure; Palladium; Quinazolinones
PubMed: 24804565
DOI: 10.1021/ol501070g -
Neurodegenerative Disease Management Dec 2020Symptomatic treatment has a great relevance for the management of patients with neurologic diseases, since it reduces disease burden and improves quality of life....
Symptomatic treatment has a great relevance for the management of patients with neurologic diseases, since it reduces disease burden and improves quality of life. Aminopyridines (APs) are a group of potassium (K+) channel blocking agents that exert their activity both at central nervous system level and on neuromuscular junction. This review describes the use of APs for the symptomatic treatment of neurological conditions. We will describe trials leading to the approval of the extended-release 4-aminopyridine for MS and evidence in support of the use in other neurological diseases.
Topics: 4-Aminopyridine; Aminopyridines; Humans; Lambert-Eaton Myasthenic Syndrome; Multiple Sclerosis; Nervous System Diseases; Potassium Channel Blockers; Quality of Life
PubMed: 33054615
DOI: 10.2217/nmt-2020-0018 -
Bioorganic & Medicinal Chemistry Letters Apr 2020Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be...
Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis (MF). Here, we described the design, synthesis, and biological evaluation of a series of 2-aminopyridine derivatives. The results of enzymatic activity assays supported compound 16m-(R) as a potential and selective JAK2 inhibitor, which exhibited high inhibitory activity with an IC of 3 nM against JAK2, and 85- and 76-fold selectivity over JAK1 and JAK3, respectively. Structure-activity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.
Topics: Aminopyridines; Cell Line; Dose-Response Relationship, Drug; Drug Discovery; Humans; Janus Kinase 2; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Structure-Activity Relationship
PubMed: 32122740
DOI: 10.1016/j.bmcl.2020.127048 -
Journal of Neurology, Neurosurgery, and... Feb 1979A new drug, 4-aminopyridine, was prepared for use in humans and tested by repeated injections in six patients with myasthenia gravis. The drug caused improvement of...
A new drug, 4-aminopyridine, was prepared for use in humans and tested by repeated injections in six patients with myasthenia gravis. The drug caused improvement of muscle strength and neuromuscular transmission as demonstrated by clinical observations and repetitive electrical nerve stimulation. The drug was effective in cases without any other treatment as well as in cases undergoing treatment with anticholinesterases. It is concluded that 4-aminopyridine may be of value as a supplementary drug in the treatment of myasthenia gravis.
Topics: Action Potentials; Adult; Aminopyridines; Female; Humans; Male; Middle Aged; Muscle Contraction; Myasthenia Gravis
PubMed: 422965
DOI: 10.1136/jnnp.42.2.171 -
The Journal of General Physiology Jul 1982The blocking action of 4-aminopyridine (4-AP) and 3, 4-diaminopyridine (Di-AP) on transient potassium current (IA) in molluscan central neurons was studied in internal...
The blocking action of 4-aminopyridine (4-AP) and 3, 4-diaminopyridine (Di-AP) on transient potassium current (IA) in molluscan central neurons was studied in internal perfusion voltage-clamp experiments. Identical blocking effects were seen when the drugs were applied either externally or internally. It was found that aminopyridines have two kinds of effects on IA channels. The first involves block of open channels during depolarizing pulses and results in a shortening of the time to peak current and an increase in the initial rate of decay of current. This effect of the drug is similar to the block of delayed potassium current by tetraethylammonium (TEA). The other effect is a steady block that increases in strength during hyperpolarization, is removed by depolarization, and is dependent on the frequency of stimulation. The voltage dependence of steady state block approximates the voltage dependence of inactivation gating a changes e-fold in approximately 10 mV. These data suggest that the strength of block may depend on the state of IA gating such that the resting state of the channel with open inactivation gate is more susceptible to block than are the open or inactivated states. A multistate sequential model for IA gating and voltage-dependent AP block is developed.
Topics: 4-Aminopyridine; Amifampridine; Aminopyridines; Animals; Electric Conductivity; In Vitro Techniques; Ion Channels; Membrane Potentials; Microelectrodes; Mollusca; Neural Inhibition; Neurons; Potassium
PubMed: 6288835
DOI: 10.1085/jgp.80.1.1 -
Archiv Der Pharmazie Apr 1986
Topics: Aminopyridines; Aminoquinolines; Animals; Anticonvulsants; Chemical Phenomena; Chemistry; Cyclization; Mice; Motor Activity
PubMed: 3718185
DOI: 10.1002/ardp.19863190410 -
Molecules (Basel, Switzerland) Oct 2016Non-heme iron(II) complexes are widespread synthetic enzyme models, capable of conducting selective C-H oxidation with H₂O₂ in the presence of carboxylic acid... (Review)
Review
Non-heme iron(II) complexes are widespread synthetic enzyme models, capable of conducting selective C-H oxidation with H₂O₂ in the presence of carboxylic acid additives. In the last years, structurally similar manganese(II) complexes have been shown to catalyze C-H oxidation with similarly high selectivity, and with much higher efficiency. In this mini-review, recent catalytic and mechanistic data on the selective C-H oxygenations with H₂O₂ in the presence of manganese complexes are overviewed. A distinctive feature of catalyst systems of the type Mn complex/H₂O₂/carboxylic is the existence of two alternative reaction pathways (as found for the oxidation of cumenes), one leading to the formation of alcohol, and the other to ester. The mechanisms of formation of the alcohol and the ester are briefly discussed.
Topics: Aminopyridines; Hydrogen Peroxide; Manganese; Oxidation-Reduction
PubMed: 27809257
DOI: 10.3390/molecules21111454