piperidines and quinoline

Epidermal growth factor and vascular endothelial growth factor-2 are important targets of tyrosine kinase for the treatment of various cancerous diseases. Combination of inhibition of both targets to produce synergy in the signal pathway is a critical approach to identify novel tyrosine kinase inhibitors. In this study, a series of new compounds derived from the 4-aminoquinoline as dual inhibitors were synthesized. The obtained results of cytotoxicity assay against human carcinoma cell lines indicated 0.8 µM for 4c against A549 showing its high efficiency in comparison to erlotinib. Pharmacophore modeling as a structure-based method was investigated on dual inhibitors and 4c which was compared with co-crystallized in the active site of EGFR and VEGFR-2. They have shown the same binding orientation as vandetanib, erlotinib and sorafenib. Molecular dynamics simulation results approved that Met769, Lys721, Asp1046, and Lys868 are key residues in two binding sites for dual activity. Ala1050 and Pro968 were identified as new amino acid interaction sites for dual inhibition. 4c showed more favorable stability than vandetanib in VEGFR-2 receptor for a 50 ns dynamic simulation. The high correlation between essential pharmacophoric features of designed compounds and lead inhibitors interactions provided a deeper insight into the structural basis of 4-aminoquinoline inhibition.

Topics: A549 Cells; Aminoquinolines; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; ErbB Receptors; Erlotinib Hydrochloride; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines; Protein Conformation; Quinazolines; Quinolines; Sorafenib; Vascular Endothelial Growth Factor Receptor-2

In the present study, anti-leishmanial evaluation of twenty four structurally diverse compounds based on benzopiperidine, benzopyridine and phenylpiperazine nucleuses against Leishmania infantum has been reported. Cytotoxicity studies of all the compounds were performed on murine non-infected splenocytes. Tested compounds exhibited weak to potent activity against promastigote (IC

Topics: Animals; Antiprotozoal Agents; Cells, Cultured; Chromatography, Thin Layer; Inhibitory Concentration 50; Leishmania infantum; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Piperazines; Piperidines; Pyridines; Quinolines; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Near-Infrared; Spleen; Tetrahydroisoquinolines

Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today's battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well-established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline-aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2-methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC₅₀ of 0.95 ± 0.12 μM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC₅₀ of 0.62 ± 0.16 μM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a-go-go-related gene (zERG).

Topics: Animals; Anti-Bacterial Agents; DNA Gyrase; Dose-Response Relationship, Drug; Drug Design; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium smegmatis; Mycobacterium tuberculosis; Piperidines; Quinolines; Structure-Activity Relationship; Topoisomerase II Inhibitors; Zebrafish

Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression.

Topics: Acetylcholinesterase; Alzheimer Disease; Amino Acid Motifs; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Catalytic Domain; Cholinesterase Inhibitors; Donepezil; Drug Discovery; Humans; Indans; Models, Molecular; Piperidines; Protein Multimerization; Protein Structure, Quaternary; Quinolines; Tacrine

The effects of T-82 (2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo [3,4-b]quinolin-1-one hemifumarate), a new quinoline derivative, on acetylcholinesterase (AChE) activity and acetylcholine (ACh) release were compared with those of the well-known cholinesterase inhibitors tacrine and E2020. T-82, tacrine and E2020 all concentration-dependently inhibited AChE in rat brain homogenate (IC50 = 109.4, 84.2 and 11.8 nM, respectively). In addition, although tacrine strongly inhibited butyrylcholinesterase (BuChE), T-82 and E2020 showed only weak activity on BuChE in human plasma. In ex vivo experiments, intraperitoneal administration of T-82 at a dose of 30 mg/kg inhibited AChE activity in the hippocampus, frontal cortex and parietal cortex of rats. The effect of T-82 on the extracellular ACh concentration in rat brain was measured using in vivo microdialysis. T-82 at doses of 10 and 30 mg/kg, i.p. increased the extracellular ACh concentration in the hippocampus and striatum in a dose-dependent manner. These findings suggest that T-82 activates the central cholinergic system by selectively inhibiting AChE activity, while weakly affecting peripheral BuChE activity, and that T-82 increases the extracellular ACh concentration in the brain, which is followed by inhibited AChE activity.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Brain; Butyrylcholinesterase; Cattle; Cholinesterase Inhibitors; Cholinesterases; Corpus Striatum; Donepezil; Dose-Response Relationship, Drug; Hippocampus; Humans; Indans; Male; Phenothiazines; Piperidines; Quinolines; Rats; Rats, Wistar; Salivation; Tacrine; Temperature

Topics: Chemistry, Pharmaceutical; Cyclohexanes; Cyclohexanones; Morpholines; Oxides; Piperidines; Pyrroles; Quinolines; Research