Plant‐Derived Flavones as Inhibitors of Aurora B Kinase and Their Quantitative Structure–Activity Relationships

Although several plant‐derived flavones inhibit aurora B kinase (aurB), quantitative relationships between the structural properties of plant‐derived flavones and their inhibitory effects on aurB remain unclear. In this report, these quantitative structure–activity relationships were obtained. For quercetagetin, found in the Eriocaulon species, showing the best IC₅₀ value among the flavone derivatives tested in this report, further biological tests were performed using cell‐based assays, including Western blot analysis, flow cytometry, and immunofluorescence microscopy. In vitro cellular experiments demonstrated that quercetagetin inhibits aurB. The molecular‐binding mode between quercetagetin and aurB was elucidated using in silico docking. Quercetagetin binds to aurB, aurA, and aurC and prevents the active phosphorylation of all three aurora kinases. In addition, quercetagetin triggers mitotic arrest and caspase‐mediated apoptosis. These observations suggest that quercetagetin is an aurora kinase inhibitor. Induction of mitosis‐associated tumor cell death by quercetagetin is a promising strategy for developing novel chemotherapeutic anticancer agents.     

Synthesis,Evaluation of Pharmacological Activities and Quantitative Structure–Activity Relationship Studies of a Novel Group of bis(4‐Nitroaryl‐1,4‐dihyropyridine)

Voltage‐dependent calcium channels are crucial targets for a wide range of clinically active pharmacological agents. From these agents, 1,4‐dihydropyridines constitute a group of small organic compounds are based on a core pyridine structure which can both block and enhance calcium currents. They are considered specific for L‐Type calcium channels; however, other channel types, and in particular certain T‐Type channels, may show sensitivity to dihydropyridine compounds. In this study, we synthesized a novel group of bis‐1,4‐dihydropyridines using the procedure reported by Dagnino that involved the condensation of n‐alkyl diacetoacetate (n = 2–7) with methyl‐3‐aminocrotonate and nitrophenylaldehyde. The synthesis was run under two conditions: (i) reflux and (ii) microwave. Calcium channels antagonist activity were determined in vitro using guinea‐pig ileum longitudinal smooth muscle assay. Synthesis of these compounds was confirmed with 1H‐NMR, IR and mass spectrometry. Then IC₅₀ of them are calculated and compared with Nifedipine. Finally, the result of this pharmacological assay was used in quantitative structure–activity relationship studies utilizing multiple linear regression analysis. Most of these compounds are less active compared with Nifedipine. Decrease in activity is the result of increase in steric hindrance. The quantitative structure–activity relationship study indicates that the activity is related to the electrostatic and topological parameters and the distance between two C5‐esteric groups of 1,4‐dihydropyridine rings.     

Synthesis,Biological Evaluation,Mechanism of Action and Quantitative Structure–Activity Relationship Studies of Chalcones as Antibacterial Agents

Forty‐eight chalcone analogs were synthesized and their in vitro antibacterial activity against Staphylococcus aureus NCIM 5021, Bacillus subtilis NCIM 2718, Phaseolus vulgaris NCIM 2813, Escherichia coli NCIM 2931, Salmonella typhi 2501 and Enterobacter aerogenes NCIM 5139 were evaluated by microdilution broth assay. Quantitative structure–activity relationships were developed for all the cases (r ² = 0.68–0.79; = 0.58–0.78; q ² = 0.51–0.68; F = 13.02–61.51). Size, polarizability, electron‐donating/withdrawing and hydrophilic nature of the molecule determine the activity against these Gram‐positive and Gram‐negative bacteria. Staphylococcus aureus was the most and S. typhi was the least hydrophobic of these organisms. These chalcones act better against more hydrophobic organisms. The more active chalcones have log P between 1.5 and 3. Compound 24 , one of the most active compounds, was found to act by damaging the cell wall of S. aureus. Slimicidal activity of five of the most active compounds ( 24 , 31 , 32 , 34 and 37 ) was found to be in the range of 48–60% against S. aureus and 40–54% against E. coli. A correlation was observed among the hydrophobicity of the compounds, hydrophobicity of the bacterial cell surface and the antibacterial activity of the compound.     

PF‐8380 and Closely Related Analogs: Synthesis and Structure–Activity Relationship towards Autotaxin Inhibition and Glioma Cell Viability

A series of PF‐8380 analogs, a recently developed autotaxin inhibitor, was explored. Inhibition of autotaxin by these analogs, as well as by all PF‐8380 synthetic intermediates, shows the importance of meta‐dichlorobenzyl and benzo[d]oxazol‐2(3H)‐one fragments. However, analogs 8 and 9 , bearing only the benzo[d]oxazol‐2(3H)‐one moiety, are more cytotoxic on the LN229 glioblastoma cell line than PF‐8380 and temozolomide (TMZ).     

Insulinotropic Actions of the Frog Skin Host‐Defense Peptide Alyteserin‐2a: A Structure–Activity Study

Alyteserin‐2a (ILGKLLSTAAGLLSNL.NH₂) stimulated the rate of insulin release from BRIN‐BD11 clonalβ cells at a concentration of 30 nm (p < 0.05) with a response of 296 ± 26% of basal release at 3 μm (p < 0.001). The insulinotropic actions of analogs containing substitutions by l ‐lysine, d ‐lysine, or l ‐tryptophan at sites that maintain amphipathicity were evaluated. The [G11K], [S7k], [S7k,G11k], and [G11k,N15K] analogs were the most potent stimulating insulin release at 0.01 nm (p < 0.05). The [S7K], [G11K], [S14K], [N15K], [G11k], and [S7K,G11K] analogs were the most effective producing an approximately twofold greater (p < 0.001) release of insulin at 3 μm compared with alyteserin‐2a. The [T8W] and [A9W] analogs were less active than alyteserin‐2a. No peptide‐stimulated release of lactate dehydrogenase at concentrations up to 3 μm , indicating that the integrity of the plasma membrane had been preserved. Membrane depolarization and an increase in intracellular Ca²⁺ concentration are involved in the mechanism of action of the peptides. Administration of [G11k]alyteserin‐2a (75 nmol/kg body weight) to high‐fat‐fed mice with obesity and insulin resistance significantly (p < 0.01) enhanced insulin release and improved glucose tolerance during the 60‐min period following an intraperitoneal glucose load.     

Structure–activity relationship of neuropeptide γ derived from mammalian and fish

Abstract: This study of relationship between structure and biologic activity was performed using five neuropeptide γs [NPγ; mammalian‐NPγ (M‐NPγ), trout‐NPγ (T‐NPγ), goldfish‐NPγ (G‐NPγ), bowfin‐NPγ (B‐NPγ), and shark‐NPγ (S‐NPγ)]. Circular dichroism (CD) spectra showed that all peptides took random structure in buffer solution. In neutral and acidic liposomes, M‐NPγ, T‐NPγ, B‐NPγ, and S‐NPγ still adopted random structure, while G‐NPγ had an α‐helical structure. The biologic activity of NPγs has been estimated by their effects on the intestinal motility and arterial relaxation. The intestinal motility was investigated with rat duodenum (RD), carp intestine (CI), and guinea‐pig ileum (GPI). The arterial relaxing effect was tested with guinea‐pig aorta (GPA) and rat mesenteric artery (RMA). In RD, the order of potency compared with the EC₅₀ value was M‐NPγ > S‐NPγ > B‐NPγ > G‐NPγ > T‐NPγ. G‐NPγ was the most contractile agent in CI. S‐NPγ was the most contractile agent in GPI. Using an arterial relaxing test, the order of potency was G‐NPγ > T‐NPγ > B‐NPγ > S‐NPγ > M‐NPγ in GPA, and all NPγs remarkably reduced relaxing activity in RMA. Despite their structural similarities to NPγs, G‐NPγ has high affinity to tachykinin receptor‐binding sites in GPA and CI, indicating an α‐helical structure may have a critical role for receptor binding. However, an α‐helical structure does not play a critical role in recognizing receptor‐binding sites in RD and GPI.     

Quantitative Structure–Activity Relationship (QSAR) Analysis of the Cytotoxicities Of Aminohydroxyguanidine Derivatives and Their Antiviral Activities in Vitro

Substituted Schiff bases of l-amino-3-hydroxyguanidine (SB-HAG) were tested for the first time against noninfected T4 lymphocytes (CEM-6 cells) and the same cell line infected by HIV-1 in vitro. Twenty-one of 23 compounds at micromolar levels did not inhibit the growth of the noninfected T4 cells, suggesting minimal cytotoxicity. The antiviral effects of these compounds in a micromolar concentration range have been shown to be nonsignificant (<30%) against HIV-1. Three-dimensional parameter focusing of the physicochemical properties (i.e., log P and V _w) and the marginal antiviral activities shows that the marginally active compounds lie in a region different from the inactive compounds. QSAR analysis of the two subsets shows that the cytotoxicity correlates well with the electronic and lipophilic parameters. The results of the QSAR analysis can serve as guidelines for further structural modification of this series of compounds to minimize the cytotoxicity against host cells.     

Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure–Activity Relationships Models,Molecular Docking,and Molecular Dynamics Simulations

A dataset of 67 berberine derivatives for the inhibition of butyrylcholinesterase (BuChE) was studied based on the combination of quantitative structure–activity relationships models, molecular docking, and molecular dynamics methods. First, a series of berberine derivatives were reported, and their inhibitory activities toward butyrylcholinesterase (BuChE) were evaluated. By 2D‐ quantitative structure–activity relationships studies, the best model built by partial least‐square had a conventional correlation coefficient of the training set (R²) of 0.883, a cross‐validation correlation coefficient () of 0.777, and a conventional correlation coefficient of the test set () of 0.775. The model was also confirmed by Y‐randomization examination. In addition, the molecular docking and molecular dynamics simulation were performed to better elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. The predicted binding free energy results were consistent with the experimental data and showed that the van der Waals energy term (ΔE_vdw) difference played the most important role in differentiating the activity among the three inhibitors (berberine, C2, and C55). The developed quantitative structure–activity relationships models provide details on the fine relationship linking structure and activity and offer clues for structural modifications, and the molecular simulation helps to understand the inhibitory mechanism of the three typical inhibitors. In conclusion, the results of this study provide useful clues for new drug design and discovery of BuChE inhibitors from berberine derivatives.     

Indolizine Derivatives as HIV‐1 VIF–ElonginC Interaction Inhibitors

Compound 1 (VEC‐5) was identified as a potent small‐molecular HIV‐1 viron infectivity factor inhibitor that targets the viron infectivity factor–ElonginC interaction. A structure–activity relationship study was carried out to develop compounds with improved efficacy against HIV‐1 and 49 indolizine derivatives of three categories were designed and synthesized. We found that five compounds exhibited promising anti‐HIV‐1 activity, and the most active compound 2g had an IC₅₀ value of 11.0 μm . These results provide new information to develop highly potent small‐molecule HIV‐1 viron infectivity factor inhibitors.