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.     

Novel Dithiocarbamic Acid Esters Derived from 6‐Aminomethyl‐4‐anilinoquinazolines and 6‐Aminomethyl‐4‐anilino‐3‐cyanoquinolines as Potent EGFR Inhibitors

Two series of dithiocarbamic acid esters, 4‐anilinoquinazoline‐6‐ylmethylcarbamodithioic acid esters and 3‐cyano‐4‐anilinoquinolin‐6‐ylmethylcarbamodithioic acid esters, were designed and synthesized. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay against three human cancer cell lines: MDA‐MB‐468, SK‐BR‐3 and HCT‐116. Most of the compounds are equally or more potent than the positive control lapatinib. Three compounds ( 14d , 14h and 14i) were identified as dual inhibitors of the EGFR and ErbB‐2 kinases and two compounds ( 14b and 14c) were identified as multi‐target kinase inhibitors, and they are very worthy of further study. Installation of the dithiocarbamic acid ester group at the 6‐position of 4‐anilinoquinazoline or 3‐cyano‐4‐anilinoquinoline could improve the inhibitory activity. Different dithiocarbamic acid ester groups significantly affect the activities.     

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.     

Quantitative Structure–Activity Relationship Analysis of a Series of Human Renal Organic Anion Transporter Inhibitors

Organic anion transporters (OATs) have been proved to play important roles in the membrane transport of numerous potentially toxic xenobiotics, drugs, and endogenous metabolites. In general, OATs substrates can compete with one another for the transporter to mutually decrease renal secretion and thus delay the clearance and prolong the duration of action of each compound. Such interactions have the potential to bring about adverse outcomes for clinical cases. Therefore, it is very important to assess the molecular bioactivity to inhibit OATs during the development of new drugs and co‐administration. In this work, the relationships between 45 chemicals and their corresponding hOAT1 and hOAT3 inhibitory activities were analyzed. The quantitative structure–activity relationship (QSAR) model was developed by genetic algorithm and multiple linear regression method. The predictive power of the proposed model was strictly evaluated, and the applicability domain was also defined. The proposed models were robust and satisfactory and could provide a feasible and effective tool for hOAT1 or hOAT3 inhibitor screening.     

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.     

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 butyrate analogues on apoptosis,proliferation and histone deacetylase activity in HCT‐116 human colorectal cancer cells

1. Butyrate, a bacteria fermentative product in the colonic lumen, has been shown to produce a wide variety of biological effects in human cancer cells in vitro. However, there are pharmacological drawbacks associated with the use of butyrate therapy and there are limited published data on the structure–activity relationship of butyrate analogues in colorectal cancer cells. Previously, we determined structure–activity relationship using HT‐29 human colorectal cancer cells. However, it was viewed as important to explore similar relationships in another colorectal cancer cell line. 2. Therefore, in the present study, the in vitro structure–activity relationship of butyrate analogues was examined by investigating their effects on apoptosis, cell proliferation, histone deacetylase (HDAC) activity and lactate dehydrogenase (LDH) leakage as a measure of cell toxicity in HCT‐116 human colorectal cancer cells. 3. Of the 32 analogues tested, only 4‐benzoylbutyrate, 3‐benzo‐ylpropionate, 4‐(4‐nitrophenyl)butyrate and 3‐(4‐fluorobenzoyl)propionate exhibited comparable biological effects to butyrate. The common structural properties of the compounds of interest were to lack amino or hydroxyl substitutions at the 2‐, 3‐ and/or 4‐position of the aliphatic moiety of butyrate. 4. The present study reveals a dissociation between the induction of apoptosis, inhibition of cell proliferation, HDAC activity and LDH leakage. The results indicate differential responses of butyrate analogues in HT‐29 and HCT‐116 colorectal cancer cells.     

Novel 3‐substituted N‐methylcarbazole–imidazolium salt derivatives: Synthesis and cytotoxic activity

A series of novel 3‐substituted N‐methylcarbazole–imidazolium salt derivatives has been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G‐2, Hela and PC12). The results suggest that the presence of substituted 2‐methyl‐imidazole or imidazole ring and substitution of the imidazolyl‐3‐position with a naphthylacyl or 4‐bromophenacyl group were important for improving cytotoxic activity. Compounds 17 , 18 , 27, and 28 with 4‐bromophenacyl and naphthylacyl groups displayed good activities with IC₅₀ values of 0.09–7.20 μm against three tumor cell lines investigated and more active than DDP. Compound 35 exhibited cytotoxic activity selectively against Hela cell.     

Structure–Function Relationship of Val/Arg‐rich Peptides: Effects of Net Charge and Pro on Activity

Our previous study reported Val/Arg‐rich peptides, and the relationship was linear between hydrophobicity and antimicrobial potency within a certain range. Here, we further develop a new series of analogs to investigate the effect of net charge and Pro residue on activity. Replacement of Gly with Ala or Pro led to the decrease in antimicrobial activity. The substitution of Gly with Ala retained its hemolytic activity, while the substitution with Pro significantly decreased the toxicity, suggesting positive effect of Pro on hemolytic activity. The increase in net charge from +4 to +6 significantly improved antimicrobial activity and decreased the hemolysis. However, antibacterial and hemolytic activities were not affected by increasing the net charge from +6 to +8, indicating a moderate net positive charge. The peptides produced larger blue shifts in PE/PG than in PC/cholesterol, suggesting a stronger affinity with negatively charged membrane over zwitterionic membrane. Lowering the net charge or insert of Pro led to the lack of α‐helical structure in SDS micelles, which may be correlated with weakened antimicrobial potency. This study indicated that Val/Arg‐rich peptides should have moderate net charge and Pro may play a role in reducing the toxicity against red blood cells.