Structure-antibacterial, antitumor and hemolytic activity relationships of cecropin A-magainin 2 and cecropin A-melittin hybrid peptides.

In order to elucidate the structure-antibiotic activity relationship of cecropin A-magainin 2 and cecropin A-melittin hybrid peptides, several truncated peptides and the analogues with amino acid substitutions were synthesized and their antibacterial, antitumor and hemolytic activities of were examined. Cecropin A-magainin 2 hybrid analog, L16-CA(1-8)-MA(1-12) (termed as L-CA-MA in this study: KWKLFKKIGIGKFLHLAKKF-NH2), is known to have potent antibacterial and antitumor activity with less hemolytic activity. We found that the C-terminal region of L-CA-MA is more involved in the alpha-helical structure on cell membrane-like environment than N-terminal one by circular dichroism analysis. Deletion of the Gly-Ile-Gly sequence, the central hinge region of L-CA-MA, produced a considerable reduction in antitumor and hemolytic activity rather than an antibacterial one. The insertion of Pro, Gly-Ile or Gly-Pro in this hinge region of L-CA-MA caused retention of both antibacterial and antitumor activity while causing a significant decrease in hemolytic activity. However, the substitution with Gly-Pro-Gly instead of the Gly-Ile-Gly in CA(1-8)-MA(1-12), CA(1-8)-ME(1-12), CA(1-13)-MA(1-13) and CA(1-13)-ME(1-13) hybrids resulted in a drastic decrease in antibacterial, antitumor and hemolytic activity. The increase of hydrophobicity at position 16 in CA(1-8)-MA(1-12) by substituting Trp or Phe induced a significant increase in hemolytic activity without a considerable change in either antibacterial or antitumor activity. Therefore, these results suggested that the appropriate flexibility in the hinge region of CA-MA and CA-ME hybrid peptides and the appropriate hydrophobicity at position 16 in the hydrophobic region of CA (1-8)-MA(1-12) are important in potent antibacterial and antitumor activity with no hemolytic effect.     

Structure-antibacterial activity relationship for 9-O,9'-O-demethyl (+)-virgatusin

The relationship between the antibacterial activity and structure of 9-O,9'-O-demethyl (+)-virgatusin (Virg 3) was examined. The conversion of hydroxy groups on the 9 and 9' positions to amino groups increased the activity. It was found that the 3'-methoxy group was more important for higher activity than the 4'-methoxy group on the 7'-phenyl group, and that the 3,4-methylenedioxy group on the 7-phenyl group was necessary for activity.     

Anti-proliferative activity and structure-activity relationship of honokiol derivatives

As a known natural product with anti-tumor activity, honokiol has been widely researched and structural modified. Lots of honokiol derivatives have been found to possess good anti-proliferative activity and showed great potential in cancer therapy, but the SAR (structure-activity relationship) was still confused. Here in, the SAR were comprehensively researched by summary of reported derivatives and synthesis of novel derivatives. Amongst novel derivatives, the promising compounds A6 and A10 exhibited potent and selective anti-proliferative activities against K562 cell line with the IC₅₀ values of 5.04 and 7.08 μM respectively. The SAR was discussed around honokiol and 79 derivatives by the means of CoMFA and theoretical calculation, which provided useful suggestion for further structural optimization of honokiol derivatives.     

Membrane-induced folding of cecropin A

Lipid membranes manifest a diverse array of surface forces that can fold and orient an approaching protein. To better understand these forces and their ability to influence protein function, we have used infrared spectroscopy with isotopic editing to characterize the 37-residue membrane-active antimicrobial polypeptide cecropin A as it approached, adsorbed onto, and finally penetrated various lipid membranes. Intermediate stages in this process were isolated for study by the use of internal reflection and Langmuir trough techniques. Results indicate that this peptide adopts well-ordered secondary structure while superficially adsorbed to a membrane surface. Its conformation is predominantly alpha-helical, although some beta structure is likely to be present. The longitudinal axis of the helical structure, and the transverse axes of any beta structure, are preferentially oriented parallel to the membrane surface. The peptide expands the membrane against pressure when it penetrates the membrane surface, but its structure and orientation do not change. These observations indicate that interactions between the peptide and deeper hydrophobic regions of the membrane provide energy to perform thermodynamic work, but separate and distinct interactions between the peptide and superficial components of the membrane are responsible for peptide folding. These results have broad implications for our understanding of the mechanism of action and the specificity of these antimicrobial peptides.     

Anti-influenza A virus activity and structure–activity relationship of a series of nitrobenzoxadiazole derivatives

Influenza viruses represent a major threat to human health and are responsible for seasonal epidemics, along with pandemics. Currently, few therapeutic options are available, with most drugs being at risk of the insurgence of resistant strains. Hence, novel approaches targeting less explored pathways are urgently needed. In this work, we assayed a library of nitrobenzoxadiazole derivatives against the influenza virus A/Puerto Rico/8/34 H1N1 (PR8) strain. We identified three promising 4-thioether substituted nitrobenzoxadiazoles (12, 17, and 25) that were able to inhibit viral replication at low micromolar concentrations in two different infected cell lines using a haemagglutination assay. We further assessed these molecules using an In-Cell Western assay, which confirmed their potency in the low micromolar range. Among the three molecules, 12 and 25 displayed the most favourable profile of activity and selectivity and were selected as hit compounds for future optimisation studies.     

家蚕天蚕素cDNA原核表达及抗菌活性检测

采用RT-PCR方法从家蚕Bombyx mori新疆品种新蚕三号组织中扩增天蚕素cDNA片段,回收并克隆至Pmd18-T载体,进行序列分析。基因序列分析结果与已发表的天蚕素B的序列同源性为98%,表明所克隆的新疆家蚕天蚕素cDNA为独特的cDNA片段。将天蚕素基因与Pgex-4T-1融合表达载体中的谷胱甘肽转移酶基因融合,在大肠杆菌中表达, 结果表明经IPTG 诱导30 min后,pGEX-4T-1/天蚕素转化后的大肠杆菌生长明显受到抑制;当诱导210 min 后,大肠杆菌数量又开始增加,逐渐恢复至正常水平。说明天蚕素与谷胱甘肽转移酶基因融合表达后,在IPTG存在的短时间内仍然对原核细胞有较强的抗菌抑杀作用。     

N-terminal analogues of cecropin A: synthesis, antibacterial activity, and conformational properties

Six analogues of the 37-residue antibacterial peptide cecropin A were synthesized by the solid-phase method: cecropin A-(2-37), [Glu2]cecropin A, [Pro4]cecropin A, [Glu6]cecropin A, [Leu6]cecropin A, and [Pro8]cecropin A. Their antibacterial activities against four test organisms were determined and related to conformational changes observed in their CD spectra and were discussed on the basis of a previously proposed amphipathic alpha-helix model. An aromatic residue in position 2 was shown to be important for activity against all tested bacteria. The highly alpha-helical 1-11 region of cecropin A did not appear to play a significant role in its activity against Escherichia coli but was clearly involved in its interaction against Pseudomonas aeruginosa, Bacillus megaterium, and Micrococcus luteus.     

Binding between lipopolysaccharide and cecropin A

Cecropin A (CA), a bioactive peptide, produced significant lethality toPantoea agglomerans (PA) at low concentrations. Significant mortality occurred immediately after addition of CA. Separate preincubations of lipopolysaccharides (LPS) from the following bacteria: PA,Serratia marcescens, Escherichia coli (EC), andSalmonella typhimurium with CA were performed prior to the bioassay. CA was also preincubated with diphosphoryl lipid A (DPL-A) from EC andS. minnesota (SM), trilinolein, palmitic, lauric and myristic acids (fatty acids contained in the lipid A of PA-LPS) and bovine brain gangliosides. Spectral analyses to determine the interaction between glycosphingolipids (sphingomyelin, bovine brain gangliosides, and galactocerebrosides) and CA were performed. Results showed that all types of LPS and DPL-A as well as the gangliosides studied blocked CA lethality to PA. The level of inhibition of CA antibacterial properties was dependent on LPS and DPL-A concentration. The individual fatty acids and trilinolein did not affect CA lethality to PA. Spectral studies showed complexation between CA and PA-LPS, both types of DPL-A, and the glycosphingolipids. Biological and chemical analyses confirm that CA binds to the diphosphoryl lipid A moiety of LPS.The U.S. Government right to retain a non-exclusive, royalty free licence in and to any copyright is acknowledged     

Conformation-activity relationship on novel 4-pyridylmethylthio derivatives with antiangiogenic activity

We found 4-pyridylmethylthio derivative 1 to be very effective in using antiangiogenesis activity to prevent proliferation of HUVECs (Human Umbilical Vein Endothelial Cells), which was induced by vascular endothelial growth factor (VEGF). Compound 1 was equally effective in inhibiting VEGF receptor2 tyrosine kinase (KDR, IC₅₀ = 26 nM). We deduced that the inhibition was the result of binding the catalytic domain of VEGF receptor2 tyrosine kinase in a similar fashion to both phthalazine derivative PTK787 2 and anthranylamide derivative AAL993 3. In this report, we will describe the conformational analyses, from ab initio MO calculation and X-ray crystallographic analyses, of compound 1 and the analogs, which include non-active 9, all in comparison with 2 and 3. The conformation–activity relationships suggest that a nonbonded intramolecular interaction between the sulfur and the carbonyl oxygen of 1 was very important in inhibiting KDR.     

Synthesis and structure-antituberculosis activity relationship of 1H-indole-2,3-dione derivatives

New series of 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones 2a-k and 5-fluoro-1-morpholino/piperidinomethyl-1H-indole-2,3-dione-3-thiosemicarbazones 3a-r were synthesized. The structures of the synthesized compounds were confirmed by spectral data, elemental and single crystal X-ray diffraction analysis. The new 5-fluoro-1H-indole-2,3-dione derivatives, along with previously reported 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 2l-v, 1-morpholino/piperidinomethyl-5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 4a-l, and 5-nitro-1H-indole-2,3-dione-3-[(4-oxo-1,3-thiazolidin-2-ylidene)hydrazones] 5a-s, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. Among the tested compounds, 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones (2p, 2r, and 2s) and its 1-morpholinomethyl derivatives (4a, 4e, 4g, and 4i) exhibited significant inhibitory activity in the primary screen. The antituberculosis activity of molecules with diverse skeletons was investigated by means of the Electronic-Topological Method (ETM). Ten pharmacophores and ten anti-pharmacophores that have been found by this form the basis of the system capable of predicting the structures of potentially active compounds. The forecasting ability of the system has been tested on structures that differ from those synthesized. The probability of correct identification for active compounds was found as equal to 93% in average. To obtain the algorithmic base for the activity prediction, Artificial Neural Networks were used after the ETM (the so-called combined ETM-ANN method). As the result, only 9 pharmacophores and anti-pharmacophores were chosen as the most important ones for the activity. By this, ANNs classified correctly 94.4%, or 67 compounds from 71.     

The chemical synthesis of cecropin D and an analog with enhanced antibacterial activity

Cecropin D was synthesized by solid-phase methods and shown to be homogeneous and of correct composition and molecular weight. It was indistinguishable from natural cecropin D and constitutes a structure proof for this peptide. Several analogs of cecropin D were synthesized and used to draw conclusions about the structural features contributing to antibacterial activity. They included [Lys1]cecropin D, [Gln3, Leu4] cecropin D, and cecropin D-(9-37). It was concluded that a strongly basic NH2-terminal segment is a prerequisite for antibacterial activity. A hybrid analog cecropin A-(1-11) D-(12-37) was designed and predicted to have enhanced potency. It was found to be 5 to 55 times as active as cecropin D against six of the bacteria tested and was slightly more active than cecropin A. However, against Bacillus subtilis Bs11 the analog was 6 times more active than cecropin A.     

Binding and action of cecropin and cecropin analogues: antibacterial peptides from insects

The mechanism of action of cecropin was studied by using liposomes as a model system. The bilayer was efficiently destroyed if the liposome net charge was zero or negative. Cecropin analogues with an impaired N-terminal helix had reduced membrane disrupting abilities that correlate with their lower antibacterial activity. The reduced bactericidal activity of the analogues was rationalized in terms of reduced binding to bacteria. The stoichiometry of cecropin killing of bacteria suggests that amounts of cecropin sufficient to form a monolayer strongly modify the bacterial membrane. Although some bacteria were resistant to cecropin they did bind large amounts in a non-productive manner. In contrast, mammalian erythrocytes achieve resistance by avoiding the binding of cecropin.     

Synthesis and structure–activity relationship of Huprine derivatives as human acetylcholinesterase inhibitors

New series of Huprine (12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolines) derivatives have been synthesized and their inhibiting activities toward recombinant human acetylcholinesterase (rh-AChE) are reported. We have synthesized two series of Huprine analogues; in the first one, the benzene ring of the quinoline moiety has been replaced by different heterocycles or electron-withdrawing or electron-donating substituted phenyl group. The second one has been designed in order to evaluate the influence of modification at position 12 where different short linkers have been introduced on the Huprine X, Y skeletons. All these molecules have been prepared from ethyl- or methyl-bicyclo[3.3.1]non-6-en-3-one via Friedländer reaction involving selected o-aminocyano aromatic compounds. The synthesis of two heterodimers based on these Huprines has been also reported. Activities from moderate to same range than the most active Huprines X and Y taken as references have been obtained, the most potent analogue being about three times less active than parent Huprines X and Y. Topologic data have been inferred from molecular dockings and variations of activity between the different linkers suggest future structural modifications for activity improvement.     

Synthesis and structure–activity relationship of novel cinnamamide derivatives as antidepressant agents

Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure–activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b–c and 6a–b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10 mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold.     

Structure-antiviral activity relationships of cecropin A-magainin 2 hybrid peptide and its analogues.

In order to elucidate the structure-antiviral activity relationship of cecropin A (1-8)-magainin 2 (1-12) (termed CA-MA) hybrid peptide, several analogues with amino acid substitutions were synthesized. In a previous study, it was shown that serine at position 16 in CA-MA hybrid peptide was very important for antimicrobial activity. Analogues were designed to increase the hydrophobic property by substituting a hydrophobic amino acid residue (S --> A, V, F or W, position 16) in the CA-MA hybrid peptide. In this study, the structure-antiviral activity relationships of CA-MA and its analogues were investigated. In particular, substitution of Ser with a hydrophobic amino acid, Val, Phe or Trp at position 16 caused a dramatic increase in the virus-cell fusion inhibitory activity. These results suggested that the hydrophobicity at position 16 in the hydrophobic region of CA-MA is important for potent antiviral activity.     

The study of structure-antiarrhythmic activity relationship of N-phenylacetamide derivatives and aromatic carbonic acid amides

Using the SARD-21 (Structure Activity Relationship & Design) computer system, structural features of high- and low-effective antiarrhythmic agents have been recognized and the influence of these features on the antiarrhythmic properties has been evaluated. This information has been used for generation of the model to predict antiarrhythmic effectiveness of pharmaceutical preparations at the recognition level of 82% by means of two different approaches. The recognized structural parameters may be successfully used to design new highly effective antiarrhythmic drugs, and also to modify structures of the already-existing anti-arrhythmic drugs in order to increase the effectiveness of their antiarrhythmic action.     

Synthesis and thromboxane A2 antagonistic activity activity of indane derivatives

A new series of indane derivatives were prepared and evaluated for their thromboxane A2 (TXA2, 1) antagonistic activity. Among these compounds, 24a (Z-335) was found to be a potent TXA2 antagonist in oral administration.     

The terminal structure plays an important role in the biological activity of cecropin CMIV

Antibacterial peptides have received increasing attention as a new pharmaceutical substance. But the molecular mechanism of lysis is still poorly understood. CMIV gene and mutant CMIV gene in GST fusion system were expressed. After cleaving with different cleavage reagents, the peptide with an excess of N-terminus and with an un-amidated C-terminus stopped the activity while the peptide with an excess Asn at the C-terminus had the activity level the same as natural CMIV. The results showed that the terminal structure of cecropin CMIV played an important role in its biological activity.     

Structure–activity relationship study of arbidol derivatives as inhibitors of chikungunya virus replication

Chikungunya virus (CHIKV), a mosquito-borne arthrogenic Alphavirus, causes an acute febrile illness in humans, that is, accompanied by severe joint pains. In many cases, the infection leads to persistent arthralgia, which may last for weeks to several years. The re-emergence of this infection in the early 2000s was exemplified by numerous outbreaks in the eastern hemisphere. Since then, the virus is rapidly spreading. Currently, no drugs have been approved or are in development for the treatment of CHIKV, which makes this viral infection particularly interesting for academic medicinal chemistry efforts.Several molecules have already been identified that inhibit CHIKV replication in phenotypic virus-cell-based assays. One of these is arbidol, a molecule that already has been licensed for the treatment of influenza A and B virus infections. For structural optimization, a dedicated libraries of 43 indole-based derivatives were evaluated leading to more potent analogues (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities higher than those of the other derivatives, including the lead compound, and with a selective index of inhibition 13.2 and 14.6, respectively, higher than that of ARB (4.6).