QSAR of aromatic substances: EGFR inhibitory activity of quinazoline analogues

The flip regression procedure that we used earlier for handling the xanthones system has been applied to phenylaminoquinazoline analogues. It is known that the substituents at the 6- and 7- positions of the polycyclic system have been identified as the most important structural features. The steric as well as the electrostatic interactions proved to be the most important for the inhibitory effect. In this contribution it is shown that the orientation of nodes in their occupied π orbitals, and also the energies of these orbitals explains a further large portion of the variance in their inhibitory activity.     

QSAR of aromatic substances: MAO inhibitory activity of xanthone derivatives

The flip regression procedure that we used earlier for handling the dibenzofuran system has been applied to xanthones. The MAO-A inhibitory activity expressed as IC50 of the xanthones is known to correlate with E-state, molecular connectivity, shape indices and in this contribution it is shown that the orientation of nodes in their occupied pi orbitals explain a further large portion of the variance in their inhibitory activity.     

Antibacterial profile against drug-resistant Staphylococcus epidermidis clinical strain and structure-activity relationship studies of 1H-pyrazolo[3,4-b]pyridine and thieno[2,3-b]pyridine derivatives

Antibacterial resistance is a complex problem that contributes to health and economic losses worldwide. The Staphylococcus epidermidis is an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices. Currently, there are several resistant strains including S. epidermidis that became an important medical issue mainly in hospital environment. In this work, we report the biological and theoretical evaluations of a 4-(arylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acids series (1, 1a-m) and the comparison with a new isosteric ring nucleus series, 4-(arylamino)thieno[2,3-b]pyridine-5-carboxylic acids derivatives (2, 2a-m). Our results revealed the 1H-pyrazolo[3,4-b]pyridine derivatives significant antibacterial activity against a drug-resistant S. epidermidis clinical strain in contrast to the thieno[2,3-b]pyridine series. The minimal inhibitory concentration (MIC) of the most active derivatives (1a, 1c, 1e, and 1f) against S. epidermidis was similar to that of oxacillin and twofold better than chloramphenicol. Interestingly, the position of the functional groups has a great impact on the activity as observed in our structure-activity relationship (SAR) study. The SAR of 1H-pyrazolo[3,4-b]pyridine derivatives shows that the highest inhibitory activity is observed when the meta position is occupied by electronegative substituents. The molecular modeling analysis of frontier molecular orbitals revealed that the LUMO density is less intense in meta than in ortho and para positions for both series (1 and 2), whereas HOMO density is overconcentrated in 1H-pyrazolo[3,4-b]pyridine ring nucleus compared to the thieno[2,3-b]pyridine system. The most active derivatives of series 1 were submitted to in silico ADMET screening, which confirmed these compounds as potential antibacterial candidates.     

Molecular orbital evaluation of charge flow dynamics in natural pigments based photosensitizers

The relationship between structure and photo electrochemical property of ten natural pigments from plants, insects and microbes has been analyzed using density functional theory (DFT) at the B3LYP/6-31G(d) level. The essential parameters for their photoelectrochemical behaviour such as ground state geometries, electronic transition energies and oxidation potentials are computed. The attachment tendency of the anchoring groups, expressed as the deprotonation order, is determined by calculating the proton affinities at different sites of the molecules. A thorough analysis of the charge flow dynamics in the molecular orbitals (HOMO and LUMO) of these molecules has been carried out and presented to emphasize the role of these orbitals in effective charge separation, the important feature of photosensitizers for DSSC. This study highlights that the flexible spatial orientation provided by the bridging aliphatic unsaturation favours the oscillator strength and the hydroxyl anchor group attached to the ring of delocalized π electron cloud acts as the effective anchor.     

Synthesis and activity of oleanolic acid derivatives, a novel class of inhibitors of osteoclast formation

Two series of oleanolic acid derivatives were synthesized and their inhibitory activity on the formation of osteoclast-like multinucleated cells (OCLs) induced by 1alpha,25-dihydroxy vitamin D3 was evaluated in a co-culture assay system. The structure-activity relationships, together with electronic structure based on the frontier molecular orbitals, for example, HOMO and LUMO, related to different amino acid substituents were studied. Derivatives with proline or phenylalanine showed a tendency to enhance the inhibitory activity.     

Electronic structure and PCA analysis of covalent and non-covalent acetylcholinesterase inhibitors

Hartree-Fock and density functional methods were used to analyze electronic and structural properties of known drugs to evaluate the influence of these data on acetylcholinesterase inhibition. The energies of the frontier orbitals and the distances between the more acidic hydrogen species were investigated to determine their contributions to the activity of a group of acetylcholinesterase inhibitors. Electrostatic potential maps indicated suitable sites for drugs-enzyme interactions. In this study, the structural, electronic and spatial properties of nine drugs with known inhibitory effects on acetylcholinesterase were examined. The data were obtained based on calculations at the B3LYP/6-31 + G(d,p) level. Multivariate principal components analysis was applied to 18 parameters to determine the pharmacophoric profile of acetylcholinesterase inhibitors. Desirable features for acetylcholinesterase inhibitor molecules include aromatic systems or groups that simulate the surface electrostatic potential of aromatic systems and the presence of a sufficient number of hydrogen acceptors and few hydrogen donors. PCA showed that electronic properties, including the HOMO-1 orbital energy, logP and aromatic system quantity, as well as structural data, such as volume, size and H-H distance, are the most significant properties.     

Designing modulators of dimethylarginine dimethylaminohydrolase (DDAH): a focus on selectivity over arginase

DDAH inhibition presents a novel promising pharmaceutical strategy to lower NO formation. To date, several potent DDAH inhibitors have been published, most of them representing analogues of l-arginine. While inhibitory effects on NOSs have already been considered, selectivity over arginase has been neglected so far. In our view, the latter selectivity is more important since an additional inhibition of arginase decreases the desired effects on NO levels. Thus, we particularly focus on selectivity over arginase. We present a comprehensive selectivity profile of known DDAH inhibitors by covering their inhibitory potency on arginase. Among the studied compounds, N(ω)-(2-methoxyethyl)-l-arginine (2a, L-257) that is already selective over NOSs also only modestly affected arginase activity and is thus far the most suitable DDAH inhibitor for pharmacological studies.     

Structure-activity relationships of tyrosinase inhibitory combinatorial library of 2,5-disubstituted-1,3,4-oxadiazole analogues

Here the tyrosinase inhibition studies of library of 2,5-disubstituted-1,3,4-oxadiazoles have been reported and their structure-activity relationship (SAR) also have been discussed. The library of the oxadiazoles was synthesized under the microwave irradiation and was structures of these were characterized by different spectral techniques. From this study it could be concluded that for a better inhibition of tyrosinase, electronegative substitution is essential as most probably the active site of the enzyme contain some hydrophobic site and position is also very important for the inhibition purposes due to the conformational space. The electronegativity of the compounds is somewhat proportional to the inhibitory activity. The compound 3e (3'-[5-(4'-bromophenyl)-1,3,4-oxadiazol-2-yl]pyridine) exhibited most potent (IC50 = 2.18 microM) inhibition against the enzyme tyrosinase which is more potent than the standard potent inhibitor L-mimosine (IC50 = 3.68 microM). This molecule can be the best candidate as a lead compound for further development of drug for the treatments of several skin disorders.     

Serpins: finely balanced conformational traps

Serine protease inhibitors (serpins) play very important roles in the maintenance of various physiologically important systems. As knowledge of the workings of proteins of this family grows, new understanding is gained of the mechanisms by which they inhibit target proteases, using conformational changes for which the structure of serpins is uniquely adapted. This finely balanced system is utilized to healthy benefit in the control of serpin function by modulators, arguably the most striking examples of which occur in the control of proteolytic cascades, such as the coagulation system. Serpins also play very important intracellular roles: one example is the protection of immune cells from their own cytotoxic proteases. The finely balanced serpin mechanism also means that it is prone to disastrous consequences if mutations should occur in vital positions in the serpin structure. Many examples of disease-associated mutations have been shown, which has the dual effect of highlighting how important these molecules are in the maintenance of health and the fine balance that must be maintained in order to preserve their active, inhibitory conformation.     

Design, synthesis, and evaluation of novel galloyl pyrrolidine derivatives as potential anti-tumor agents

A series of novel galloyl pyrrolidine derivatives were synthesized as potential anti-tumor agents. Their inhibiting activities on gelatinase (MMP-2 and -9) were tested with succinylated gelatin as the substrate. Structure-activity analyses demonstrate that introduction of longer and more flexible side chains at the C(4) position of the pyrrolidine ring brings higher activity against gelatinase. Free phenol hydroxyl group is more favorable than the methylated one, which confirms the important role of the phenol hydroxyl group when inhibitors interact with gelatinase. In particular, (2S,4S)-4-(3-(3,4-dimethoxyphenyl)acrylamido)-N-hydroxy-1-(3,4,5- trimethoxybenzoyl)pyrrolidine-2-carboxamide (18) stood out as the most attractive compound (IC(50) = 0.9 nM). The anti-metastasis model of mice bearing H(22) tumor cells was used to evaluate their anti-tumor activities in vivo. The assay in vivo revealed that most of these inhibitors displayed favorable inhibitory activities (inhibitory rate >35%) and no significant toxic effects were observed. The inhibition for 62.37% of 19 indicates the strategy used to design MMP inhibitors (MMPIs) of galloyl pyrrolidine derivatives as potential anti-tumor agents is promising.     

Novel monosaccharides as potent inhibitors of cell proliferation

The effects of several novel monosaccharides upon thymidine incorporation into both normal and tumour cells were investigated. The monosaccharide 2-deoxy-3-[1-(R)-(ethoxycarbonyl)ethyl]-α-D -allo-pyranose had the most inhibitory effect on proliferation, with the (S)-enantiomer having less inhibitory effects. The chiral centre at carbon-7 was found to be an important part of the molecule, as 2-deoxy-3-[methoxycarbonyl methyl]-α-D -allo-pyranose had greatly decreased anti-proliferative properties in comparison with the parent compound. In addition, the 2-deoxy structure at carbon-2 was also found to be important, as 3-[1-(S)-(ethoxycarbonyl)ethyl]-α-D -allo-hexopyranose had greatly decreased inhibitory properties in comparison with the parent compound. The results indicate that these novel monosaccharides possess potent anti-proliferative properties, related to their chiral carbon-7 and 2-deoxy carbon-2 structure and suggest that further substitutions of the functional group at carbon-7 may improve these properties and possibly produce inhibitor selectivity for tumour cells in preference to normal cells. © 1997 John Wiley & Sons, Ltd.     

An insight into the general relationship between the three dimensional structures of enzymes and their electronic wave functions: Implication for the prediction of functional sites of enzymes

In this study, we explored the general relationship between the three-dimensional (3D) structures of enzymes and their electronic wave functions. Furthermore, we developed a method for the prediction of their functionally important sites. For this purpose, we first performed linear-scaling molecular orbital calculations for 112 nonredundant, non-homologous enzymes with known structure and function. In consequence, we showed that the canonical molecular orbitals (MOs) of the enzymes could be classified into three groups according to the degree of electron delocalization: highly localized orbitals (Group A), highly delocalized orbitals whose electrons are distributed over almost the whole molecule (Group B), and moderately delocalized orbitals (Group C). The MOs belonging to Group A are located near the HOMO-LUMO band gap, and thereby include the frontier orbitals of a given enzyme. We inferred that the MOs of Group B play a role in stabilizing the 3D structure of the enzyme, while those of Group C contribute to constructing the covalent bond framework of the enzyme. Next, we investigated whether the frontier orbitals of enzymes could be used for identifying their potential functional sites. As a result, we found that the frontier orbitals of the 112 enzymes have a high propensity to be colocalized with the known functional sites, especially when the enzymes are hydrated. Such a propensity is shown to be remarkable when Glu or Asp is a functional site residue. On the basis of these results, we finally propose a protocol for the prediction of functional sites of enzymes.     

The effect of loop size in antisense and target RNAs on the efficiency of antisense RNA control.

Most natural antisense RNAs display a high degree of secondary structure with stem-loops as their most prominent feature. Mutations affecting the inhibitory activity of these RNAs most often map in or close to loop regions in both the antisense and target RNAs. The primary recognition loops often contain 5-7 unpaired nucleotides. Nucleotide changes in the loops affect the binding rate and, hence, the inhibitory effect on the activity of the target RNA. Here we address the question whether loop sizes affect binding rates between antisense and target RNAs, using the replication control system of plasmid R1 as a model system. By creating a series of loop size mutants we show that loop size alterations have strong effects on the binding rates between the two reactant RNAs in vitro, and that most of the mutations analyzed display corresponding effects on antisense RNA control in vivo. Our data suggest that the three-dimensional structures of antisense and target RNA stem-loops are crucial for determining binding rates. The implications of these results for the design of efficient artificial antisense RNA control systems are discussed.     

Synthesis of resveratrol analogues, and evaluation of their cytotoxic and xanthine oxidase inhibitory activities

Thirteen resveratrol (=5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol) analogues with a CHO group have been prepared by partial synthesis from resveratrol. The synthesized compounds have been evaluated for their cytotoxic activity against a human nasopharyngeal epidermoid tumor cell line KB, as well as for their xanthine oxidase inhibitory activity. Compounds 2, 3, and 6a showed the most significant cytotoxic activities against the cell line KB, and compound 2 also exhibited strong xanthine oxidase inhibitory activity.     

Designing modulators of dimethylarginine dimethylaminohydrolase (DDAH): A focus on selectivity over arginase

DDAH inhibition presents a novel promising pharmaceutical strategy to lower NO formation. To date, several potent DDAH inhibitors have been published, most of them representing analogues of l-arginine. While inhibitory effects on NOSs have already been considered, selectivity over arginase has been neglected so far. In our view, the latter selectivity is more important since an additional inhibition of arginase decreases the desired effects on NO levels. Thus, we particularly focus on selectivity over arginase. We present a comprehensive selectivity profile of known DDAH inhibitors by covering their inhibitory potency on arginase. Among the studied compounds, N^ω-(2-methoxyethyl)-l-arginine (2a, L-257) that is already selective over NOSs also only modestly affected arginase activity and is thus far the most suitable DDAH inhibitor for pharmacological studies.     

萘查耳酮类化合物的设计合成及对CYP1B1酶的抑制活性评价

目的:设计并合成几类新型的萘查耳酮衍生物,初步测定其对CYP1B1酶的抑制活性,筛选具有良好抗癌作用的CYP1B1抑制剂。方法:以1,5-二羟基萘为原料,首先合成两个重要的中间体2-乙酰基-1,4,5,8-四甲氧基萘、1,5,6-三甲氧基-2-萘乙酮,然后利用羟醛缩合反应合成所需要的化合物。结果:合成了19个目标化合物,其结构均经过核磁共振氢谱确证,所有化合物均为全新化合物。对所合成的新化合物均进行了EROD酶实验测定。结论:所合成的化合物均具有较强的CYP1B1酶一抑制活性,其中4-1、4-2、5'-1对CYP1B1的抑制活性强于CYP1B1强抑制剂α-萘黄酮(IC50=11 nmol/L),他们的IC50分别为6.5、0.47、8nmol/L。     

Theoretical studies of the magnetic couplings and the chemical indices of the biomimetic models of oxyhemocyanin and oxytyrosinase

Magnetic interactions and the nature of the chemical bonds of the biomimetic Cu₂(μ-η²:η²-O₂) complexes of oxyhemocyanin and oxytyrosinase have been investigated with hybrid density functional theory. The Cu₂(μ-η²:η²-O₂) species has drawn attention in type III copper proteins because this structure is suggested as an important motif in biological systems. Many synthetic modeling approaches have been performed and greatly developed our understanding of the character of the Cu₂(μ-η²:η²-O₂) species. Natural orbital analysis clearly shows that the superexchange interaction of the d_xy orbitals of the Cu ions through the π^∗ orbitals of μ-η²:η² peroxide is responsible for the antiferromagnetic couplings of these Cu₂O₂ system and that the distortion of the Cu₂O₂ core from a planar structure to a butterfly structure and elongation of the Cu-O bonds cause the reduction of orbital interactions between the d_xy ± d_xy orbitals of the dicopper site and the σ^∗ and π^∗ orbitals of peroxide, weakening the magnetic coupling between the Cu sites via μ-η²:η²-peroxide.     

Identification of the molecular target of small molecule inhibitors of HDL receptor SR-BI activity

Scavenger receptor, class B, type I (SR-BI), controls high-density lipoprotein (HDL) metabolism by mediating cellular selective uptake of lipids from HDL without the concomitant degradation of the lipoprotein particle. We previously identified in a high-throughput chemical screen of intact cells five compounds (BLT-1-5) that inhibit SR-BI-dependent lipid transport from HDL, but do not block HDL binding to SR-BI on the cell surface. Although these BLTs are widely used to examine the diverse functions of SR-BI, their direct target(s), SR-BI itself or some other component of the SR-BI pathway, has not been identified. Here we show that SR-BI in the context of a membrane lipid environment is the target of BLT-1, -3, -4, and -5. The analysis using intact cells and an in vitro system of purified SR-BI reconstituted into liposomes was aided by information derived from structure-activity relationship (SAR) analysis of the most potent of these BLTs, the thiosemicarbazone BLT-1. We found that the sulfur atom of BLT-1 was crucially important for its inhibitory activity, because changing it to an oxygen atom resulted in the isostructural, but essentially inactive, semicarbazone derivative BLT-1sc. SAR analysis also established the importance of BLT-1's hydrophobic tail. BLTs and their corresponding inactive compounds can be used to explore the mechanism and function of SR-BI-mediated selective lipid uptake in diverse mammalian experimental models. Consequently, BLTs may help determine the therapeutic potential of SR-BI-targeted pharmaceutical drugs.     

1,3,4-Oxadiazole-3(2H)-carboxamide derivatives as potential novel class of monoamine oxidase (MAO) inhibitors: synthesis, evaluation, and role of urea moiety

A new series of 1,3,4-oxadiazole-3(2H)-carboxamide derivatives have been synthesized by direct heterocyclization reaction of substituted benzoylisocyanate with various aroylhydrazones as novel monoamine oxidase inhibitors (MAOIs). The target molecules have been identified on the basis of satisfactory analytical and spectra (IR, (1)H NMR, (13)C NMR, and HR-MS) data. The newly synthesized compounds were evaluated for their MAO inhibitory activity by kynuramine fluorimetric assay method. The preliminary results showed that most of the compounds have moderate inhibitory activities toward MAO at the concentration of 10(-5)-10(-3)M. This work may provide a novel class of lead compounds with potential MAO inhibitions for further optimization.