Terms Of Structure-activity Relationships Research Articles

4-methoxybenzalacetone, the cinnamic acid analog as a potential quorum sensing inhibitor against Chromobacterium violaceum and Pseudomonas aeruginosa.

The continuous increase in the incidence of infectious diseases and the rapid unchecked rise in multidrug-resistance to conventional antibiotics have led to the search for alternative strategies for treatment and clinical management of microbial infections. Since quorum sensing (QS) regulates numerous virulence determinants and pathogenicity in bacteria, inhibition of QS promises to be an attractive target for development of novel therapeutics. In this study, a series of cinnamic acid analogs and benzalacetone analogs were designed and synthesized, and their QS-inhibitory activities explored. We found that, among the test compounds, 4-methoxybenzalacetone (8) exhibited potent anti-quorum sensing property, as evidenced by inhibition of QS-controlled violacein production of Chromobacterium violaceum ATCC12472. The inhibitory activity of such a compound, which was the methyl keto analog of the corresponding cinnamic acid, was not only stronger than the parent cinnamic acid (1), but also superior to that of furanone, the reference drug. Based on our observations, its mechanism of quorum sensing inhibition is likely to be mediated by interference with N-acyl-homoserine lactones (AHL) synthesis. Moreover, 4-methoxybenzalacetone (8) also suppressed the production of pyocyanin, rhamnolipids and swarming motility of Pseudomonas aeruginosa, suggesting a broad spectrum of anti-QS activities of this compound. In terms of structure-activity relationship, the possible chemical substitutions on the scaffold of cinnamic acid required for QS inhibitory activity are also discussed. Since 4-methoxybenzalacetone (8) showed no toxicity to both bacteria and mammalian cells, our findings therefore indicate the anti-QS potential of this compound as a novel effective QS inhibitor.

Nature and identity of the active site via structure-dependent microkinetic modeling: An application to WGS and reverse WGS reactions on Rh

We propose a methodology to perform a structure-dependent microkinetic analysis of a catalytic process. The methodology makes it possible to unveil the nature and identity of the active site in a self-consistent manner. The morphology of heterogeneous catalyst nanoparticles as a function of the gas chemical potential is determined using ab initio thermodynamics and Wulff-Kaishew construction methods. The reaction rates are calculated by integrating a microkinetic model which describes the catalytic activity of the crystal facets exposed by the catalyst under reaction conditions. The method is applied for the analysis of the direct and reverse water-gas shift (WGS) reacting systems on a 4% Rh/α-Al2O3 kinetic experiments from the literature. Our findings make it possible to rationalize that far from equilibrium the two different reacting systems not only follow different reaction pathways in agreement with the experimental evidence but also show that the dominant active sites are different for WGS and reverse WGS. Indeed, the WGS reaction occurs mainly on the Rh(111) facet, whereas reverse WGS proceeds on the active sites of Rh(100). As a whole, this methodology makes it possible a concomitant description of the nature of the catalyst material in reaction conditions and of its catalytic consequences in terms of reactivity. As such, it paves the way towards the use of first-principles methods for the interpretation of the experimental evidence in terms of structure-activity relationships.

Approach in Improving Potency and Selectivity of Kinase Inhibitors: Allosteric Kinase Inhibitors.

Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have a distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for the treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structure-activity relationships, ligand-protein interactions, and in vitro and in vivo activity. Additionally, challenges, as well as opportunities, are also presented.

Parallel synthesis of a bis-triazoles library as psammaplin A analogues: A new wave of antibiofilm compounds?

Synthesis of psammaplin A analogues is described. Screening for antibiofilm activity of the targeted library afford some interesting elements in terms of structure-activity relationships. Some compounds exhibited EC50 in the range of ampicillin against three strains of gramnegative bacteria without toxic effect.

Diving for Accurate Structures in the Ocean of Molecular Systems with the Help of Spectroscopy and Quantum Chemistry.

The prediction and interpretation of structural properties are the starting points for a deep understanding of thermochemistry, kinetics, and spectroscopic signatures of molecular systems. To give an example, detailed knowledge of the conformational behavior of the main building blocks of biomolecules in the gas phase (i.e., without the perturbing effect of the environment) is a mandatory prerequisite toward the understanding of the role played by different interactions in determining the biological activity in terms of structure-activity relationships. The first step to take is an unambiguous definition of molecular structure. We address the so-called Born-Oppenheimer equilibrium structure, which is defined in a rigorous manner and isotopically independent, and the target accuracy. For the latter, we aim at so-called "spectroscopic" accuracy, which implies uncertainties of a few milliangstroms for bond lengths and smaller than a tenth of degree for angles. If on one side the continuous enhancements of the experimental techniques give access to new and unprecedented spectroscopic determinations, on the other side they require increasing efforts for an unbiased interpretation and analysis. Among the pieces of information, accurate molecular structures play a particularly important role. Indeed, there is a strong relationship between the experimental outcome and the electronic structure of the system. Spectroscopic techniques, in particular those exploited in the gas phase, are therefore accurate and reliable sources for structural information. However, it is seldom straightforward to derive molecular structures directly from the experimental information. Indeed, even in the favorable case of investigations in the gas phase, vibrational effects are always present, and disentangling their contributions requires collection of information for all vibrational modes, a nearly impossible task. To overcome these limitations, joint theory-spectroscopy strategies can be identified, which are referred to as "top-down" and "bottom-up". The first approach, denoted as the semiexperimental approach, relies on extracting from experimental outcomes the equilibrium structure by using quantum-chemical computations to recover vibrational effects. The bottom-up approach consists in verifying the computed equilibrium geometry by means of a comparison between calculated and experimental spectroscopic parameters that probe structural characteristics. In this contribution, we try to review the most important challenges in accurate molecular structure determinations, with particular emphasis on the "solution" provided by a joint theoretical-experimental approach and on the current state of the art. Starting from the illustration of different strategies, we proceed by addressing the increasing complexity in the derivation of equilibrium geometries: we start from the construction of a database of accurate structures, we then face the problem of extending the dimension of the systems amenable to accurate structural determinations, and finally we move to the challenge of understanding the nature of intermolecular interactions.

Yapı Aktivite İlişkisi (SAR): Bromlanmış 8-hidroksikinolin ve ftalonitril türevlerinin çeşitli kanser hücre hatları üzerine antiproliferatif aktivitelerinin incelenmesi

In this study, phthalonitriles 6 , 7 and their corresponding bromo derivatives 8 , 9 were synthesized from 8-hydroxyquinoline to investigate antiproliferative and cytotoxic activities on C6 (rat brain tumor), HeLa (human cervix carcinoma) and HT29 (human colon carcinoma) cancer cell lines of these molecules. The antiproliferative and apoptotic effects of 7-bromo- and 5,7-dibromo-8-hydroxyquinoline derivatives ( 2 and 3 ) and phthalonitrile 6 , 7 and their brominated derivatives 8 , 9 were compared in terms of Structure Activity Relationship (SAR). Although bromohydroxyquinoline derivatives 2 and 3 exhibited high antiproliferative activity according to literature, it has been determined that phthalonitrile compounds 6 , 7 and their brominated 8 , 9 derivatives are significantly reduced in antiproliferative activity. The SAR of the quinoline core at C-8 revealed that OH group lead to antiproliferative and apoptotic activity. In addition, biological activity was decreased when alkyl or substituted cyclic groups bounded to OH of quinoline, and the bromination of these derivatives did not increase the antiproliferative activity.

A chalcone with potent inhibiting activity against biofilm formation by nontypeable Haemophilus influenzae.

Nontypeable Haemophilus influenzae (NTHi), an important human respiratory pathogen, frequently causes biofilm infections. Currently, resistance of bacteria within the biofilm to conventional antimicrobials poses a major obstacle to effective medical treatment on a global scale. Novel agents that are effective against NTHi biofilm are therefore urgently required. In this study, a series of natural and synthetic chalcones with various chemical substituents were evaluated in vitro for their antibiofilm activities against strong biofilm-forming strains of NTHi. Of the test chalcones, 3-hydroxychalcone (chalcone 8) exhibited the most potent inhibitory activity, its mean minimum biofilm inhibitory concentration (MBIC50 ) being 16 μg/mL (71.35 μM), or approximately sixfold more active than the reference drug, azithromycin (MBIC50 419.68 μM). The inhibitory activity of chalcone 8, which is a chemically modified chalcone, appeared to be superior to those of the natural chalcones tested. Significantly, chalcone 8 inhibited biofilm formation by all studied NTHi strains, indicating that the antibiofilm activities of this compound occur across multiple strong-biofilm forming NTHi isolates of different clinical origins. According to antimicrobial and growth curve assays, chalcone 8 at concentrations that decreased biofilm formation did not affect growth of NTHi, suggesting the biofilm inhibitory effect of chalcone 8 is non-antimicrobial. In terms of structure-activity relationship, the possible substituent on the chalcone backbone required for antibiofilm activity is discussed. These findings indicate that 3-hydroxychalcone (chalcone 8) has powerful antibiofilm activity and suggest the potential application of chalcone 8 as a new therapeutic agent for control of NTHi biofilm-associated infections.

Development of a general and efficient route to highly lipophilic benzoxazole-2ylphosphonates and their antineoplastic properties

As a continuation of our efforts to discover and develop the 2-substituted-5,7-di-tert-butyl-2,3-dihy- drobenzo(d)oxazol-2-ylphosphonate series of apoptosis inducers as potential anticancer agents, we explored new substitutions at the 2- and 3-positions of the oxazole ring to identify the development of antitumor candidates. This modification, in combination with synthesizing their relevant 2-benzoxazaphosphole 2-oxides and enamino- phosphonates, resulted in obtaining an ensemble of 13 new phosphonates in high yields (70-76 %). The synthesized phosphonates were analyzed using the reversed-phase, high performance liquid chromatography method for the lipo- philicity measurement (logK) as a prediction tool. Later on, selected compounds were evaluated as antitumor agents at a dose of 10 lmol cm -3 against breast, prostate, and mela- noma carcinoma cell lines. The results were discussed in terms of structure-activity relationships.

Structure-activity relationship of benzophenanthridine alkaloids from Zanthoxylum rhoifolium having antimicrobial activity.

Zanthoxylum rhoifolium (Rutaceae) is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1–3), and nine benzophenanthridine alkaloids (4–12) were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10), followed by avicine (12) and dihydrochelerythrine (4). The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A) of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14) was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective effect considering the decrease in TBARS and AOPP (advanced oxidized protein products) levels when compared to the control group.

Toward the Discovery of Novel Anti‐HIV Drugs. Second‐Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti‐HIV Activity: Synthesis, Structure–Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation

A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.

Ionisation constants and partition coefficients of some analgesically active 2-benzylbenzimidazole derivatives and related compounds.

Abstract The ionisation constants (in aqueous ethanol) and the partition coefficients (in a water-cyclohexane system) of some analgesically active 2-benzylbenzimidazole derivatives and related compounds are reported. The results are discussed in terms of structure-activity relationships.

Recent Advances on Platensimycin: A Potential Antimicrobial Agent

Platensimycin, an active metabolite of Streptomyces platensis, was initially discovered by a combination of RNA interferin induced gene-silencing and library screening to microbial extracts. Platensimycin selectively inhibits beta - ketoacyl-acyl carrier protein (ACP) synthase II (FabF) that is recognized as an effective broad-spectrum antibiotic against drug-resistant microorganism strains. Its novel scaffold and extraordinary antibacterial activity have drawn great attentions in recent years. So far, a number of synthetic strategies have been explored for the total synthesis of platensimycin. Moreover, many analogues have been investigated in terms of structure-activity relationships (SAR). This review provides a detailed overview of updated studies on platensimycin, focusing on various total and formal synthetic strategies, development of analogues, and the structure-activity relationships.

Medicinal Chemistry of Paclitaxel and its Analogues

Paclitaxel belongs to the most successful anticancer drugs developed and utilised during the past two decades. Nevertheless, the development of resistance of tumor cells and severe side effects in the patients require further improvement of the drug. In this review, we provide a detailed overview of the state-of-the-art in the medicinal chemistry of paclitaxel and its analogues. A number of strategies have been explored to obtain sufficient amounts of paclitaxel for clinical use from natural resources. Semi-synthesis from its precursor, 10-deacetylbaccatin III, which can be extracted from Taxus leavesturned out as the most appropriate method for commercial production. So far, many paclitaxel derivatives have been synthesized, and their effect on microtubules stabilization and cytotoxicity were investigated in terms of structure-activity relationships (SAR). One of them, docetaxel, was approved as a more potent anticancer agent than paclitaxel towards a variety of tumor types. This review summarizes current possibilities to harvest sufficient amount of drugs from natural sources, including the production of taxanes in bioreactors and synthetic approaches for paclitaxel and its analogues, their mechanism of action and structure-activity relationships. In addition, future developments and perspectives for this class of compounds are outlined.

Synthesis of Antimicrobial N-Phthaloyl-alanyl-derived Amidophosphates and Triazoles

N-Phthaloyl-alanylazide reacts smoothly with trialkyl phosphites producing the corresponding α- aminophosphates. With dialkyl hydrogenphosphonates in the presence of benzoyl peroxide, amidophosphates were the isolated products whereas the oxoaziridin-1-yl-phosphonic diamide was preferentially provided from the reaction of the azide with tris(dimethylamino)phosphine. The azide was also allowed to react with α-keto-, α-ethoxycarbonyl- and α-cyanomethylenetriphenylphosphorane to give the corresponding linear disubstituted 1,2,3-triazoles. Screening results of antibiotic potency for the products were discussed in terms of structure-activity relationship (SAR), and an attempt was made to define the structural features for lead compounds.

OH-Initiated Degradation of Unsaturated Esters in the Atmosphere: Kinetics in the Temperature Range of 287−313 K

The kinetics of the gas-phase reactions of hydroxyl radicals (OH) with methyl methacrylate (k(1)), butyl methacrylate (k(2)), butyl acrylate (k(3)), and vinyl acetate (k(4)) have been investigated for the first time as a function of temperature using the relative technique. The experiments were performed in a 1080 L quartz glass photoreactor over the temperature range (T = 287-313 K) at a total pressure of 760 +/- 10 Torr synthetic air using in situ FTIR absorption spectroscopy to monitor the concentration-time behaviors of reactants. OH radicals were produced by the 254 nm photolysis of hydrogen peroxide (H(2)O(2)). The following Arrhenius expressions (in units of cm(3) molecule(-1) s(-1)) adequately describe the measured rate coefficients as a function of temperature: k(1) = (1.97 +/- 0.95) x 10(-12) exp[(921 +/- 52)/T], k(2) = (1.65 +/- 1.05) x 10(-11) exp[(413 +/- 34)/T], k(3) = (4.4 +/- 2.5) x 10(-13) exp[(1117 +/- 105)/T], and k(4) = (4.06 +/- 2.02) x 10(-12) exp[(540 +/- 49)/T]. All of the rate coefficients display a negative temperature dependence and low pre-exponential factor, which supports an addition mechanism for the reactions involving reversible OH-adduct formation. The rate coefficients (in units of cm(3) molecule(-1) s(-1)) determined at room temperature (298 K) were as follows: k(1) = (4.30 +/- 0.98) x 10(-11), k(2) = (6.63 +/- 1.42) x 10(-11), k(3) = (2.17 +/- 0.48) x 10(-11), and k(4) = (2.48 +/- 0.61) x 10(-11). The results are compared with previous values of the rate coefficients reported in the literature, which were mainly measured at room temperature. The reactivity of the various unsaturated esters toward the OH radical is discussed in terms of structure activity relationships and parallels are drawn with the OH-radical activities of structurally similar compounds. Using the kinetic parameters determined in this work, residence times of the esters in the atmosphere with respect to their reaction with OH have been determined and are compared with other possible degradation pathways. Possible atmospheric implications of the various degradation pathways studied are discussed.

Antimicrobial activity of novel fused nitrogen, sulfur and phosphorus containing-heterocycles and relevant phosphonates with difurylpyridazine species

Treatment of 5,6-di(2-furyl)-3-thioxo-2,3-dihydropyridazine-4-carbonitrile with phosphonate carboanions stabilised with electron withdrawing group (CO2R, CN, SR’) led, under microwave irradiation and the effect of basic catalysis, to excellent yields of a variety of condensed sulfur, nitrogen and phosphorus-containing heterocycles as major products, along with fused thieno- and thiazole ring systems bearing a phosphonate moiety. On the other hand, fused thiazaphosphinine oxide and thiopyranone phosphonate were obtained in equal yields from the reaction of 5,6-di(2-furyl)-3-thioxo-2,3-dihydropyridazine-4-carbonitrile with diethyl vinylphosphonate. Screening results of antimicrobial potency for the products were discussed in terms of structure-activity relationships (SAR), and an attempt was made to define the structural features for lead compounds.

Strategy to improve the characterization of chitosan for sustainable biomedical applications: SAR guided multi-dimensional analysis

The biopolymer chitosan has shown great potential for a tremendous number of applications despite the fact that typical chitosan preparations are always mixtures of different chemical entities, natural impurities and process-induced impurities. However, chitosan preparations described in the literature or offered on the market are analytically highly undefined. Here we propose a T-SAR (thinking in terms of structure-activity-relationships) guided multi-dimensional analysis of distinct chitosan preparations with the aim a) to obtain the information needed for the production of reproducible chitosan preparations and b) to predict biological effects and technological properties of certain chitosan preparations. First, a physico-chemical description (molecular weight (MW), polydispersity (MW/MN), fraction of acetylation (FA), pattern of acetylation (PA), hydrodynamic radius (Rh), intrinsic viscosity ([η])) of six selected samples was done. Furthermore chitosan properties like solubility, crystallinity, conformation (Mark-Houwink-plot) and impurities of all the chitosan preparations from different origins were determined and biological effects were also analyzed using test systems with two different bacteria (Escherichia coli, Vibrio fischeri). It was found that the presence of HCl enabled the water solubility of chitosan, while chloride-free chitosan was only soluble in acetic acid. The pattern of acetylation PA showed no impact on this behavior. The analyzed biological effects revealed growth inhibition within 30 minutes for E. coli and a decreased bioluminescence for V. fisheri (IC50 = 0.035 w%). Thus, the strategy to check biological effects within a multi-dimensional analysis kit proved to be effective for detecting general structure-property-relationships of chitosan in relation to its biological effects.

Timosaponin A-III Induces Autophagy Preceding Mitochondria-Mediated Apoptosis in HeLa Cancer Cells

Timosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, exhibits potent cytotoxicity and has the potential to be developed as an anticancer agent. Here, we provide evidence that TAIII induces autophagy in HeLa cells followed by apoptotic cell death. TAIII-induced autophagy was morphologically characterized by the formation of membrane-bound autophagic vacuoles recognizable at the ultrastructural level. TAIII-treated cells expressing green fluorescent protein (GFP)-labeled microtubule-associated protein 1 light chain 3 (LC3) displayed punctate fluorescence indicative of LC3 recruitment to the autophagosome. This was associated with the conversion of LC3-I (the cytosolic form) into LC3-II (the lipidated form located on the autophagosome membrane). TAIII treatment also induced mitochondrial dysfunction involving overproduction of reactive oxygen species and reduction of mitochondrial membrane potential accompanied by induction of mitochondrial permeability transition. Prolonged exposure to TAIII resulted in cytochrome c release and caspase-3 activation, events that signified the onset of apoptotic cell death. TAIII-induced autophagy preceded apoptosis, as evidenced by early autophagic vacuole formation, GFP-LC3 translocation, and LC3-II increase in the absence of caspase-3 cleavage. Notably, TAIII-mediated apoptotic cell death was potentiated by treatment with autophagy inhibitor 3-methyladenine or small interfering RNA against the autophagic gene beclin 1. These findings suggest that TAIII-elicited autophagic response plays a protective role that impedes the eventual cell death. In terms of structure-activity relationship, the sugar chain in TAIII is indispensable to the drug action, as the sugar-lacking aglycone sarsasapogenin did not induce autophagy and exhibited weaker cytotoxicity.

Combining Ligand- and Structure-Based Methods in Drug Design Projects

In todays drug discovery projects, the use of virtual screening tools, either ligand-based or structure-based techniques, is gaining momentum. Taken separately, these techniques obviously present some genuine advantages on some specific tasks, for example and for a given target, it is possible to explore the local variation of the chemical space in terms of structure activity relationship (SAR), or to sample the pharmaco-topological profile of potential hit molecules in a target structure driven manner (docking). Thus, while inherent limits are associated with each of these screening techniques that are not about to be easily solved, their combination in a hybrid protocol can help to balance these limitations and capitalize on their mutual strengths. Here we review some recent studies integrating ligand- and structure-based screening protocols, and show how this concept directly benefits the quality of the hit molecules.

Lantadenes and Their Esters as Potential Antitumor Agents

Lantadenes are pentacyclic triterpenoids of the weed Lantana camara. Five new lantadenes (14-18) and their methyl esters (20-24) were synthesized, characterized, and screened for cytotoxicity against four human cancer cell lines. The parent compound (1) and the four most active compounds (15, 16, 21, and 22) were further studied for their in vivo tumor inhibitory potential on squamous cell carcinogenesis in Swiss albino mice induced by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). These results were supported by histopathological studies and discussed in terms of structure-activity relationships. The results inferred the importance of the groups attached to C-22 and C-17 in relation to the antitumor activity of these compounds.