Simple Structure-activity Relationship Research Articles

Exploring the Impact of Active Site Structure on the Conversion of Methane to Methanol in Cu-Exchanged Zeolites.

In the past, Cu-oxo or -hydroxy clusters hosted in zeolites have been suggested to enable the selective conversion of methane to methanol, but the impact of the active site's stoichiometry and structure on methanol production is still poorly understood. Herein, we apply theoretical modeling in conjunction with experiments to study the impact of these two factors on partial methane oxidation in the Cu-exchanged zeolite SSZ-13. Phase diagrams developed from first-principles suggest that Cu-hydroxy or Cu-oxo dimers are stabilized when O2 or N2O are used to activate the catalyst, respectively. We confirm these predictions experimentally and determine that in a stepwise conversion process, Cu-oxo dimers can convert twice as much methane to methanol compared to Cu-hydroxyl dimers. Our theoretical models rationalize how Cu-di-oxo dimers can convert up to two methane molecules to methanol, while Cu-di-hydroxyl dimers can convert only one methane molecule to methanol per catalytic cycle. These findings imply that in Cu clusters, at least one oxo group or two hydroxyl groups are needed to convert one methane molecule to methanol per cycle. This simple structure-activity relationship allows to intuitively understand the potential of small oxygenated or hydroxylated transition metal clusters to convert methane to methanol.

Kinetic and reactivity of gas-phase reaction of acyclic dienes with hydroxyl radical in the 273-318 K temperature range.

As dienes contain two C[double bond, length as m-dash]C bonds, theoretically, they are much more chemically reactive with hydroxyl radical (˙OH) than alkenes and alkanes, and the reaction with ˙OH is one of the main atmospheric degradation routes of dienes during the daytime. In our work, rate coefficients of three types of acyclic dienes: conjugated as 3-methyl-1,3-pentadiene (3M13PD), isolated as 1,4-hexadiene (14HD), and cumulated as 1,2-pentadiene (12PD) reaction with ˙OH were measured in the temperature range of 273-318 K and 1 atm using the relative rate method. At 298 ± 3 K, the rate coefficients for those reactions were determined to be k3M13PD+OH = (15.09 ± 0.72) × 10-11, k14HD+OH = (9.13 ± 0.62) × 10-11, k12PD+OH = (3.34 ± 0.40) × 10-11 (as units of cm3 per molecule per s), in the excellent agreement with values of previously reported. The first measured temperature dependence for 3M13PD, 14HD and 12PD reaction with ˙OH can be expressed by the following Arrhenius expressions in units of cm3 per molecule per s: k3M13PD+OH = (8.10 ± 2.23) × 10-11 exp[(173 ± 71)/T]; k14HD+OH = (9.82 ± 5.10) × 10-12 exp[(666 ± 123)/T]; k12PD+OH = (1.13 ± 0.87) × 10-12 exp[(1038 ± 167)/T] (as units of cm3 per molecule per s). The kinetic discussion revealed that the relative position between these two C[double bond, length as m-dash]C could significantly affect the reactivity of acyclic dienes toward ˙OH. A simple structure-activity relationship (SAR) method was proposed to estimate the reaction rate coefficients of acyclic dienes with ˙OH.

Surface engineering of non-platinum-based electrocatalysts for sustainable hydrogen production: Encapsulation, doping, and decoration approach

The hydrogen evolution reaction's electrocatalytic reduction of water to molecular hydrogen may one day provide a long-term sustainable source of energy. However, the use of precious platinum catalysts makes it difficult to commercialize. So far, all alternatives to platinum are based on non-precious metals and transition metals. Hence, tuning the catalytic activity of nanomaterials through surface engineering might offer significant advantages. Herein, we step-wisely modulate the surface of all carbon fullerene nanomaterial by encapsulation, doping and decoration with alkali and transition metals to produce a hybrid catalyst which demonstrated excellent hydrogen evolution activity with comparable Gibbs free energy with both experimentally developed and theoretically modelled electrocatalyst. The adsorption of H* intermediate on the doped and decorated metal sites has been investigated in comparison with the pristine C24 fullerene structure. The electronic properties, the density of state (PDOS), reaction-free energy (ΔG) and transition states have all been carefully considered at appropriate theoretical levels. The ΔG of hydrogen adsorption on H@IndecNidopMgencC24 was found to be closer to zero (0.0328 eV) because of the concomitant effect of the encapsulation, doping and decoration with transition metals thus, demonstrating the effectiveness of this approach to tuning catalytic activity. The encapsulated metal enhanced the catalyst surface's conductivity and electronic attributes, leading to improved HER activity. The catalytic HER was also found to follow the Volmer-Tafel pathways, resulting in a lower free energy barrier. Overall, this work demonstrates a simple structure-activity relationship between metallic effects and substrate engineering and could open new dimensions for the development of novel non-platinum-based electrocatalysts.

Drug repurposing strategy II: from approved drugs to agri-fungicide leads.

Epidemic diseases of crops caused by fungi deeply affected the course of human history and processed a major restriction on social and economic development. However, with the enormous misuse of existing antimicrobial drugs, an increasing number of fungi have developed serious resistance to them, making the diseases caused by pathogenic fungi even more challenging to control. Drug repurposing is an attractive alternative, it requires less time and investment in the drug development process than traditional R&D strategies. In this work, we screened 600 existing commercially available drugs, some of which had previously unknown activity against pathogenic fungi. From the primary screen at a fixed concentration of 100 μg/mL, 120, 162, 167, 85, 102, and 82 drugs were found to be effective against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, Phytophthora capsici, Fusarium graminearum and Fusarium oxysporum, respectively. They were divided into nine groups lead compounds, including quinoline alkaloids, benzimidazoles/carbamate esters, azoles, isothiazoles, pyrimidines, pyridines, piperidines/piperazines, ionic liquids and miscellaneous group, and simple structure-activity relationship analysis was carried out. Comparison with fungicides to identify the most promising drugs or lead structures for the development of new antifungal agents in agriculture.

Unusual constituents from the medicinal mushroom Ganoderma lingzhi.

Extensive studies have revealed that triterpenoids, meroterpenoids, and polysaccharides are the main constituents of the well-known traditional Chinese medicinal mushroom Ganoderma. In this study, we report seven previously undescribed sesquiterpenoids, including six gymnomitranes (1–6) and a novel type of sesquiterpenoid (8), together with a polyketide (7) and a known steroid (9) from the fruiting bodies of Ganoderma lingzhi, a fungus used as traditional medicine and food supplement in East Asia for ages. The structures of 1–8 were deduced by analysis of spectroscopic data, X-ray single crystal diffractions and TDDFT/ECD calculations. Compound 8 possessed an unusual 14(7→6)-cuparane scaffold. Compound 9 exhibited weak cytotoxicity against the five human cancer cell lines HL-60, MCF-7, SW480, A549, and SMMC-7721 with IC50 values of 18.0–32.3 μM. A simple structure-activity-relationship (SAR) investigation by acetylating the 5-OH of 9 (9a) suggested that the 5-OH is essential for its cytotoxicity. Additionally, the biosynthetic pathways for compounds 2 and 8 are discussed.

11-Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action.

The synthesis of various new structures of a library of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines (BP) and 11-substituted 6-aminobenzo[c]phenanthridines (BP-D) is presented. These structures, further synthetic modifications, and the preparation of follow-up products which delivered about 40 new derivatives are described. Their potential as antiproliferative drug candidates was investigated by comparison of NCI 60 developmental therapeutics program (DTP) human tumor cell line screening data based on the results of in vitro tumor cell growth inhibition, including about 40 hitherto unpublished compound test results with up to 60 cancer cell lines. NCI-COMPARE studies helped to suggest the modes of action of the highly active antiproliferative drugs. These findings are supported by in vitro biological investigations showing either inhibition of tubulin polymerization and depolymerization or topoisomerase inhibition. Together with physicochemical parameters of the drug candidates, structure-activity relationships are critically discussed. Tubulin interaction or inhibition of topoisomerase I and IIα/β activity are two rationales that can explain the antiproliferative activity observed in the NCI 60 DTP human tumor cell line screen. However, it can also be reasonably assumed that these compounds address several targets, thus prohibiting the identification of simple structure-activity relationships. The new structures described herein are thought to act as so-called multitarget drugs, thus being of special interest in the area of multidrug resistance.

Discovery of a Novel 2,6-Difunctionalized 2H-Benzopyran Inhibitors Toward Sphingosylphosphorylcholine Synthetic Pathway as New Anti-inflammatory Target

Novel 2,6-difuctionalized 2H-benzopyrans were synthesized and evaluated for a sphingosylphosphorylcholine(SPC) inhibitor. The synthetic 2H-benzopyrans 1c and 3a showed high potency in SPC-induced cell proliferation assay (<TEX>$IC_{50}$</TEX> < 20 nM). Neither hERG <TEX>$K^+$</TEX> channel binding (> <TEX>$10{\mu}M$</TEX>) nor CYP inhibitions (> <TEX>$10{\mu}M$</TEX>) were observed. Also, the simple structure-activity relationship (SAR) results were obtained from analysis of 2H-benzopyran derivatives 1-3 and the anti-SPC effect of 2H-benzopyran 1c was confirmed by a HUVEC tube formation assay.

Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities

A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50=58.43μM) as well as for SIRT2 (IC50=45.12μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure–activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.

Three new 11,20-epoxy-ent-kauranoids from Isodon rubescens

Three rare and new 11,20-epoxy-ent-kaurane diterpenoids, named jianshirubesins D-F (1-3), along with one known analogue (4), were isolated from the aerial parts of Isodon rubescens. Their structures were established by analysis of spectroscopic data. Found in the MTT assay to evaluate the cytotoxicity of compounds 1, 2, and 4, only 1 could selectively inhibit certain cell lines from proliferating. In addition, a simple structure-activity relationship discussion might suggest a new bioactive moiety, different from the α,β-unsaturated ketone group.

Design, Synthesis, and In vitro Antitumor Activity Evaluation of Novel 4‐pyrrylamino Quinazoline Derivatives

Here, we describe the design and synthesis of two series of 4-pyrrylamino quinazolines as new analogs of the epidermal growth factor receptor inhibitor gefitinib. In vitro antitumor activity of these novel compounds against pancreatic (Miapaca2) and prostate (DU145) cancer cell lines was evaluated. Compared with the parental gefitinib, all 18 derivatives show a greatly increased cytotoxicity to cancer cells. In vitro kinase inhibitory activity on epidermal growth factor receptor was also investigated. Among them, compounds GI-6, GII-4, GII-6, GII-8, and GII-9 are more potential receptor tyrosine kinase (RTK) inhibitors. Based on these results, we propose simple structure-activity relationship to provide information for designing and developing more potent antitumor agents.

Structural Insight into the Differential Effects of Omega-3 and Omega-6 Fatty Acids on the Production of Aβ Peptides and Amyloid Plaques

Several studies have shown the protective effects of dietary enrichment of various lipids in several late-onset animal models of Alzheimer Disease (AD); however, none of the studies has determined which structure within a lipid determines its detrimental or beneficial effects on AD. High-sensitivity enzyme-linked immunosorbent assay (ELISA) shows that saturated fatty acids (SFAs), upstream omega-3 FAs, and arachidonic acid (AA) resulted in significantly higher secretion of both Aβ 40 and 42 peptides compared with long chain downstream omega-3 and monounsaturated FAs (MUFA). Their distinct detrimental action is believed to be due to a structural template found in their fatty acyl chains that lack SFAs, upstream omega-3 FAs, and AA. Immunoblotting experiments and use of APP-C99-transfected COS-7 cells suggest that FA-driven altered production of Aβ is mediated through γ-secretase cleavage of APP. An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F), corroborated in vitro findings by showing lower levels of Aβ and amyloid plaques in the brain, when they were fed a low fat diet enriched in DHA. Our work contributes to the clarification of aspects of structure-activity relationships.

Thermodynamic considerations of solvent/enhancer uptake into a model membrane

The aim of this study was to conduct a thermodynamic analysis of the uptake of solvents into a model membrane as a precursor to skin transport studies. The investigation was designed so that the methodology may be applied to analyse data produced from measurement of the uptake of enhancers into skin. The uptake of a series of alcohols into polydimethylsiloxane (silicone) membranes in the temperature range 5–45 °C was examined. A thermodynamic analysis of the data was performed to provide fundamental insight into the uptake process. A simple structure activity relationship was found to exist for the uptake of alcohols with a carbon chain length greater than four, with additional methylene groups exponentially decreasing the equilibrium uptake. Two separate straight lines were observed in the van’t Hoff plot for the equilibrium solvent uptake above and below 16 °C. The two separate straight lines in the van’t Hoff plot suggest a change in the mechanism of solvent uptake and solvent structure in the membrane above and below 16 °C. This is likely to have implications for the effect of the solvents on the partitioning of drugs into the membrane and will be used to provide insight into dynamic measurements of the effect of temperature on the transport of drug molecules in the same vehicles, across the membrane. The analysis described here should provide a useful methodology for investigating the uptake of solvents into model membranes.

Synthesis and chain-dependent antifungal activity of long-chain 2 H-azirine-carboxylate esters related to dysidazirine

Analogues of the antifungal marine natural product ( E)-dysidazirine were prepared and evaluated in broth ro-dilution assays against a panel of fungal pathogens. A simple structure–activity relationship was developed which provides insight into the mechanism of action of long-chain 2 H-azirine carboxylates.

Molecular Structure Optimization and Molecular Dynamics Using Hamiltonian Algorithm: Structure of Benzodiazepine Minor Tranquilizers—Towards Non-Empirical Drug Design—

Abstract We have studied the molecular dynamics of the benzodiazepine and thienodiazepine minor tranquilizers using a Hamiltonian Algorithm (HA) combined with ab initio molecular orbital methods. The HA utilizes classical dynamics for optimization of the complicated systems. We show that the HA gives an effective search of the potential energy surfaces and we can find an energy minimum even if we start from another energy local minimum. The conformers of these minor tranquilizers are calculated after computation of the molecular dynamics. Relations between electronic states and strength of tranquilizers are studied for about 17 species of benzodiazepines and thienodiazepines which are sold in the Japanese market as minor tranquilizers. The orbital energy levels of the next highest occupied molecular orbital (next-HOMO or HOMO−1) are found to be strongly related to the strength of the tranquilizers. The simple structure–activity relationship is obtained by considering just one-electron properties, i.e., the molecular orbital energies.

Atmospheric fate of small alkoxy radicals: recent experimental and theoretical advances

New results concerning the kinetics and the atmospheric fate of small alkoxy radicals (ethoxy, 1-propoxy, 2-propoxy, 2-butoxy, t-butoxy, and 3-pentoxy) are reviewed here. The three main reactions of atmospheric relevance are considered to be: the bimolecular reaction with O 2, the unimolecular isomerization, and the unimolecular decomposition. Concerning the latter, significant advances have been achieved thanks to the combination of direct time resolved techniques and theoretical (ab initio and statistical) calculations. Based on a reasonable accord between theory and experiment, a few simple structure activity relationships (SAR), proposed recently by different authors, are compared and should allow a reliable prediction of the unimolecular decomposition rate constant of many alkoxys. On the other hand, new measurements concerning the reaction of a few alkoxys with O 2 confirm that the generic value of k O 2 =(8±2)×10 −15 cm 3 molecule −1 s −1 at 298 K is indeed applicable for all alkoxy radicals. Concerning the unimolecular isomerization, all recent experimental data (from indirect experiments) confirm the order of magnitude estimates proposed by Atkinson [Int. J. Chem. Kinet. 29 (1997) 99] for the isomerization rate constants but only direct absolute measurements, still lacking, will allow a reliable SAR to be developed.

A structure–activity relationship (SAR) for predicting rate constants for the reaction of NO3, OH and O3 with monoalkenes and conjugated dienes

A simple method of predicting rate constants for the reaction between NO3, OH or O3 and substituted alkenes (monoalkenes and conjugated dienes) has been demonstrated using a simple structure–activity relationship (SAR) based on the structure of the alkene. The SAR is useful in providing an initial estimate of an unknown rate constant for a reaction of an alkene and the important tropospheric oxidants NO3, OH or O3.

Conformational studies on histamine H 2-receptor antagonists: deduction of a simple structure-activity relationship

For a series of compounds with H 2-antihistaminic activity the most stable conformations were calculated using molecular mechanics methods. For all the drugs studied there are three conformations which exist with equal probabilities with respect to their conformational energies. Two conformations form a ten-member ed ring by intramolecular interactions between the aromatic ring and the planar structure at the end of the sidechain. A third conformation has these two parts of the molecule arranged in parallel planes separated by a distance of 3 Å. This was confirmed using semiempirical quantum mechanical methods. In one of the preferred conformations a marked relationship is found between the distances of the amidine structure from the plane of the aromatic moiety and the biological activities of the respective derivatives. When the distance of the sidechain from a hypothetical binding site is varied, there are corresponding differences in the interaction energy. As a consequence, the different biological activities of the compounds can easily be explained.

Antifeedant activity of quassinoids

The antifeedant activity of 13 quassinoids of different structural types has been studied against the Mexican bean beetle (Epilachna varivestis Mulsant) 4th instar larvae and the southern armyworm (Spodoptera eridania Crawer) 5th instar larvae. All quassinoids tested displayed significant activity against the Mexican bean beetle and, thus, do not reveal a simple structure-activity relationship. Five quassinoids were active against the southern armyworm. Interestingly, four of these-bruceantin (I), glaucarubinone (VI), isobruceine A (VIII), and simalikalactone D (XI)-possess the required structural features for antineoplastic activity. The noncytotoxic quassin (X) is an exception; it is active against both pests.

Structure-activity and metabolism studies on organophosphate teratogens and their alleviating agents in developing hen eggs with special emphasis on Bidrin

Bidrin (3-hydroxy- N, N-dimethyl- cis-crotonamide dimethyl phosphate) is teratogenic in hen eggs when injected into the yolk sac at a dosage of 0.03 mg per egg or higher; the cis-crotonamide isomer is the active teratogenic component. The response is dose dependent and the effect is at a maximum with injection on or about day 4 of incubation. Signs include straight legs, micromelia, short spine, wry neck, parrot beak, abnormal feathering, edema and, more rarely, syndactyly and visceral hernia. Many other organophosphates are teratogenic, including the Bidrin metabolites that are not hydrolysis products, but no simple structure-activity relationship is evident. Nicotinic acid, nicotinamide and certain of their precursors, analogs and derivatives are active alleviating agents for Bidrin-induced teratogenesis. The active nicotinic acid analogs are those that may be converted to nicotinic acid or nicotinamide, while the inactive analogs probably are not converted to these products. Treatment with nicotinamide prior to incubation and up to day 10 of incubation greatly alleviates teratogenesis. At equimolar levels, nicotinamide and pyridine nucleotide coenzymes show the same alleviating activity, the only exception to this relationship being the 3-acetyl-pyridine analog of the coenzyme. It is not known whether the active alleviating agent is a pyridine nucleotide or any one of several 3-pyridyl compounds. Bidrin is rapidly biodegraded in the egg; successive N-demethylation occurs through the N-hydroxymethyl analogs to yield the unsubstituted amide. Extensive hydrolysis is also involved. Bidrin metabolism between days 4 and 10 of incubation is not affected by nicotinamide; thus, the alleviating agents do not appear to act by altering the metabolism of the teratogenic agents. The metabolism of nicotinic acid is unaffected by the terattogen, Bidrin. Therefore, the alleviating action of nicotinic acid analogs for Bidrin teratogenesis results from mechanisms different from those involving altered rates of metabolism of the teratogen or the alleviating agents.