Structure–Activity and Structure–Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity

Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by using a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure–activity and structure–toxicity relationships. Most compounds displayed potent activity against asexual blood-stage P. falciparum parasites, with IC₅₀ values in the range of 0.0052–0.25 μm and promising selectivity over mammalian cells (SI^Pf3D7/HepG2: 170–1483). In addition, several compounds showed encouraging sub-micromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-isopropylbenzamide ( 2 h ) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC₅₀ Pf3D7=0.0052 μm , IC₅₀ PbEEF=0.016 μm ).     

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis,Structure–Activity Relationships,and Sleep-Promoting Properties in Rats

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone ( 3 ), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone ( 51 ), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.     

Structure–Activity Relationships of WOx-Promoted TiO2–ZrO2 Solid Acid Catalyst for Acetalization and Ketalization of Glycerol towards Biofuel Additives

Catalysis Letters - WOx-promoted TiO2–ZrO2 solid acid catalyst was prepared and applied in the catalytic acetalization and ketalization of glycerol with carbonyl compounds to produce biofuel...     

Discovery and Structure–Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors

Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure–activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC₅₀ of 14 nm for the target and an IC₅₀ of 0.49 μm for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.     

Structure–Activity Relationships of Benzoic Acid Derivatives as Antifeedants for the Pine Weevil, Hylobius abietis

Aromatic organic compounds found in the feces of the pine weevil, Hylobius abietis (L.) (Coleoptera: Curculionidae), have been shown to deter feeding behavior in this species, which is a serious pest of planted conifer seedlings in Europe. We evaluated 55 benzoic acid derivatives and a few homologs as antifeedants for H. abietis. Structure–activity relationships were identified by bioassaying related compounds obtained by rational syntheses of functional group analogs and structural isomers. We identified five main criteria of efficiency as antifeedants among the benzoic acid derivatives. By predicting optimal structures for H. abietis antifeedants, we attempted to find a commercial antifeedant to protect conifer seedlings against damage by H. abietis in regenerating forests. New, highly effective antifeedants are methyl 2,4-dimethoxybenzoate, isopropyl 2,4-dimethoxybenzoate, methyl 2-hydroxy-3-methoxybenzoate, methyl (3,5-dimethoxyphenyl)acetate, and methyl (2,5-dimethoxyphenyl)acetate. Of these, methyl 2,4-dimethoxybenzoate and isopropyl 2,4-dimethoxybenzoate have the highest antifeedant indices of all substances tested and are the best candidates for practical applications in order to protect planted seedlings in the field.     

Biosynthesis and Structure–Activity Relationship Investigations of the Diazeniumdiolate Antifungal Agent Fragin

Only a few natural products incorporating a diazeniumdiolate moiety have been isolated, and these compounds usually display a broad range of biological activities. Only recently has the first diazeniumdiolate natural product biosynthetic gene cluster been identified in Burkholderia cenocepacia H111, which produces the fungicide (−)-fragin and the signal molecule rac-valdiazen. In this study, l -valine was identified as the initial substrate of (−)-fragin biosynthesis with the aid of feeding experiments using isotopically labelled amino acid. The formation of the diazeniumdiolate was chemically studied with several proposed intermediates. Our results indicate that the functional group is formed during an early stage of the biosynthesis. Furthermore, an oxime compound was identified as a degradation product of (−)-fragin and was also observed in the crude extract of the wild-type strain. Moreover, a structure–activity relationship analysis revealed that each moiety of (−)-fragin is essential for its biological activity.     

Structure–Activity of Valencenoid Derivatives and Their Repellence to the Formosan Subterranean Termite

Eight valencenoid derivatives were evaluated for their repelling activity against Formosan subterranean termites, Coptotermes formosanus Shiraki. Among them, 1,10-dihydronootkatone was the strongest repellent, and valencene was the weakest. Results of the structure-repellency relationships indicated (1) reduction of the ketone group to the alcohol on position 2 of nootkatone curtailed the activity; (2) because of the low activity of valencene relative to nootkatone that the ketone group was essential for repellent activity; (3) reduction of the 1,10 double bond (1,10-dihydronootkatone and tetrahydronootkatone) produced compounds more repellent than nootkatone; (4) the isopropenyl group probably does not participate in binding as evidenced by no significant difference in the repellent activity among nootkatone (double bond between position 11 and 12), isonootkatone (double bond between position 7 and 11), and 11,12-dihydronootkatone.     

Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases

Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs. To address this issue, a large number of diverse heterocyclic compounds were prepared. Straightforward synthetic approaches tolerated pre-functionalized structures, giving rise to a structurally diverse set of analogs. We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 29 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei, respectively (antitrypanosomal activities <10 μM). The present work discusses the structure−activity relationships of new fused-ring scaffolds based on imidazopyridine/pyrimidine and furopyridine cores. This library of compounds shows significant potential for anti-trypanosomiases drug discovery.     

Synthesis and Digestibility Inhibition of Diarylheptanoids: Structure–Activity Relationship

(±)-5-Hydroxy-1,7-bis-(4-hydroxyphenyl)-3-heptanone (2a), (±)-5-hydroxyl-1-(4-hydroxyphenyl)-7-phenyl-3-heptanone (2b), (±)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenyl-3-heptanone (2c), and (±)-5-hydroxy-1,7-bis-(phenyl)-3-heptanone (2d) have been synthesized to study the structure–activity relationship regarding digestibility inhibition in vitro in cow rumen fluid. The activities were compared with the activity of chiral (S)-2a and its glucoside platyphylloside (1), isolated from Betula pendula. Compound 2a was slightly less active, 2b and 2c were more active, and 2d was less active than (S)-2a and platyphylloside.     

Relationship Between the Synthesis and Structure of Ceramic Precursors of the TiO2–CeO2–ZrO2 System

Refractories and Industrial Ceramics - Tetragonal solid solutions based on the TiO2–CeO2–ZrO2 system stable up to 1,350°C were obtained. A method of pH titration of the initial...     

Numerical simulation of mixing at 1–1 and 1–2 microfluidic junctions

Computational fluid dynamics (CFD) simulations are carried out to evaluate mixing in different types of 1–1 and 1–2 microfluidic junctions. Computational approach adopted in the study is validated by comparing its predictions with theoretical and experimental results. Asymmetric microfluidic junctions are found to show better mixing than symmetric microfluidic junctions. Among asymmetric microfluidic junctions, mixing is found to improve with increasing skewness of the junction. A new 1–1 microfluidic junction named as OA 10⁰–20⁰ W-junction is found to give the best mixing among all 1–1 microfluidic junctions evaluated in this study. Based on this new 1–1 microfluidic junction, several 1–2 microfluidic junctions are conceptualized. Among these 1–2 microfluidic junctions a junction named as 10⁰–20⁰–165⁰ WY-junction is found to give the best mixing. Different approaches to improve microfluidic mixing viz simple-junction–complex-layout, complex-junction–simple-layout and complex-junction–complex-layout, are compared.     

Structure−Activity Relationships of Cinnamate Ester Analogues as Potent Antiprotozoal Agents

Protozoal infections are still a global health problem, threatening the lives of millions of people around the world, mainly in impoverished tropical and sub-tropical regions. Thus, in view of the lack of efficient therapies and increasing resistances against existing drugs, this study describes the antiprotozoal potential of synthetic cinnamate ester analogues and their structure-activity relationships. In general, Leishmania donovani and Trypanosoma brucei were quite susceptible to the compounds in a structure-dependent manner. Detailed analysis revealed a key role of the substitution pattern on the aromatic ring and a marked effect of the side chain on the activity against these two parasites. The high antileishmanial potency and remarkable selectivity of the nitro-aromatic derivatives suggested them as promising candidates for further studies. On the other hand, the high in vitro potency of catechol-type compounds against T. brucei could not be extrapolated to an in vivo mouse model.     

Gas-Wall Partitioning of Oxygenated Organic Compounds: Measurements,Structure–Activity Relationships,and Correlation with Gas Chromatographic Retention Factor

Gas-wall partitioning of 50 oxygenated organic compounds was investigated by using gas chromatography to monitor time-dependent gas-phase concentrations of authentic standards added to a large Teflon environmental chamber. Compounds included C₈–C₁₄ monofunctional ketones and alcohols, C₅–C₉ monoacids, and C₄–C₁₀ diols with linear and cyclic structures. Measured time constants for reaching gas-wall partitioning equilibrium ranged from ～10 to 100 min with an average value of ～30 min and exhibited no obvious trend with compound structure, whereas the extent of equilibrium partitioning to the walls ranged from ～0 to 100% and increased with increasing carbon number and with functional group composition in the order ketones < alcohols < monoacids < diols. When results were modeled using an approach analogous to one commonly used to describe absorptive gas-particle partitioning in terms of compound vapor pressure and aerosol mass loading it was determined that the absorptive properties of the Teflon film walls were equivalent to 2–36 mg m^?3 of liquid organic aerosol particles. These results, when combined with those obtained in previous studies, indicate that most multifunctional products formed from the oxidation of atmospherically important hydrocarbons including isoprene, monoterpenes, aromatics, and alkanes have the potential to undergo significant partitioning to the walls of Teflon chambers and thus be lost from further chemical reaction and secondary organic aerosol formation as well as from gas and particle analyses. Two approaches for estimating equilibrium gas-wall partitioning in such studies are presented: one is a structure–activity relationship based on the absorptive gas-wall partitioning model and the other involves the use of observed correlations between gas-wall partitioning and compound retention on a gas chromatographic column.

Copyright 2015 American Association for Aerosol Research     

Structure–Activity Relationship of Inhibition of Fish Feeding by Sponge-derived and Synthetic Pyrrole–Imidazole Alkaloids

We investigated the relationship between the structures of pyrrole-containing alkaloids from marine sponges of the genus Agelas and their capacity to deter feeding by the omnivorous Caribbean reef fish, Thalassoma bifasciatum. Seven natural products were assayed at volumetric concentrations of 1, 5, and 10 mg/ml: dispacamide A, keramadine, oroidin, midpacamide, 4,5-dibromopyrrole-2-carboxylic acid, 4,5-dibromopyrrole-2carboxamide, and racemic longamide A. We also assayed 14 structural analogs obtained mostly by chemical synthesis. Of the seven natural products, only rac-longamide A was not significantly deterrent at any of the assay concentrations. The pyrrole moiety was required for feeding inhibition activity, while the addition of the imidazole group enhanced this activity. Variously functionalized imidazoles lacking the pyrrole moiety were not deterrent. Combinations of the natural products appeared to have an additive effect on feeding inhibition; there was no evidence of synergy. Given their high concentrations in sponge tissue, dispacamide A and oroidin most probably serve as the primary chemical defenses of many Agelas sp., while minor compounds such as keramadine are not present in high enough concentrations to contribute much to chemical defense.     

Structure of NaF–TeO2 glasses and glass-ceramics

The structure of NaF–TeO₂ glasses and glass-ceramics has been studied by XRD, TEM, SEM, Raman and FTIR techniques. The results suggest that, for NaF ≤10 mol%, the entire NaF content enters the structure to convert TeO₄ units into TeO_3/2F and Na⁺[TeO₃₊₁]^– units. It has also been shown that NaF partially forms amorphous and/or crystalline phases for higher NaF content, where the relative concentration of each phase depends on the NaF content. SEM images show agglomerates of different sizes, which are discrete and spread within the structure. XRD revealed formation of crystalline Te₂O₃F₂ for NaF ≤50 mol%, and a dominant phase of crystalline NaF for NaF >50 mol%. Raman and FTIR spectra have been analyzed to calculate the concentrations of the various structural units in glasses and glass-ceramics.     

Raman Spectra and the Structure of Melts in the Na2O–P2O5–SiO2System

Raman spectra of melts in the Na₂O–P₂O₅–SiO₂system are measured at high temperatures. The differences between the Raman spectra of melts and glasses with identical compositions are considered. It is demonstrated that the structural inhomogeneity of the system slightly increases with a decrease in temperature and vitrification of the melt.     

Structure of the phase diagram of the 2-methyl-1,3-butadiene–2-methyl-2-butene–acetonitrile–water system

The structure of the liquid–liquid–vapor diagram of the industrially important four-component system 2-methyl-1,3-butadiene–2-methyl-2-butene–acetonitrile–water has been determined. A model of the phase equilibrium has been derived from experimental data. The evolution of the three-phase immiscibility region in the concentration simplex has been investigated.