Development of potent cholinesterase inhibitors based on a marine pharmacophore.

The management of neurological disorders such as dementia associated with Alzheimer's or Parkinson's disease includes the use of cholinesterase inhibitors. These compounds can slow down the progression of these diseases and can also be used in the treatment of glaucoma and myasthenia gravis. The majority of the cholinesterase inhibitors used in the clinic are derived from natural products and our current paper describes the use of a small marine pharmacophore to develop potent and selective cholinesterase inhibitors. Fourteen small inhibitors were designed based on recent discoveries about the inhibitory potential of a range of related marine secondary metabolites. The compounds were evaluated, in kinetic enzymatic assays, for their ability to inhibit three different cholinesterase enzymes and it was shown that compounds with a high inhibitory activity towards electric eel and human recombinant acetylcholinesterase (IC50 between 20-70 µM) could be prepared. It was also shown that this compound class was particularly active against horse serum butyrylcholinesterase, with IC50 values between 0.8-16 µM, which is an order of magnitude more potent than the clinically used positive control neostigmine. The compounds were further tested for off-target toxicity against both human umbilical vein endothelial cells and bovine and human erythrocytes and were shown to display a low mammalian cellular toxicity. Overall, the study illustrates how the brominated dipeptide marine pharmacophore can be used as a versatile natural scaffold for the design of potent, and selective cholinesterase inhibitors.

Synthesis of aromatic lactone analogues of Lipoxin A4.

OBJECTIVE: Synthesis of novel aromatic Lipoxin A4 lactone analogues. RESULTS: Novel para-substituted aromatic lactone analogues of Lipoxin A4 have been synthesized in a convergent manner with six steps in the longest linear sequence in 12-13% yields, employing 2-deoxy-D-ribose as a chiral pool starting material and the classical E-selective Wittig olefination.

Structure-Activity Relationship Probing of the Natural Marine Antifoulant Barettin.

The sponge derived 2,5-diketopiperazine metabolite barettin is a potent antifouling compound effective against the settlement and metamorphosis of barnacles. Simplified derivatives of barettin have previously been shown to display similar inhibitory properties. The synthetic derivative benzo[g]dipodazine has been reported to display significantly improved antifouling properties in comparison with the native barettin with inhibitory activities as low a 0.034 µM reported against barnacle cyprid settlement. In the current study we report the antifouling activity of 29 synthetic analogs designed and inspired by the potent antifouling effect seen for benzo[g]dipodazine. The library contains mainly not only dipodazine derivatives but also disubstituted diketopiperazines and compounds incorporating alternative heterocyclic cores such as hydantoin, creatinine, and rhodanine. Several of the prepared compounds inhibit the settlement of Amphibalanus improvisus cyprids at low micromolar concentrations, in parity with the natural barettin. While several highly active compounds were prepared by incorporating the benzo[g]indole as hydrophobic substituent, the remarkable antifouling effect reported for benzo[g]dipodazine was not observed when evaluated in our study.

Synthesis of 5,7-diarylindoles via Suzuki-Miyaura coupling in water.

The synthesis of novel 5,7-diaryl and diheteroaryl indoles has been explored via efficient double Suzuki-Miyaura coupling. The method notably employs a low catalyst loading of Pd(PPh3)4 (1.5 mol%/coupling) and water as the reaction solvent to obtain 5,7-diarylated indoles without using N-protecting groups in up to 91% yield. The approach is also suitable for N-protected and 3-substituted indoles and constitutes an important green and convenient arylation strategy for the benzenoid ring of indoles. The synthesized diarylindoles are fluorescent.

Halogen Bonding: An Odd Chemistry?

Halogen bonding is a flourishing field of research, but has for long been little recognized. The same goes for its scientific hero, Odd Hassel, who laid the foundations for all current developments. The crystallographic observation of halogen-oxygen interatomic distances shorter than the sum of the van der Waals radii of the involved atoms, and the interpretation of this phenomenon as a charge-transfer interaction, have been ground-breaking. Today, charge-transfer to a polarized halogen is not any longer seen as "odd", but is commonly referred to as halogen bonding, and is widely exploited in chemistry. Despite the recognition of Hassel's work with a Nobel prize in 1969, surprisingly little appreciation is given to date to the devoted scientist, who established a world-leading laboratory during one of the darkest eras of history. Herein, we wish to revive the legacy and highlight the impact of Odd Hassel's ground-breaking discoveries.

Phidianidine A and Synthetic Analogues as Naturally Inspired Marine Antifoulants.

Stationary and slow-moving marine organisms regularly employ a natural product chemical defense to prevent being colonized by marine micro- and macroorganisms. While these natural antifoulants can be structurally diverse, they often display highly conserved chemistries and physicochemical properties, suggesting a natural marine antifouling pharmacophore. In our current report, we investigate the marine natural product phidianidine A, which displays several chemical properties found in highly potent marine antifoulants. Phidianidine A and synthetic analogues were screened against the settlement and metamorphosis of Amphibalanus improvisus cyprids, and several of the compounds displayed inhibitory activities at low micromolar concentrations with IC50 values down to 0.7 µg/mL observed. The settlement study highlights that phidianidine A is a potent natural antifoulant and that the scaffold can be tuned to generate simpler and improved synthetic analogues. The bioactivity is closely linked to the size of the compound and to its basicity. The study also illustrates that active analogues can be prepared in the absence of the natural constrained 1,2,4-oxadiazole ring. A synthetic lead analogue of phidianidine A was incorporated in a coating and included in antifouling field trials, where it was shown that the coating induced potent inhibition of marine bacteria and microalgae settlement.

Discovery of a Lead Brain-Penetrating Gonadotropin-Releasing Hormone Receptor Antagonist with Saturable Binding in Brain.

We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin-releasing hormone receptor (GnRH-R) antagonists with nanomolar binding affinity. A small library of GnRH-R antagonists was synthesised in 20-67 % overall yield with the aim of identifying a high-affinity antagonist capable of crossing the blood-brain barrier. Binding affinity to rat GnRH-R was determined by autoradiography in competitive-binding studies against [125 I]buserelin, and inhibition constants were calculated by using the Cheng-Prusoff equation. The radioligands were obtained in 46-79 % radiochemical yield and >95 % purity and with a molar activity of 19-38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor-saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain.

A scalable and green one-minute synthesis of substituted phenols.

A mild, green and highly efficient protocol was developed for the synthesis of substituted phenols via ipso-hydroxylation of arylboronic acids in ethanol. The method utilizes the combination of aqueous hydrogen peroxide as the oxidant and H2O2/HBr as the reagent under unprecedentedly simple and convenient conditions. A wide range of arylboronic acids were smoothly transformed into substituted phenols in very good to excellent yields without chromatographic purification. The reaction is scalable up to at least 5 grams at room temperature with one-minute reaction time and can be combined in a one-pot sequence with bromination and Pd-catalyzed cross-coupling to generate more diverse, highly substituted phenols.

Evaluation by metabolic profiling and in vitro autoradiography of two promising GnRH-receptor ligands for brain SPECT imaging.

The increased expression of gonadotropin releasing hormone receptor (GnRH-R) in brain has been strongly linked to Alzheimer disease. Therefore, the development of radiolabeled imaging agents for GnRH-R is relevant for early diagnosis of Alzheimer disease. We have recently disclosed the discovery of two promising compounds displaying nanomolar-range affinity for the GnRH-R. In the present study, a preclinical evaluation of the compound properties was performed to evaluate their potential as single photon emission computed tomography (SPECT) radiotracers for imaging the GnRH-receptor. The compounds were assessed in vitro by performing serum stability analysis by human and rat serum, metabolic profiling by human liver microsomes, and exploratory rat brain autoradiography. The investigated compounds displayed satisfactory stability against human, rat serum, and liver microsomal metabolism, which favors their potential as SPECT-imaging agents. Additionally, we identified and quantified the formation rate of the metabolites by fragmentation of up to five mass spectrometric stages. The GnRH-R rat brain specificity of these compounds was tested in competition with a known ligand for the receptor and the in vitro autoradiography confirmed that compounds 3 and 4 binds to rat GnRH-R in different rat brain regions.

Temporal dynamics of intra-and extra-cellular microcystins concentrations in Koka reservoir (Ethiopia): Implications for public health risk.

This study was carried out with a view of understanding the temporal dynamics of microcystin concentrations in both algal seston and water samples and the associated public health risk. All the major MC variants, namely MC-LR, MC-YR, and MC-RR, were detected in both the algal seston and water samples. In the majority of the samples, the most potent variant, MC-LR, constituted the greatest proportion of the total MC concentration suggesting extremely high potential public health risk. The exceptionally high concentrations (µg L-1) of all the variants, MC-LR (815), MC-YR (466.6) and MC-RR (265.68), were observed in May. Although the extracellular MCs were relatively less concentrated and less frequently detected, concentrations (µg L-1) of up to 20 of MC-LR, 6.13 of MC-YR, and 1.27 MC-RR were encountered. The strong and significant association between Microcystis abundance and concentration of nitrate (Spearman Rank Order Correlation r = 0.793, p < 0.001) may suggest that nitrate is the key dictating factor in the dynamics of Microcystis, and may have consequently influenced the MC levels in the reservoir.

Heterocyclic cellular lipid peroxidation inhibitors inspired by the marine antioxidant barettin.

The marine environment remains a rich source for the discovery and development of novel bioactive compounds. The present paper describes the design, synthesis and biological evaluation of a library of small molecule heterocyclic mimetics of the marine 2,5-diketopiperazine barettin which is a powerful natural antioxidant. By mainly focusing on the influence from the brominated indole and heterocyclic core of barettin, a library of 19 compounds was prepared. The compounds comprised a heterocyclic core, either a 2,5 diketopiperazine, an imidazolidinedione or a thioxothiazolidinone, which were mainly monosubstituted with ranging bulky substituents. The prepared compounds were screened for activity in a cellular lipid peroxidation assay using HepG2 cells. Several of the synthetic compounds showed antioxidant properties superior to the positive control barettin. Two of the prepared compounds displayed inhibitory activity similar to commercial antioxidants with significant inhibition at low µg/mL concentrations. The toxicity of the compounds was also investigated against MRC-5 lung fibroblasts and none of the included compounds displayed any toxicity at 50 µg/mL.

First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor.

OBJECTIVES: In vivo evaluations of a gonadotropin releasing hormone-receptor single photon emission computed tomography radiotracer for non-invasive detection of gonadotropin releasing homone-receptors in brain. RESULTS: We have used a simple, robust and high-yielding procedure to radiolabel an alpha-halogenated bioactive compound with high radiochemical yield. Literature findings showed similar alpha-halogenated compounds suitable for in vivo evaluations. The compound was found to possess nano molar affinity for the gonadotropin releasing hormone-receptor in a competition dependent inhibition study. Furthermore, liquid chromatography-mass spectrometry analysis in saline, human and rat serum resulted in 46%, 52% and 44% stability after incubation for 1 h respectively. In addition, rat brain single photon emission computed tomography and biodistribution studies gave further insight into the nature of the compound as a radiotracer.

Concentrations of microcystins in the muscle and liver tissues of fish species from Koka reservoir, Ethiopia: A potential threat to public health.

Herein, we report the presence and concentrations of three most common variants of microcystin (MC-LR, -RR and -YR) in the liver and muscle tissues of wild Nile Tilapia (Oreochromis niloticus), Common Carp (Cyprinus carpio) and African Sharp Tooth Catfish (Clarias gariepinus), which were collected from two study sites of the present study on Koka reservoir, Ethiopia. A total of 36 fish liver and 36 fish muscle samples were collected for six months. Microcystins (MCs) were quantified using LC-ESI-HRMS. The results show that MCs were found in most of the fish liver samples, while they were below the detection limit of the method of analysis used in the muscle samples. In addition to the three most common congeners of MCs, eight other microcystin variants and cylindrospermopsin were detected in the fish liver samples although further detailed study is needed. Among the three most common MC congeners, MC-LR was more prevalent than MC-RR and MC-YR in the liver samples of the three fish species. The highest MC concentration was found in Nile Tilapia collected in April (591.60 µg/g DW of MC-LR), whereas the lowest detected concentration was in Catfish collected in March (2.23 µg/g DW of MC-RR). The results of this study suggest that further intensive assessment and monitoring of the reservoir from different perspectives should be conducted in order to reduce the concentrations of the MCs and seek solutions to the potential public health risk. Moreover, this is the first study ever to report detailed quantification of MCs in fish liver and muscle samples collected from Ethiopia.

Cryptophanes for Methane and Xenon Encapsulation: A Comparative Density Functional Theory Study of Binding Properties and NMR Chemical Shifts.

The host-guest chemistry of cryptophanes is an active research area because of its applications in sensor design, targeting small molecules and atoms in environmental and medical sciences. As such, the computational prediction of binding energies and nuclear magnetic resonance (NMR) properties of different cryptophane complexes are of interest to both theoreticians and experimentalists working in host-guest based sensor development. Herein we present a study of 10 known and some newly proposed cryptophanes using density functional theory (DFT) calculations. We benchmark the description of nonbonding interactions by different DFT functionals against spin-component-scaled, second-order Møller-Plesset theory (SCS-MP2) and predict novel host molecules with enhanced affinity toward methane and Xenon, two representative systems of high interest. We demonstrate the power and limitations of the different computational methods in describing the binding and NMR properties of these established and novel host systems. The results show the importance of including dispersion corrections in the DFT functionals. The overall analysis of the dispersion corrections indicated that results obtained from pure DFT functionals should be used cautiously when conclusions are drawn for molecular systems with considerable weak interactions. Proposed analogues of cryptophane-A, where the alkoxy bridges are replaced by alkyl chains, are predicted to display enhanced affinity toward both methane and Xenon.

Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor.

In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition. Our main purpose was to find a more soluble compound based on the WAY207024 lead with nanomolar potency to inhibit the GnRH receptor. A late stage diversification by the use of click chemistry was, furthermore developed to allow for expansion of the library in future optimisations. All compounds were tested in a functional assay to determine the individual potency of inhibiting stimulation of the receptor by the endogenous agonist GnRH. In conclusion, we found that compound 8a showed improved solubility compared to WAY207024 and nanomolar affinity to GnRH receptor.

Synergy between experimental and computational approaches to homogeneous photoredox catalysis.

In this Frontiers article, we highlight how state-of-the-art density functional theory calculations can contribute to the field of homogeneous photoredox catalysis. We discuss challenges in the fields and potential solutions to be found at the interface between theory and experiment. The exciting opportunities and insights that can arise through such an interdisciplinary approach are highlighted.

Mechanism and Site Selectivity in Visible-Light Photocatalyzed C-H Functionalization: Insights from DFT Calculations.

Visible-light photocatalyzed (VLPC) late-stage C-H functionalization is a powerful addition to the chemical synthesis toolkit. VLPC has a demonstrated potential for discovery of elusive and valuable transformations, particularly in functionalization of bioactive heterocycles. In order to fully harvest the potential of VLPC in the context of complex molecule synthesis, a thorough understanding of the elementary processes involved is crucial. This would enable more rational design of suitable reagents and catalysts, as well as prediction of activated C-H sites for functionalization. Such knowledge is essential when VLPC is to be employed in retrosynthetic analysis of complex molecules. Herein, we present a density functional theory (DFT) study of mechanistic details in the C-H functionalization of bioactive heterocycles exemplified by the methylation of the antifungal agent voriconazole. Moreover, we show that readily computed atomic charges can predict major site-selectivity in good agreement with experimental studies and thus be informative tools for the identification of active C-H functionalization sites in synthetic planning.

Sensitive on-chip methane detection with a cryptophane-A cladded Mach-Zehnder interferometer.

We report a methane sensor based on an integrated Mach-Zehnder interferometer, which is cladded by a styrene-acrylonitrile film incorporating cryptophane-A. Cryptophane-A is a supramolecular compound able to selectively trap methane, and its presence in the cladding leads to a 17-fold sensitivity enhancement. Our approach, based on 3 cm-long low-loss Si3N4 rib waveguides, results in a detection limit as low as 17 ppm. This is 1-2 orders of magnitude lower than typically achieved with chip-scale low-cost sensors.