Being the most common form of dementia, Alzheimer’s disease (AD) currently affects over 46 million people worldwide.¹ However, currently prescribed drugs for the management of AD mostly consist of acetylcholinesterase (AChE) or both AChE and butyrylcholinesterase (BChE) inhibitors that cause an increase in acetylcholine brain levels, but allow only temporary symptomatic relief. Despite continuous efforts over the past 30 years, no cure is possible with the drugs delivered to the market so far.

Widely reported for their neuroprotective effects, natural flavonoids such as quercetin, apigenin and chrysin have the ability to decrease amyloid-β (Aβ)-induced neurotoxicity while reducing β-secretase-mediated amyloid precursor protein (APP) processing, improving cognitive function and memory retention in rodents.^2-4 Due to the rather complex and multifactorial nature of AD, we envisage that the broad activity of flavonoids comes across as a desirable feature of new multitarget drug leads able to interfere with several pathological features at once, thus maximizing the chances of blocking neurodegenerative progression in an effective way.

Preliminary assays conducted by our group have shown that flavones tend to be more effective in inhibiting the formation of Aβ_1-42 amyloid fibrils than analogue flavanones or isoflavones. In particular, 3-hydroxyflavone quercetin displayed a remarkable anti-amyloidogenic effect, which encouraged us to synthesize flavone analogues with drug-like properties and to investigate the role of C-C linked glucose units, that stabilize amyloid polypeptides in their disaggregated state.⁵ Ultimately, it is our goal to disclose structural requirements for the anti-amyloidogenic and neuroprotective effects, and to find new blood brain barrier (BBB)-permeable molecules that combine key features of the flavone scaffold with the potential benefits of the sugar moiety.

In this communication, we will present the synthesis of C-glycosylated and non-glycosylated flavone analogues with potential neuroprotective effects. Furthermore, given the known relationship between type 2 diabetes and AD, the utility of this type of compounds in type 2 diabetic patients with cognitive impairment will also be discussed.

References:

[1] Prince M., Wimo A., Guerchet M., Ali G.C., Wu Y.T., Prina M. World Alzheimer’s Report 2015.

[2] Sabogal-Guáqueta A.M., Muñoz-Manco J.I., Ramírez-Pineda J.R., Lamprea-Rodeiguez M., Osorio E., Cardona-Gómez G.P. Neuropharmacology, 2015, 93, 134.

[3] Zhao L. Wang J.L. Liu R., Li X.X., Li J.F., Zhang L. Molecules, 2013, 18(8), 9949.

[4] Li. R. Zang A., Zhang L., Zhang H., Zhao L., Qi Z. Wang H. Neurol Sci, 2014, 35, 1527.

[5] Ladiwala A.R.A, Mora-Pale, Lin C., Bale S.S., Fishman Z.S., Dordick J.S., Tessier P.M. ChemBioChem, 2011, 12(11), 1749.

Acknowledgements: The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 612347. The authors also acknowledge “PERsonalised ICT supported Service for Independent Living and Active Ageing” (PERSSILAA), FP7-ICT-2013-10, GA. 610359 and Fundação para a Ciência e a Tecnologia for the support of the project MULTI/UID 0612/2013 and for the Ph.D. grant awarded to Ana M. Matos (SFRH/BD/93170/2013).

Supercritical fluid technique (SCF), in this case using supercritical CO₂ as a medium, offers promising approach of morphology changes of materials  and moreover reduction of particle size at moderate operating conditions. Thus SCF could be suitable for treatment of many thermally unstable compounds, for example the pharmaceuticals [1]. In this study a commercially supplied device Spe-ed SFE-4 (Applied Separations, USA) has been used for size reduction of selected biologically active substances cimetidine and caffeine. Procedures were carried out by techniques of rapid expansion of supercritical mixtures (RESS) or using supercritical CO₂ as an anti-solvent (GAS).

Submicron particles and nanoparticles of caffeine were prepared using RESS procedure; moreover the increasing of temperature caused the reduction of caffeine nanoparticles size and had an impact on the shape of the resulting particles. Cimetidine submicron particles were obtained using GAS method. In this case higher pressure leads to the smaller particles which have enormous tendency to agglomerate; the influence of higher temperature could be summarized as positive.

It is evident that the use of supercritical CO₂ could lead to interesting morphology modification, as well as to reduction of the particles size. This has a positive impact on improvements in the terms of bioavailability of drugs.

This work was supported by MSMT projects LO1203, LO1404 and SP2016/65.

References:

¹ Michael Turk, Particle formation with supercritical fluids, Supercritical Fluid Science and Technology, Vol. 6, Editor: Erdogan Kiran, Elsevier 2014

 Microwave induced synthesis has various advantages over conventional synthesis, such as highly accelerated reaction rate , reasonable better yields, simple open systems, no solvent or very less amount of solvents required, eco friendly method, clean heating system and control on reaction parameters .In the present work novel Schiff’s bases containing thiadiazole scaffold and benzamide group, through appropriate pharmacophore were designed and synthesized , because of the important biological properties associated with these three moieties/groups. The coupling of these important moieties was achieved under microwave irradiation. A facile, solvent-free synthesis of a series of N-((5-(substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl)benzamide was carried out under microwave-irradiation. Solvent free synthesis of novel Schiff bases was achieved by cyclo-addition of various aromatic aldehydes (0.01 mol) and N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)benzamide(0.01 mol)in presence of catalytic amount of glacial acetic acid under microwave irradiation. The same compounds were also synthesized using conventional approach. The conventional method required 15-18 hrs, while microwave irradiation method required only 15-20 minutes and gave better yields. Total 12 final compounds were synthesized as per the scheme reported. Structures of synthesized compounds were confirmed by IR, NMR, and Mass spectral study. All the designed hybrids were evaluated for their in vitro anticancer activity against a panel of three human cancer cell lines viz SK-MEL-2(melanoma), HL-60 (leukemia) and MCF-7 using MTT assays method. Most of the synthesized compounds exhibited promising anticancer activity with the some compounds having GI₅₀ values similar to that of the Adriamycin. The compounds 7k, 7l, 7b, and 7a were found to be the most promising in this study. A computational study of synthesized compounds 7(a–l) was performed for prediction of ADMET. The absorption, distribution, metabolism, excretion and Toxicity (ADMET) properties of all compounds were predicted using Qikprop v3.5 (Schrödinger LLC).

Adenoviruses (Ads) are common pathogens in patients with compromised immunity being a potentially life-threatening disease. Human Ads are usually associated with respiratory infections, gastroenteritis or viral conjunctivitis among others pathologies with significant clinical impact.

Pharmacological approach for the treatment of these Ads involves several targets such as DNA polymerase, coxsackievirus and adenovirus receptor or human adenovirus proteinase (AVP). Recently, privileged structures based on piperazin-2-one have been used as effective molecules for Ad DNA replication through unknown mechanism so far.

Herein, we report an easy synthesis of both mono and disaccharides ureidyl-glucosamine derivatives in good yields, that mimic a feasible interaction with active sites of Ad proteinase. All new compounds were characterised by means of ¹H, ¹³C NMR as well as mass spectrometry. Finally, a biological screening for synthesized compounds on human epithelial cell was carried out. 

Increase the performance of functional molecules is an important challenge in biotechnology, if leads to greater using of them in pharmaceutical applications. Metal-organic frameworks (MOFs) are a class of porous materials which due to their special properties including high surface area, regular porosity and available pores are extremely significant to use in catalytic, sensing, separation, gas adsorption and more recently in drug delivery.
Herein we used MOFs as a platform for controlled drug release and reported a technique, which pharmaceutical agents are encapsulated in a zinc zeolitic imidazolate framework (ZIF-8). In this work, metformin, an oral antihyperglycemic agent for the treatment of type II diabetes trapped inside the ZIF-8 pores through a mechanochemical ball-milling technique. Due to having regular porosity and zinc ions, ZIF-8 could help to better absorption of metforminin. The synthesis of the MOF and the encapsulating process of the drug were performed by using a convenient solvent-free one pot technique. It was shown that with this approach, metformin is released in the stomach via a controlled manner over a longer time that leads to increases of metformin bioavailability.

The ionic liquids (ILs) are often denominated as “green fluids”, because they are considered as innocuous due to their negligible volatility. Due to this apparent innocuousness, the ILs are attracted a great attention as an alternative to traditional organic solvents, highly contaminant. However, the problem of contamination is not limited to the atmosphere, since also aquatic and terrestrial environments can be affected. Therefore, and because the toxic effects of ILs on the environment are largely unknown, research studies are needed to deepen this aspect before to assign them the appellation of “green fluids”. Nevertheless, and despite the increased number in the last few years of studies on different aspects of ILs, the toxicity of these compounds to the environment in general, and to the soils in particular, only rarely is investigated. One of the most used ILs in different applications is 1-butyl-3-methylimidazolium tetrafluoroborate (BMIMBF4). Among all the soil properties, those determining the edaphic metabolism, and especially the enzymatic activities, are highly sensitive to ascertain the disturbance caused by any external agent. Given the lack of studies investigating the effect of ILs on the edaphic environment, before the use of enzymatic activities as indicators of the toxicity for soils of any given IL, it is necessary to test if classical methods to determine the soil enzymatic activities are adequate for their use in soils spiked with that given IL.

In this study we investigated the suitability of dehydrogenase method to determine the activity of this enzyme in soils with spiked BMIMBF4, modifying the method according to the problems identified.

Acknowledgments. This research was financed by the Spanish Ministerio de Economía y Competitividad (Project No. CGL2015-66857-C2-1-R). The authors thank Ana I. Iglesias-Tojo for assistance in carrying out the analyses.

Although the ionic liquids (ILs) are considered as green solvents, mainly due to their negligible vapor pressure, the effects on the environment are scarcely studied.

In this work, effects of the IL 1-butyl-3-methylimidazolium triflate, [BMIN] [OTf], on germination and on growth during the seedling stage of two herbaceous forest species with wide geographical distribution: Daucus carota L. and Avena sulcata (Gay ex Boiss.) was determined. Changes on soil microbial activity of Quercus robur L. oakland as consequence of the addition of different concentrations of this IL were also studied.

Different effects of this IL on plants and soil have been found. Thus, in terms of germination, the dose of 10% (of IL in distillated water) presented total inhibition in the germination of both species; whereas this dose presented a stimulant effect on soil microbial activity. The effect of IL on plant growth is similar to that obtained in the germination test. Concentration of 50% of IL provoked the total inhibition of the soil microbial activity.

Beyond their traditional usage in fuel cell applications, the category of protic ionic liquids (PILs) has been recently signalled as a potential candidate for battery applications [1]. Despite being the oldest known IL [2], and of having been extensively characterized in most of its properties [3], a full thermal and stability analysis of ethylammonium nitrate (EAN) both in its solid and liquid phases is still lacking. In the present work thermal analysis techniques were used to characterize its thermal transitions and thermal stability.

A differential scanning calorimeter DSC Q100 TA-Instruments with aluminium pans hermetically sealed was used to determine the different state transitions experienced by the IL during heating and cooling cycles [4]. Results showed that this IL is a very good crystal-former with melting and freezing peaks at 17ºC and -28ºC respectively. Moreover, stability analysis has been performed by means of a thermogravimetric analyser (TGA 7-Perkin Elmer) operating in dynamic and isothermal modes, under nitrogen and dry air atmospheres was used to perform thermal stability analysis [5]. Similar onset temperatures in air and nitrogen of 248±4ºC were obtained. Additionally, activation energy of the degradation process of this IL has been determined using the Arrhenius equation.

 Acknowledgments

This work was funded by the Xunta de Galicia (Spain) through grants EM2013/031 and AGRUP2015/11 and by the network REGALIS R2014/015. The financial support of the Spanish Ministry of Economy and Competitiveness through grants MAT2014-57943-C3-1-P, MAT2014-57943-C3-2-P and MAT2014- 57943-C3-3-P is also gratefully acknowledged. Funding from the European Union (COST Action CM 1206) is also acknowledged.

References

[1] S. Menne, J. Pires, M. Anouti, A. Balducci, Electrochem. Commun. 31, 39 (2013).

[2] P. Walden, Chem. Zentralbl. 85: 1800 (1914).

[3] S. Bouzón Capelo, T. Méndez-Morales, J. Carrete, E. López Lago, J. Vila, O. Cabeza, J. R. Rodríguez, M. Turmine, and L. M. Varela, J. Phys. Chem. B, 116 ,11302 (2016).

[4] M. Villanueva, J. J. Parajó, P.B. Sánchez, J. García, J. Salgado, J. Chem. Thermodyn. 91, 127 (2015).

[5] J. Salgado, J. J. Parajó, J. Fernández, M. Villanueva, J. Chem. Thermodyn. 74, 51(2014).

Hybrid mesoporous organosilica was first introduced in 1999, built from bridged organosilane precursors ((ŔO)₃Si–R–Si(OŔ)₃; R: organic bridging group, Ŕ: methyl or ethyl). Such mesoporous hybrids have been classified as periodic mesoporous organosilicas (PMOs). In these materials, the bridging organic moieties which are well distributed inside the inorganic pore wall not only increase mechanical and hydrothermal stabilities, but also higher organic loading and greater avoidance of channel blockage can be achieved in comparison with mesoporous silicas functionalized with terminal organic groups.

Polyhydroquinolines, as a family of 1,4-dihydropyridine derivatives, are one of the most important groups of nitrogen heterocycles that have attracted extensive interest because of their promising pharmacological and therapeutic activities such as calcium channel blockers, bronchodilating, antiatherosclerotic, antitumor, vasodilating, geroprotective, hepatoprotective, and antidiabetic.

The nanocatalyst were characterized by X-ray diffraction, scanning electron microscopy and thermogravimetric analysis.

Bisphosphonic acids are beneficial antihypercalcemic medicines and could be utilized as remedial factors for the therapy of illnesses which are specified by unusual calcium metabolism.^[1] They have showed efficiency in detention bone decline and restituing normocalcemia in patients with metastatic bone disease, hypercalcemia of malignancy, osteoporosis and Paget’s disease and they have the potential for other medical usages as well. In this paper a convenient synthesis of imidazol-1-yl-acetic acid is described. Condensation reaction of a benzyl alcohol and a chloroacetyl chloride in the presence of N,N-diisopropylethylamine gave a benzyl 2-chloroacetate, which on treatment with an imidazole and then a hydrochloric acid afforded the imidazol-1-yl-acetic acid in good yield.