Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes-6

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...]

Functional Porous Carbon Nanospheres from Sustainable Precursors for High Performance Supercapacitors

Functional porous carbon nanospheres with tunable textural properties and nitrogen functionalities were synthesized from cheap and sustainable phenolic carbon precursor (tannic acid) and nitrogen precursor (urea) using a facile one-step salt-templating method. The diverse functional carbons were obtained by calcination of mixtures of different molar ratios of urea to tannic acid (0:1, 5:1, 9:1, 13:1 and 17:1) with a eutectic salt (NaCl/ZnCl2) that was used as porogen. Physico-chemical characterization of obtained microporous carbons demonstrated that textural properties, morphology, surface functionalities, and conductivity were strongly influenced by molar ratio of urea to tannic acid. The nitrogen content in the carbons increased with the molar ratio of urea, reaching a maximum of 8.83 % N at the highest molar ratio while the specific surface area (SBET) of microporous carbons varied from 890 m2g-1 to 1570 m2g-1 depending on the synthesis conditions. Electrochemical performance of carbon nanospheres in the ionic liquid 1-butyl-1-methylpyrrolidinium bis(fluorosulfonyl)imide (PYR14FSI) was also significantly influenced by the synthesis conditions due to combined effect of textural properties, morphology, nitrogen functionalities and electrical conductivity. Supercapacitors based on functional porous carbon synthesized with a molar ratio of urea to tannic acid of 9:1 exhibited the best performance, with specific capacitance as high as 110 Fg-1 and real energy density of 33 Whkg-1, when charged-discharged at 3.5V in PYR14FSI

Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases

A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (Abeta) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Abeta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases

Novel Donepezil-Based Inhibitors of Acetyl- and Butyrylcholinesterase and Acetylcholinesterase-Induced Beta-Amyloid Aggregation

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A antiaggregating activity, which makes them promising anti-Alzheimer drug candidates

Recurrence of venous thromboembolism in patients with recent gestational deep vein thrombosis or pulmonary embolism: Findings from the RIETE Registry

Introduction The aim of this study was to investigate the recurrence rate of venous thromboembolism (VTE) and the prevalence of major bleeding or death in patients with previous VTE in pregnancy and puerperium. Risk factors for VTE recurrence were also assessed. Materials and methods We evaluated a cohort of patients enrolled in the international, multicenter, prospective Registro Informatizado de la Enfermedad Trombo-Embólica (RIETE) registry with objectively confirmed VTE. Results In the registry, 607 women were presenting with VTE that occurred during pregnancy or puerperium. The 2-year VTE recurrence rate was 3.3% (CI: 95 1.5-5.0%) and the recurrent VTE incidence rate was 2.28 events/100 patients-year. Among the 16 cases of VTE recurrence 11 cases appeared during drug treatment while only five cases were diagnosed after therapy discontinuation. No significant difference was found in treatment duration among these two subgroups of VTE recurrence cases and women without recurrence. Furthermore, the use of thrombolytics and inferior vena cava filter in initial treatment was associated to an increased risk of VTE recurrence. Conclusions The current study provides new insights on VTE recurrence rate in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) that occurred in pregnancy or postpartum period. These findings can contribute to risk assessment of thrombotic burden, thereby allowing for better decision making regarding antithrombotic management in this clinical setting

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead