6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17β-HSD10 and potential drugs for Alzheimer's disease treatment : design, synthesis and in vitro evaluation

Background : The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer’s disease (AD). ABAD/ 17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβ toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods : As ABAD’s enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/ 17β-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structure-activity relationship QSAR and pharmacophore studies have been performed. Results and Conclusions : Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40µM) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.PostprintPeer reviewe

The antibacterial effects of new N-alkylpyridinium salts on planktonic and biofilm bacteria

An increasing microbial resistance to known antibiotics raises a demand for new antimicrobials. In this study the antimicrobial properties of a series of new N-Alkylpyridinium quaternary ammonium compounds (QACs) with varying alkyl chain lengths were evaluated for several nosocomial pathogens. The chemical identities of the new QACs were determined by NMR, LC-MS, and HRMS. All the planktonic bacteria tested were susceptible to the new QACs as evaluated by MIC and MBC assays. The antimicrobial effect was most pronounced against Staphylococcus aureus clinical isolates. Live/dead staining CLSM was used to test the effectiveness of the QACs in biofilms. The effectiveness was up to 10-fold lower than in the plankton. When QACs were used as irrigants in Er:YAG – SSP photoacoustic steaming, their effectiveness significantly increased. The combined use of irrigants and photoacoustic streaming increased biofilm removal from the surface and increased the killing rate of the cells remaining on the surface. This may allow for a shorter chemical exposure time and lower dosage of QACs used in applications. The results demonstrate that the new QACs have potential to be applied as antibacterial compounds effective against planktonic and biofilm bacteria as well as irrigants in removal of difficult-to-reach biofilms

Synthesis and Decontamination Effect on Chemical and Biological Agents of Benzoxonium-Like Salts

Benzoxonium chloride belongs to the group of quaternary ammonium salts, which have been widely used for decades as disinfectants because of their high efficacy, low toxicity, and thermal stability. In this study, we have prepared the C10-C18 set of benzoxonium-like salts to evaluate the effect of their chemical and biological decontamination capabilities. In particular, biocidal activity against a panel of bacterial strains including Staphylococcus aureus in biofilm form was screened. In addition, the most promising compounds were successfully tested against Francisella tularensis as a representative of potential biological warfare agents. From a point of view of chemical warfare protection, the efficiency of BOC-like compounds to degrade the organophosphate simulant fenitrothion was examined. Notwithstanding that no single compound with universal effectiveness was identified, a mixture of only two compounds from this group would be able to satisfactorily cover the proposed decontamination spectrum. In addition, the compounds were evaluated for their cytotoxicity as a basic safety parameter for potential use in practice. In summary, the dual effect on chemical and biological agents of benzoxonium-like salts offer attractive potential as active components of decontamination mixtures in the case of a terrorist threat or chemical or biological accidents

Wide-antimicrobial spectrum of picolinium salts

Nosocomial infections, which greatly increase morbidity among hospitalized patients, together with growing antibiotic resistance still encourage many researchers to search for novel antimicrobial compounds. Picolinium salts with different lengths of alkyl chains (C$_{12}$, C$_{14}$, C$_{16}$) were prepared by Menshutkin-like reaction and evaluated with respect to their biological activity, i.e., lipophilicity and critical micellar concentration. Picolinium salts with C$_{14}$ and C$_{16}$ side chains achieved similar or even better results when in terms of antimicrobial efficacy than benzalkoniumsnotably, their fungicidal efficiency was substantially more potent. The position of the methyl substituent on the aromatic ring does not seem to affect antimicrobial activity, in contrast to the effect of length of the N-alkyl chain. Concurrently, picolinium salts exhibited satisfactory low cytotoxicity against mammalian cells, i.e., lower than that of benzalkonium compounds, which are considered as safe

Investigation of New Orexin 2 Receptor Modulators Using <i>In Silico</i> and In Vitro Methods

The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1&#8315;L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC50 of 2.2 &#181;M, offering some promise mainly for the treatment of insomnia

Report of the training workshop for trainers on results-based monitoring and evaluation (RBM&E), Adama, 2-5 July 2012

Alzheimer’s disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT₆ receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound <b>12</b> has displayed balanced activity as an antagonist of 5-HT₆ receptors (<i>K</i>_i = 18 nM) and noncompetitive inhibitor of cholinesterases (IC_{50<i>h</i>AChE} = 14 nM, IC_{50<i>eq</i>BuChE} = 22 nM). In further <i>in vitro</i> studies, compound <b>12</b> has shown amyloid β antiaggregation activity (IC₅₀ = 1.27 μM) and ability to permeate through the blood–brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy