Jan Honegr

Current Approaches Against Alzheimer's Disease in Clinical Trials

Alzheimers disease (AD) is a progressive degenerative brain disease which causes mental and physical decline, gradually resulting in death. Currently, this disease represents one of the uppermost human issues, both from the medical and economic point of view. Interest in the discovery of a drug for AD is enormous. However, despite the long-term and worldwide effort for a more effective therapy, the only available treatment is a symptomatic use of acetylcholinesterase inhibitors (AChEIs) and memantine. New therapeutic approaches as well as those based on cholinergic or amyloid theory have not brought the desired benefits yet. Thus, the question is whether an effective drug for this progressive disease will ever be developed or whether people will have to rely only on prevention and minimize risk factors of AD.

Ligand-based 3D QSAR analysis of reactivation potency of mono- and bis-pyridinium aldoximes toward VX-inhibited rat acetylcholinesterase

To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure-activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R(2)=0.9989, Q(LOO)(2)=0.9090, Q(LTO)(2)=0.8921, Q(LMO(20%))(2)=0.8853, R(ext)(2)=0.9259, SDEP(ext)=6.8938; 2. R(2)=0.9962, Q(LOO)(2)=0.9368, Q(LTO)(2)=0.9298, Q(LMO(20%))(2)=0.9248, R(ext)(2)=0.8905, SDEP(ext)=6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds.

6-Hydroxyquinolinium salts differing in the length of alkyl side-chain: Synthesis and antimicrobial activity

Quaternary ammonium salts substituted with a long alkyl chain exemplify a trustworthy group of medicinal compounds frequently employed as antifungal and antibacterial agents. A great asset of these surfactants underlying their widespread use is low local and system toxicity in humans. In this Letter, a series of novel quaternary 6-hydroxyquinolinium salts with varying length of N-alkyl chain (from C10 to C18) was synthesized and tested for in vitro activity against pathogenic bacterial and fungal strains. 6-Hydroxyquinolinium salt with C12 alkyl chain seems to be very interesting candidate due to a high antimicrobial efficacy and cytotoxic safety.

Structural Properties of Potential Synthetic Vaccine Adjuvants - TLR Agonists.

Toll like receptors (TLRs) are a family of transmembrane proteins which play a key role in innate immunity. When TLRs come into contact with a potential threat, they initiate a signaling cascade leading to release of cytokines and chemokines, maturation of antigen presenting cells and immune activation. Molecules which can activate TLRs may be utilized for vaccine development and act as vaccine adjuvants. Adjuvants can facilitate production of more effective vaccines based on antigens produced by recombinant techniques or by DNA vaccines, which are often poorly immunogenic since they lack the endogenous innate immunostimulatory components of the pathogen. In this paper the structural properties of such prospective compounds are thoroughly discussed.

Synthesis, antimicrobial evaluation and molecular modeling of 5-hydroxyisoquinolinium salt series; the effect of the hydroxyl moiety.

In the present paper, we describe the synthesis of a new group of 5-hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C10-C18), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non-hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C18) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C14, C16) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G- bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C14) against G+ strains and 15 (C16) against fungi. The electronic properties and desolvation energies of 5-hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy.

Gulf war syndrome – a syndrome or not?

Abstract After the Gulf war, new diagnostic entity was claimed: the Gulf War Syndrome (GWS). A wide spectrum of exposures is widely discussed in order to explain the reported symptoms. Investigating tentative culprits we did not find clearly conclusive data about the existence of the GWS. The origin of described symptoms can be associated to the use of pesticides and the PB pill. However, the data about the use of both are influenced by a lack of precise records. Although other agents such as nerve agent exposure could not be definitively ruled out, its link to symptoms seems to be improbable.

Rational Design of a New Class of Toll-Like Receptor 4 (TLR4) Tryptamine Related Agonists by Means of the Structure- and Ligand-Based Virtual Screening for Vaccine Adjuvant Discovery

In order to identify novel lead structures for human toll-like receptor 4 (hTLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the hTLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate hTLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6.

Dynamic Modeling of the Czech Republic Population with a Focus on Alzheimer’s Disease Patients

This article focuses on the Czech population modeling with the main aim to predict the Alzheimer’s disease patients numbers. We choose a system dynamics as a modeling tool for this phenomenon. The article describes Alzheimer’s disease and its causes, the expected development of the population by 2100, the AD patient’s development, and last but not least the theory of system thinking. The outputs are based on the statistical data analysis and created by a dynamic model, which can simulate the development of the Czech Republic population and the AD patients.