The complex compounds SnCl4 with salicyloyl hydrazones benzaldehyde and 4-bromobenzaldehyde exhibit different pharmacological activities, one of which is anti-inflammatory. To study the correlation between structure and activity, we have studied the contribution to the overall anti-inflammatory activity of the components of this complex compounds, benzaldehydes and salicylic acid.

The study was conducted on the the histamine, trypsin, carrageenan and formalin models of the inflammation. During the modeling trypsin and histamine inflammation, the test substances were administered 30 minutes before the injection of the inflammatory agent. Treatment by oral administration of certain components began a day after the development of inflammation on the carrageenan inflammation model and three days later on the formalin model.

The obtained data indicate that the components of the complex compounds SnCl4 - benzaldehyde, 4-bromobenzaldehyde and salicylic acid have their own anti-inflammatory activity on models of short and long-term inflammation. Also, they make a contribution to the overall pharmacological activity of the studied compounds.

Alzheimer's disease (AD) is considered the leading and most common age-related dementia, accounting for 50-60% of cases. The most commonly used pharmacotherapeutic approach for the symptomatic control of AD is anticholinesterase drugs, that is, they have an inhibitory activity on the enzyme acetylcholinesterase (AChE), thus increasing the cerebral levels of the neurotransmitter acetylcholine (Ach). For many years, Traditional Chinese Medicine has been cataloging numerous medicinal plants, which present various pharmacological activities, such as anti-Alzheimer's activity. This variety of plants present compounds that interact with multiple proteins that are involved in several pathways associated with AD. The main objective of this study is an in silico study of 14 natural compounds, for which molecular docking and pharmacokinetic and toxicological predictions were carried out. As a first step the following molecules were selected in the literature: 1,8-cineole, bornil acetate, α-pinene, β-pinene, camphor, cariophilene epoxide, physostigmine, galantamine, γ-terpinene, honokiol, huperzine A, licoramine , magnolol and resveratrol, and later designed with the Chemsketch program and the chemical structures optimized with the Hartree-Fock method and the base function 6-31G ** previously validated in the Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem) and implemented in the Gaussian program 03. The second step was the molecular docking study carried out with the software GOLD 4.1 where it was possible to study the intermolecular interactions among the selected natural products with the amino acids present in the active site of the AChEenzyme, the connections were largely hydrophobic interactions and hydrogen bonds and all 14 molecules showed interactions with the amino acid residues TRP286, PHE295, TYR341, TYR72 present in the catalytic site of the target enzyme, but only 13 presented three or more interactions, predominantly. In order to predict the pharmacokinetic properties of the selected molecules, the QikProp module of the Schrödinger software was used, which computed some important properties such as: molecular weight, polar surface area (PSA), logP, logBB, percentage of human oral absorption, activity predicted in the central nervous system, apparent permeability in cells and MDCK. As a result, all 14 molecules were found to have satisfactory PSA, LogBB, permeability to Caco-2 and MDCK cells, but only 7 molecules were able to cross the blood-brain barrier. The toxicity profile of the 14 molecules selected was performed by the DEREK program, where a total of 19 structural alerts were verified. The molecules that presented these alerts were: camphor, caryophyllene epoxide, physostigmine, honokiol, magnolol and resveratrol. Based on the results presented by the study, the following compounds were found: α-pinene, β-pinene, galantamine, γ-terpinene and licoramine presented potential for use in the planning and development of new anti-Alzheimer drug candidates.

Complex, focused anticancer therapy approach has been developed in the Latvian Institute of Organic Synthesis by making use of privileged partially hydrogenated nitrogen-containing heterocycles, namely dihydropyridines, dihydropyrimidines, their oxidized heteroaromatic derivatives. Topics of research include:

1. Conventional approach by chemotherapy and synergism of anticancer drugs [1];

2. Inhibition of multidrug resistance by inhibition of drug efflux pumps [2];

3. Mitigation of cancer risk factors – e.g., hepatitis B virus chemotherapy for prevention of chronic liver diseases, because chronic hepatitis, in up to 40% of cases, progresses to cyrrhosis and further to hepatocellular carcinoma [3];

4. Improvement of efficacy of cancer radiotherapy by use of radioprotectors to prevent damage of normal tissues. So, radioprotector diethone (dietone) for skin protection was discovered, elaborated, and developed as ointment. Compounds for protection of eyes, mucous tissues, salivary glands etc have been synthesized. Toxicity of dietone and novel radioprotectors is very low;

5.Amphiphilic compounds have been synthesized, nanoparticles for anticancer drug and gene delivery have been created, pleiotropic properties have been checked, inclusion of magnetic particles for targeted transport performed [4].

Acknowledgements

The research was partially supported by the Latvian State Program Biomedicine.

References

1.Bisenieks E., Duburs G. et al., Pharmaceutical combination of 5-fluorouracil and derivatives of 1,4-dihydropyridine. US 8492413B2, 2013.

2.Krauze A., Grinberga S. et al., Thieno[2,3-b]pyridines – a new class of multidrug resistance (MDR) modulators. Bioorg.Med.Chem. 2014, 22 (21), 5860-5870.

3.Sipola A., Dubova U., et al., Synthesis and evaluation of 1,4-dihydropyrimidine derivatives – hepatitis B virus capsid self-assembly inhibitors. EFMC International Symposium on Medicinal Chemistry. Ljubljana, Slovenia, 2018, P176.

4.Pajuste K. et al., Gene delivery agents possessing antiradical activity: Self-assembling cationic amphiphilic 1,4-dihydropyridine derivatives. New J.Chem. 2013, 37 (10), 3062-3075.

Imidazole occurs in most proteins as part of the side chain of histidine and constitutes a binding site for various transition metal ions in a large number of metalloproteins [1]. Consequently, the bonding between imidazole and transition metal ions is widely known [2] and of considerable interest especially in biological systems [3,4]. Consequently, copper(II)–imidazole systems with different ratios of imidazole to copper have been prepared and investigated by several researchers [5]. Moreover, being studied as models for copper proteins that contain both functionalities in the side chain [6], some mononuclear copper(II)–imidazole complexes with carboxylate ligands have been found to display a variety of pharmacological effects, including antitumor [7], superoxide dismutase and catecholase activities [8]. In order to contribute to the study of these systems, we have synthesized two new penta-coordinated copper(II) complexes with mixed-ligands, namely: imidazole and citric acid. The resulting compounds have shown remarkable antimicrobial and antifungal inhibition activities, which have been predicted by exploring the computational chemical reactivity of the two complexes [9].

References :

[1] J. Reedijk & E. Bouwman, Bioinorganic Catalysis, Marcel Dekker Inc., New York & Basel, 1999.

[2] K. D. Karlin & Z. Tyeklar, Bioinorganic Chemistry of Copper, Chapman & Hall, New York, 1993.

[3] E. Colacio, M. Ghazi, R. Kivekäs, M. Klinga, F. Lloret & J. M. Moreno, Inorg. Chem, 2000, 39(13), 2770–2776.

[4] M. T. Caudle, J. W. Kampf, M. L. Kirk, P. G. Rasmussen & V. L. Pecoraro, J. Am. Chem. Soc, 1997, 119(39), 9297–9298.

[5] (a) S. M. Morehouse, A. Polychronopoulou & G. J. B. Williams, Inorg. Chem, 1980, 19(12), 3558–3561. (b) G. Fransson & B. K. S. Lundberg, Acta Chem. Scand. A, 1974, 28(5), 578–588. (c) D. L. McFadden, A. T. McPhail, C. D. Garner & F. E. Mabbs, J. Chem. Soc., Dalton Trans, 1976, 47–52.

[6] H. Beinert, Coord. Chem. Rev, 1980, 33, 55.

[7] J. R. J. Sorrenson, Prog. Med. Chem, 1989, 26, 437. (and references therein).

[8] A. L. Abuhijleh & C. Woods, Inorg. Chim. Acta, 1993, 209, 187.

[9] Direm, A. Abdelbaky, M. S. M. Sayın, K. Cornia, A. Abosede, O. & García-Granda, S. (2018). Inorg. Chim. Acta. 478. 59–70.

Antimicrobial peptides (AMPs) are key components of innate immune systems. Because of their lasting potency, AMPs are regarded as useful candidates for developing the next generation of antimicrobials to meet the challenge of antibiotic resistance. According to CDC, 90% infections are related to the difficult-to-treat ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. In this lecture, I will discuss peptide design based on human cathelicidin LL-37, one of the best-studied host defense peptides. Both synthetic peptide library and structure-based design methods were utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region in 2006. However, the minimal region of LL-37 can be function-dependent. In 2014, we reported successful conversion of LL-37 into17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. The European group identified IG-24 derived P60.4 by using the peptide library approach. In 2018, they selected SAAP-148 as a candidate with a reduced binding to blood plasma. Interestingly, both 17BIPHE2 and SAAP-148 eliminated the ESKAPE pathogens and showed topical in vivo antibiofilm efficacy. In addition, a better antibiofilm outcome could be obtained when 17BIPHE2 was used in combination with traditional antibiotics. Finally, I summarize what we have learned from human LL-37 engineering.

Video from the Keynote Speaker Dr. Guangshun Wang can be found:

https://youtu.be/1OOpTs6Sszk