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Terapeutyczny potencjał pochodnych izotiazolowych : wpływ struktury związku na aktywność

Jęśkowiak I., Mączyński M., Ryng S.

Wiadomości Chemiczne

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2018

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[Z] 72, 11-12

867--885

EN

Isothiazole derivatives are compounds with potentially interesting biological activity. The work on the isothiazole ring was successfully conducted by Machoń from the Department of Organic Chemistry at Wrocław Medical University. Machoń received an isothiazole derivative – Denotivirum, which is an original Polish drug. This compound has antiviral, anti-inflammatory and bacteriostatic activity against Staphylococcus aureus. Within the group of isothiazolpyrimidine derivatives, Machoń selected a compound with a very strong antitumor effect (IP-10). This combination has gone through a preclinical study. The high antitumor activity was confirmed by the Bethesda USA Research Center, which qualified him for clinical trials [1–5]. The aim of the study was to review and evaluate the latest scientific works in the field of isothiazole derivatives and, above all, the dependence of their structure on activity. The Chemical Abstracts Database and Reaxys, together with other sources of information, was searched using isothiazole keyword. As a result of the search, the majority of works describing isothiazole derivatives for the anticancer (Tab. 1), immunological among other anti-inflammatory, immunosuppressive (Tab. 2) and antiviral (Tabs 3 and 4) activity were selected. Some substances have been tested for antibacterial, antifungal, insecticidal, antiparasitic, analgesic, antidiabetic and neuroprotective properties (Tab. 5). Analyzed were only compounds containing the isothiazole ring, which are not belong to condensed heterocyclic compounds such as benzoisothiazoles, isothiazolpyridines or furoisothiazoles. In conclusion, the most interesting works presented herein illustrate a wide range of activities of isothiazole derivatives depending on their structure, which also extend the scope of biological research revealing previously barren activities of this group of compounds.

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Nowoczesne metody pozyskiwania substancji biologicznie aktywnych przy zastosowaniu reakcji wieloskładnikowych ze szczególnym uwzględnieniem reakcji Ugi

Ryng S., Jęśkowiak I.

Wiadomości Chemiczne

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2017

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[Z] 71, 1-2

45--63

EN

In the last decade a change of thought has taken place in the pharmaceutical industry which has led to a renaissance of the Multicomponent reactions (MCRs) [1]. Under the inspiration of diversity-oriented-synthesis (DOS), numerous efforts have been devoted to find powerful synthetic tools for rapidly accessing maximum molecular diversity with minimum cost. In the toolbox enabling DOS for generating molecular libraries, MCRs are now recognized as one of the most useful and powerful strategies [2], which provide the highest number of compounds for the least synthetic effort [3]. Following the rapid progress in the research area of MCRs, widespread application has been found in many different areas such as chemical biology, natural product synthesis, pharmaceuticals as well as agrochemistry [2]. The overall aim of a DOS is to generate a small-molecule collection with a high degree of structural, and thus functional, diversity that interrogates large areas of chemical space simultaneously [4]. In Targed-Oriented Synthesis (TOS) a complex target is transformed into a sequence of progressively simpler structures by formally performing chemical reactions in the reverse-synthetic direction [3]. Special subclasses are isocyanide based MCRs (IMCRs). They are particularly interesting because they are more versatile and diverse than the remaining MCRs. Today most MCRs chemistry performed with isocyanides relates to the classical reactions of Passerini and Ugi (Scheme 1)[5]. In Ugi four-component reaction (U-4CR), carboxylic acids, primary amines and oxo components (aldehydes or ketones) react with isocyanides in polar solvents to obtain -amino carboxamides (Schemes 2 and 3). Occasionally however, selective conversion of amide groups into other functional groups is desirable for an increase of diversity of the IMCR-derived compounds [6]. In this reaction two substituted amide groups are formed under release of one equivalent of water. Thus, the U-4CR is an atom-economic and environmentally friendly reaction. It was also shown that water can be used as the solvent. This reaction is typically performed by stirrling the components for approximately 1 day in small quantities of a protic solvent (e.g. methanol or trifluoroethanol) [7]. The examples of Ugi reactions are described in the Schemes 4–10. Multicomponent reactions have become attractive tools in modern synthetic organic chemistry. Among their many advantages, they allow the creation of large chemical libraries of diverse, complex molecular structures, starting from simple materials within a short time frame. Not surprisingly, these particular features have made MCRs especially appealing to medicinal chemists [8].

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Najnowsze kierunki poszukiwań cząsteczek o aktywności przeciwprątkowej

Płoszaj P., Piwowar A., Ryng S.

Wiadomości Chemiczne

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2016

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[Z] 70, 1-2

35--56

EN

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) remains a leading cause of morbidity and mortality in developing countries [1]. With the discovery of chemotherapeutic agents in the 1940s and implementation of directly- -observed therapy short course (DOTS) in the 1980s, it was believed that TB would decline globally. Although a declining trend was observed in most developed countries, this was not evident in other parts of the world [2]. In addition, the rate of successful treatment has been compromised in recent years due to the increasing prevalence of multidrug-resistant (MDR-) and extensively drug-resistant TB ( XDR-TB) strains [3]. Accordingly, significant efforts have been made to discover and develop new treatment modalities against TB. This article serves as a summary of the most recent developments in search for novel anti-tubercular compounds. Here we focus on reviewing the results of basic research and clinical trials obtained in 2015 including: a) the phase IV clinical trials conducted for newly developed: bedaquiline, delamanid, clofazimine (previously registered for treatment of leprosis) b) phase III for fixed-dose combination of existing drugs: pretomanid – moxifloxacin – pyrazinamide) and c) the phase II clinical trials for sutezolid, AZD5847 and SQ109 [4]. All newly developed compounds used in these studies have been briefly characterized and their synthesis pathways fully described. In addition we review the most recent and promising results on nicotinic acid hydrazides, thienyl-pirimidines imidazole- -thiadiazole-benzimidazole and benzocoumarine derivatives presenting their synthesis pathways, most active chemical structures and their potential applications. Throughout this paper the ultimate direction for new drug development strategies, in search for the anti-tubercular agents, have been reviewed.

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Studies on the Deamination of the Ethyl Ester of 5-Amino-3-methylisoxazole-4-carboxylic Acid

Ryng S., Szostak M.

Polish Journal of Chemistry

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2009

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Vol. 83, nr 5

887-893

EN

The unusual behavior of the ethyl ester of 5-amino-3-methylisoxazole-4-carboxylic acid (1) during deamination is described. Possible explanations for the anomalies of the diazotization reaction are proposed. Deamination methods leading to ethyl ester of 3-methylisoxazole-4-carboxylic acid (5) are presented. 5 will serve as a lead compound for a new series of immunomodulatory agents.

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Novel Synthesis of 3-Methylisoxazolo[5,4-e][1,2,4]triazepin-4-ones

Ryng S., Zimecki M., Mączyński M., Głowiak T.

Polish Journal of Chemistry

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2009

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Vol. 83, nr 11

1967-1976

EN

A convenient and general method for the preparation of new 7-substituted 3-methyl - isoxazolo[5,4-e][1,2,4]triazepin-4-ones from 5-amino-3-methylisoxazole-4-carboxylic acid methylhydrazide and carbonyl compounds is described. The synthesized compounds exhibited immunosuppressive properties in the murine humoral immune response in vivo and the proliferative response of mouse splenocytes to mitogens. The X-ray structure of a representative compound is reported.

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Synthesis, X-ray Crystallography and Computer-Aided Design of 5-Amino-3-methylisoxazole-4-carboxylic Acid N-(2,4,6-Trimethylpyridinium)amide Chlorate(VII) Salt and Its Analogues

Jezierska A., Zygmunt J., Głowiak T., Koll A., Ryng S.

Polish Journal of Chemistry

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2003

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Vol. 77 / nr 11

1461-1471

EN

Experimental and theoretical investigations were performed for 5-amino-3-methylisoxazole- 4-carboxylic acid N-(2,4,6-trimethylpyridinium)amide chlorate(VII) salt, which belongs to the group of isoxazole derivatives, potential antibacterial or antifungal agents. The results related to its synthesis and X-ray diffraction are presented. Quantum- chemical DFT calculations were carried out for the title molecule and its analogues. Atomic charges were calculated according to Bader's Atoms In Molecules Theory in order to find the quantum similarities of the molecules. The Polarizable Continuum Model (SCRF/PCM) with water (_ = 78.39) as a solvent was used to determine the environment effects on molecular properties. The solid-state geometry optimization with Geodecker's pseudopotentials and plane-wave basis set was used to compare experimental and calculated geometrical parameters for the title compound.

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Quantum-Chemical study with Application of the PCM Model on Correlation Between Biological Activity and Molecular Structure of 5-Amino-3-methylisoxazole-4-carboxylic Acid Hydrazide Schiff Base Derivatives

Jezierska A., J. Panek J., Ryng S., Zimecki M., Fedorowicz A., Koll A.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 9

1255-1262

EN

Theoretical calculations on 5-amino-3-methylisoxazole-4-carboxylic acid hydrazide Schiff base derivatives using Polarizable Continuum Model in order to account for water solvation effects are presented. The compounds studied exhibit biological (immunosuppressing or immunostimulating) activity, measured experimentally in various assays. The quantum chemical DFT calculations are used to obtain electronic descriptors of molecular structure. These descriptors, together with other physicochemical parameters, are used to derive quantitative relationships between the structure and the biological activity.