Retro Diels-Alder reakció alkalmazása kondenzáltvázas heterociklusok előállítására = Application of retro Diels-Alder reaction for preparation of fused-heterocycles

Kiszélesítettük a retro Diels-Alder reakció alkalmazásának lehetőségeit. Eddig a ciklopentadién hordozón felépített vegyületek "kvázi aromás" szerkezetűek voltak, azaz a képződött új heterogyűrű oxo-, dioxo- vagy tioxocsoporttal szubsztituált. Mivel a furán könnyebben lehasítható mint a ciklopentadién, kísérleteinkben a furán maleinsavanhidriddel készült származékából előállított diexo-amino-oxanorbornénkarbonsavat aminoalkohollá redukáltuk. Ezt oxokarbonsavakkal ciklizáltuk és a furánt hevítéssel eltávolítva, a kialakult heterogyűrűn oxocsoportot nem tartalmazó retro Diels-Alder termékeket: pirrolo-oxazint, oxazino-izoindolokat, benzo-indolo-benzoxazint és pirrolo-pirimidineket állítottunk elő. A retro Diels-Alder reakció alkalmazásának eredményeiről összefoglaló közleményben számoltunk be. Tapasztalataink alapján összesen 4 review közleményünk jelent meg az oxokarbonsavak előállításáról, az izoindolok szintéziséről valamint a réz(II)-halogenidek organikus reakciókban való felhasználásáról. Leírtuk a diexo-amino-norbornán- és -norbornénkarbonsavak, diendo-analógoktól eltérő levulinsavas reakcióját, amikor az előbbiek Claisen-típusú reakcióval kettőskötést tartalmazó kondenzált származékká alakulnak. A sztereoizomer amino-norbornénkarbonsavakra új reakciót írtunk le. 2-Oxociklohexil-acetáttal kettőskötést tartalmazó pentaciklusos származékokat izoláltunk. Ezekben a kísérletekben százat meghaladó számú új heterociklust állítottunk elő. | The possibilities of the application of the retro Diels-Alder reaction for the preparation of new heterocycles have been broadened. Earlier, compounds were built up on cyclopentadiene as carrier. The heterocycles with one or more condensed rings prepared in this way, have a quasi-aromatic structure, i.e. the new heterorings formed are substituted with an oxo, dioxo or thioxo group(s). As the furan is an easy leaving group, and therefore better than cyclopentadiene, we have now applied it. By cyclization of the starting aminoalcohol with oxocarboxylic acids, the products, containing no oxo group on the new heteroring, were heated to the melting point, when a pyrrolooxazine, oxazinoisoindolones, benzoindolobenzoxazine and pyrrolopyrimidines were prepared. A review has appeared on the applications of the retro Diels-Alder reaction. Two other reviews have dealt with the preparations of isoindolones and one each with the preparation of oxocarboxylic acids and the application of copper(II) halides in the organic reactions. Some other reactions of diexo-aminonorbornanecarboxylic acids with levulinic acid have been described, resulting in condensed derivatives containing a double bond in consequence of a Claisen condensation. A new reaction with 2-oxocyclohexylacetate has been found when a pentacyclic condensed compound is isolated. In these studies, more than a hundred new heterocycles have been synthetized

Aliciklusos beta-aminosavak új felhasználási lehetőségei: enantioszelektív átalakítások, kombinatorikus kémia, foldamer szintézis =

A pályázati munka során a Szegedi Tudományegyetem Gyógyszerkémiai Intézetében sok éve eredményesen művelt heterociklusos kémiai kutatások mellett, azt folytatva és kiegészítve új irányokat kezdtünk. E munkákban elsősorban az aliciklusos béta-aminosavakat és származékaikat a szintetikus szerves kémia közelmúltban dinamikus fejlődésnek indult új területein kívántuk hasznosítani. Munkánk főbb irányai: (a) Heterociklus szintézisek és vizsgálatok; (b) Enzimes kinetikus rezolválási és deszimmetrizálási reakciók alkalmazása aliciklusos béta-aminosavszármazékok és prekurzoraik előállítására; Sztereoszelektív reakciók alkalmazása új aliciklusos béta-aminosavszármazékok készítésére; (c) Aliciklusos béta-aminosavszármazékok felhasználása szilárd hordozón végzett reakciókban és kombinatorikus könyvtárak létrehozásában; (d) Aliciklusos beta-aminosav-alapú önszerveződő oligomerek szintézise, konformációs és stabilitási vizsgálata. Az elért eredményekből 88 eredeti tudományos közleményünk és 7 összefoglaló közleményünk jelent meg. A közlemények összimpakt faktora 198.85. A Tudományos Iskola pályázatának is köszönhetően, 2003-2005. év során a 9 fő szerzett PhD fokozatot. | On the basis of our earlier experience at the Institute of Pharmaceutical Chemistry, University of Szeged, with the chemistry of alicyclic beta-amino acids, this project seeks to find new areas of application of these compounds in the continuously developing new fields of synthetic organic chemistry (enantioselective syntheses, enzymatic resolutions, syntheses on solid supports, combinatorial chemistry, synthesis and investigation of foldamers). The most important activities: Synthesis of alicyclic beta-amino acid derivatives and their precursors by enzymatic kinetic resolution and desymmetrization reactions. Synthesis of new alicyclic beta-amino acid derivatives by stereoselective transformations. Application of alicyclic beta-amino acids in reactions performed on solid supports. Synthesis of combinatorial libraries, starting from alicyclic beta-amino acids (synthesis of combinatorial libraries from beta-amino acids by using Ugi 4CC condensation, and synthesis of peptide libraries from beta-amino acids). Conformational and stability studies on self-organizing oligomers prepared from alicyclic beta-amino acids. Creation of artificial tertiary beta-peptide structures. 88 research papers and 7 review articles were published, their impact is 198.85. Nine young scientist has got PhD degree in the frame of the project

Insights on carbapenem-resistant Pseudomonas aeruginosa : phenotypic characterization of relevant isolates

Pseudomonas aeruginosa (P. aeruginosa) is ubiquitous in nature, and may be a causative agent in severe, life-threatening infections. In >60% of cases, β-lactam antibiotics are used in the therapy of P. aeruginosa infections, therefore the emergence of carbapenem-resistant P. aeruginosa (CRPA) is a significant clinical concern. In this study, phenotypic methods were used to characterize fifty-four (n = 54) P. aeruginosa isolates, which were included based on their suspected non-susceptibility to meropenem. Minimum inhibitory concentrations (MICs) of meropenem, ceftazidime, cefepime, ciprofloxacin, gentamicin, were determined using E-tests, while colistin MICs were determined using broth microdilution. The isolates were subjected to the modified Hodge test (MHT), the modified carbapenem-inactivation method (mCIM) and the imipenem/EDTA combined disk test (CDT). AmpC and efflux pump overexpression was studied using agar plates containing cloxacillin and phenylalanine-arginine β-naphthylamide (PAβN), respectively. Assessment of biofilm-formation was carried out using the crystal violet tube-adherence method. 38.9% of the strains showed meropenem MICs in the resistant range (>8 mg/L). Efflux-pump overexpression and AmpC-hyperproduction was seen in 44.4% and 35.2% of isolates, respectively. 88.8% of the isolates were characterized as strong biofilm-producers. On the other hand, the presence of carbapenemases was suspected in a minority (16.7%) of tested isolates. As safe and effective therapeutic options in carbapenem-resistant Gram-negative infections are severely limited, characterization of these isolates using phenotypic and molecular-based methods is important to provide insights into the epidemiological features of these pathogens

Antimicrobial Resistance in the Context of the Sustainable Development Goals: A Brief Review

The reduction in infectious disease morbidity and mortality may be attributed to a variety of factors; however, improved sanitation and public health, and the introduction of vaccines and antibiotics are among the most significant. The development of antimicrobial resistance (AMR) in bacterial pathogens is an expected consequence of evolutionary adaptation to these noxious agents and the widespread use of these drugs has significantly sped up this process. Infections caused by multidrug resistant pathogens are directly associated with worse clinical outcomes, longer hospital stays, excess mortality in the affected patients and an increasing burden and costs on the healthcare infrastructure. The Sustainable Development Goals (SDGs) were published in 2015 by the United Nations to serve as a global blueprint for a better, more equitable, more sustainable life on our planet. The SDGs contextualize AMR as a global public health and societal issue; in addition, the continuing emergence of AMR may limit the attainment on many SDGs. The aim of this mini-review is to provide insight on the interface between attainment of SDGs and the clinical problem of drug resistance in bacteria

Insights on carbapenem-resistant Pseudomonas aeruginosa: phenotypic characterization of relevant isolates

Pseudomonas aeruginosa (P. aeruginosa) is ubiquitous in nature, and may be a causative agent in severe, life-threatening infections. In >60% of cases, β-lactam antibiotics are used in the therapy of P. aeruginosa infections, therefore the emergence of carbapenem-resistant P. aeruginosa (CRPA) is a significant clinical concern. In this study, phenotypic methods were used to characterize fifty-four (n = 54) P. aeruginosa isolates, which were included based on their suspected non-susceptibility to meropenem. Minimum inhibitory concentrations (MICs) of meropenem, ceftazidime, cefepime, ciprofloxacin, gentamicin, were determined using E-tests, while colistin MICs were determined using broth microdilution. The isolates were subjected to the modified Hodge test (MHT), the modified carbapenem-inactivation method (mCIM) and the imipenem/EDTA combined disk test (CDT). AmpC and efflux pump overexpression was studied using agar plates containing cloxacillin and phenylalanine-arginine β-naphthylamide (PAβN), respectively. Assessment of biofilm-formation was carried out using the crystal violet tube-adherence method. 38.9% of the strains showed meropenem MICs in the resistant range (>8 mg/L). Efflux-pump overexpression and AmpC-hyperproduction was seen in 44.4% and 35.2% of isolates, respectively. 88.8% of the isolates were characterized as strong biofilm-producers. On the other hand, the presence of carbapenemases was suspected in a minority (16.7%) of tested isolates. As safe and effective therapeutic options in carbapenem-resistant Gram-negative infections are severely limited, characterization of these isolates using phenotypic and molecular-based methods is important to provide insights into the epidemiological features of these pathogens