Darbo tikslas: nustatyti galimą nifumezino ir į jį panašių junginių struktūros-aktyvumo ryšį. Tyrimo metodai: susintetintų nifumezino analogų preliminarūs antimikrobinio aktyvumo tyrimai in vitro ir antimikrobinio aktyvumo prognozė PASS programa. Tyrimo rezultatai: atlikus antimikrobinio aktyvumo tyrimus in vitro nustatyta, kad junginiai AM-3 ir AM-4 yra praktiškai neaktyvūs, kai koncentracija 500 µg/ml. Junginiai AM-3-1 ir AM-4-1 veikia S. aureus, E. faecalis, S. epidermidis. AM-5 aktyvus prieš S. aureus ir B. subtillis. Nė vienas iš susintetintų junginių nėra aktyvus prieš P. aeruginosa, P. mirabilis ir E. coli. Atlikus kompiuterinį aktyvumo prognozavimą PASS programa, nustatyta, kad stipriausias antibakterinis poveikis prognozuojamas AM-3-1 ir AM-4-1 junginiams (Pa>0,4). Priešgrybelinis poveikis prognozuotas junginiui AM-3-1. Prognozuojamas didžiausias toksiškumas (Pa>0,6) AM-3-1 ir AM-4-1 junginiams. AM-4 prognozuojami 4 nepageidaujami farmakologiniai poveikiai, o AM-5 – 6. Tyrimo išvados: Nustatyta, kad antimikrobiniam poveikiui yra svarbus nitrofuraldehido pakaitas 5-oje padėtyje ir sulfadimidino pakaitas. Sulfadimidino vieta rodanino žiede (3-ia ar 4-a padėtis) reikšmingos įtakos neturi, tačiau dalinai skiriasi junginių aktyvumas prieš skirtingas bakterijų rūšis. PASS programa gali nuspėti junginių aktyvumą ir pagreitinti galimų veiklių junginių atranką ir kryptingą sintezę. / Aim of study: to identify potential nifumezine and similar compounds structure- activity relationship. Study methods: antimicrobial activity tests in vitro and prognosis of antimicrobial activity by PASS program. Study results: antimicrobial activity tests in vitro showed that the compouds AM-3 and AM-4 is inactive at concentration 500 µg/ml. Compounds AM-3-1 and AM-4-1 are active against S. aureus, E. faecalis, S. epidermidis. None of the synthesized compounds are not active against P. aeruginosa, P. mirabilis and E. coli. Activity prognosis by PASS program showed that the strongest antibacterial effect predisted compound AM-3-1 and AM-4-1, but these compouds have also the bigest risk to be toxic. Conclusions: it was found that the nitrofuraldehyde in 5-position is important to antimicrobial effects. The position of sulfadimidine (3rd or 4th position)is not significantly affected in rhodanine ring, bet different compounds could be active against different type of bacteria. PASS program can predict the activity of compounds.

Ce travail de thèse a eu pour but la synthèse de nouveaux composés hétérocycliques (rhodanines et pyrazoles) potentiellement actifs sur des protéines kinases, des lignées cellulaires tumorales, les influx SOCE (Store Operated Calcium Entry) et a ciblé principalement comme pathologies la malaria, la leishmaniose et le cancer. La première partie de cette étude a permis la synthèse d'une nouvelle famille de dérivés 5-arylidène rhodanines dissymétriques comportant un bras espaceur diaminé et ce par l'intermédiaire de la technologie micro-onde. Sur les 7 protéines kinases testées avec ces composés, CK1δ/ε et CDK5/p25 ont été inhibées spécifiquement avec des CI50 comprises entre 1,1 et 10 µM. L'activité anticancéreuse enregistrée est moyenne avec des CI50 variant de 8 à 23 µM. Les travaux réalisés au cours de la seconde partie de cette étude se sont appuyés sur le SKF-96365 comme modèle structural et ont permis d'accéder à 3 librairies inédites d'analogues comportant les plateformes pyrazole et rhodanine. L'activité pharmacologique visée ici était une modulation des influx SOCE et diverses variations structurales ont été effectuées en vue de réaliser une étude Relation Structure-Activité (RSA). Plusieurs analogues "pyrazoles" ont montré une activité supérieure à celle du SKF-96365 et de la GSK-7975A sur les influx SOCE de la lignée HEK-293. Les 2 composés montrant la meilleure activité (30f et 30h), sont également plus actifs que la Synta 66 aux faibles concentrations. Ces analogues ont également une activité sélective des canaux SOCE concernés car totalement inactifs sur l'ensemble des protéines kinases testées. Les CI50 les plus significatives pour l'activité anticancéreuse varient entre 3 et 8 µM. / This thesis work has been aimed the synthesis of new heterocyclic compounds (rhodanines and pyrazoles) potentially active on kinase proteins, tumor cell lines, SOCE impulses (Store Operated Calcium Entry) and has mainly targeted pathologies such as malaria, leishmaniasis and cancer. The first part of this study allowed the synthesis of a new family of 5-arylidene rhodanine derivatives asymmetric having a diamino spacer arm and via microwave technology. Of the 7 protein kinases tested with these compounds, CK1δ/ε and CDK5/p25 have been specifically inhibited with IC50 between 1.1 and 10 µM. The recorded anticancer activity is average with IC50 ranging from 8 to 23 µM. The work carried out during the second part of this study was based on SKF-96365 as structural model and provided access to 3 unpublished libraries of analogs containing pyrazole and rhodanine platforms. The desired pharmacological activity was SOCE modulating and various structural changes were made to undertake a study Structure-Activity Relationship (SAR). Several "pyrazole" analogs have shown a higher activity than SKF-96365 and GSK-7975A on SOCE of HEK-293 line. The two compounds showing the best activity (30f and 30h) are also more active than Synta 66 at low concentrations. These analogs are completely inactive on all protein kinases tested, indicating selectivity for SOCE channels concerned. The most significant IC50 for the anticancer activity vary between 3 and 8 µM.

Darbo tikslas – sintetinti potencialius antibakterinius ir priešgrybelinius 3-amino rodanino darinius su pakaitais 3-oje ir 5-oje padėtyse bei ištirti jų struktūros įtaką aktyvumui. Tyrimo metodai – junginių antimikrobinio ir priešgrybelinio aktyvumo bei toksiškumo prognozė atlikta naudojant PASS programą. Antimikrobinis ir priešgrybelinis aktyvumas tirtas in vitro serijinio skiedimo standžioje terpėje metodu. Tyrimo rezultatai – PASS programa priešgrybelinį aktyvumą prognozavo visiems junginiams didesne tikimybe nei antibakteriniam. Pastarojo neprognozavo trims junginiams. Junginiams, kuriems prognozuotas didžiausias aktyvumas – tikimybė būti toksiškiems taip pat buvo didžiausia. Atlikus tyrimus in vitro paaiškėjo, kad nitrofurano liekana smarkiai padidina 3-amino rodanino aktyvumą prieš tiriamas organizmų kultūras. Radikalo įjungimo vieta į 3-amino rodanino žiedą daro svarbią įtaką aktyvumui: aktyviausi junginiai turi pakaitus trečioje padėtyje, o neaktyvūs – penktoje. 3-amino rodanino žiedo išskleidimas įvedant pakaitą per amino grupę padidino priešgrybelinį veikimą. Gauti rezultatai parodė, kad aromatinių benzaldehidų įtaka aktyvumui priklauso nuo pakaitų pobūdžio ir vietos juose. Išvados – aktyvumo programa PASS gali padėti iš anksto tikėtis rezultato ir pagal tai kryptingai pasirinkti junginius, tačiau būtina atlikti tyrimus ir in vitro. 3-amino rodanino darinių aktyvumas priklauso nuo pakaitų įvedimo padėties. Atsižvelgiant į gautus rezultatus, išskirti... [toliau žr. visą tekstą] / Aim of study – synthesize potential antibacterial and antifungal 3-amino rhodanine compounds with substitutes in 3 and 5 places and analyze their structure influence to the activity. Study methods – prognosis of antifungal, antibacterial and toxicity of synthesized compounds was made by PASS program. Antibacterial and antifungal activity was tested in vitro by serial dilution in stiff environment. Study results – PASS program predicted antifungal activity to all compounds with higher probability than antifungal. 3 compounds had no predictions to antibacterial activity. According to PASS results, the most active compounds could be the most toxic. Research in vitro showed, that moiety of nitrofuraldehyde increases activity of 3-amino rhodanine against microbes and fungi cultures. Activity depends on the place of derivative in the ring of 3-amino rhodanine: the most active compounds had derivatives in 3rd place, and inactive – in 5th. Opening of the ring of 3-amino rhodanine during reaction in 3rd place increased antifungal activity. Results showed, that the influence of aromatic benzaldehydes to the activity depends on derivatives nature and place in aldehydes. Conclusions – activity program PASS could help predict result and accordingly choose compounds. However it is necessary to perform studies in vitro. Activity of 3-amino rhodanine compounds depends on derivatives place in the ring. With respect to results in vitro, 2 most active compounds were sorted: EK-1 and EK-14 which... [to full text]

Darbo tikslas: susintetinti naujus antibakterinius ir priešgrybelinius 5-ariliden-4-tiazolidinon-N-aminorūgščių (leucino, triptofano) ir naujus 2-acetil-1-naftolio junginius ir prijungtų pakaitų įtaką junginių priešmikrobiniam aktyvumui. Uždaviniai: 1. Apžvelgti esamą literatūrą apie bakterijų ir grybelių sukeliamas infekcijas, kovos prieš infekcijas metodus, strategijas. 2. Optimizuoti naujų galimų vaistų struktūrų paieškas pasitelkiant kompiuterinio modeliavimo programą ,,SYBYL-X“ ir junginių biologinio aktyvumo prognozavimo programą ,,PASSonline“. 3. Susintezuoti naujus 5-ariliden-4-tiazolidinon-N-aminorūgščių (leucino, triptofano) ir naujus 2-acetil-1-naftolio junginius. 4. Atlikti junginių charakteristikų analizę, pasitelkiant junginių plonasluoksnės chromatogafijos, lydimosi temperatūrų, ESC, UV, IR spektrų metodus. 5. Nustatyti susintezuotų junginių mikrobiologinį aktyvumą prieš Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Bacillus subtillis, Bacillus cereus, Candida albicans. Tyrimo metodai: junginių priešmikrobinis aktyvumas buvo prognozuojamas naudojant PASSonline ir kompiuterinio molekulių modeliavimo programą SYBYL-X 1.1. Antimikrobinis aktyvumas buvo tiriamas ,,in vitro” atmetimo būdu, ,,užnuodytos lėkštelės metodu“ bakterijas užnešant ant junginio tirpalo suspenduoto Miulerio-Hintono agare. Tyrimo rezultatai: Gauti plačiausią aktyvumo spektrą... [toliau žr. visą tekstą] / The goal: to synthesize new antibacterial and antifungal 5-aryliden-4-thiazolidinone-N-amino acids (leucine, tryptophan) and a new 2-acetyl-1-naphthol compounds and associated substitutions influence on compounds for anti-microbial activity. Objectives: 1. Review the existing literature on bacterial and fungal infections, anti-infection techniques, strategies. 2. Optimize new structures of potential drug searches through computer simulation program, Sybyl - X compounds and biological activity prediction program, PASSonline. 3. Synthesise new 5 - ariliden - thiazolidine - 4 -N - amino acids (leucine, tryptophan) and a new 2-acetyl-1-naphthol compounds. 4. Perform an analysis of the characteristics of compounds using thin layer chromatography, melting temperatures, HPLC, UV, IR spectra methods. 5. Set synthesised compounds of microbial activity against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Bacillus subtillis, Bacillus cereus, Candida albicans. Research methods: antimicrobial activity of the compounds were predicted using “PASSonline” and computer molecular modeling program “Sybyl -X 1.1”. Antimicrobial activity was studied “in vitro” rejection method as “poisoned dish method”- bacteria applied on the solution suspending in a Muller - Hinton agar. The results: Synthesised compounds having the widest spectrum of activity with two... [to full text]

In der Alzheimer-Forschung (engl.: Alzheimer Disease, AD) wird immenser Aufwand zur Entwicklung von den Krankheitsverlauf verändernden Medikamenten betrieben. Studien zeigten, dass die abnormale Aggregation des Tau-Proteins offenbar zum Zusammenbruch der Zellkommunikation führt. Niedermolekulare Substanzen, die die Tau-Protein-Aggregation inhibieren und sogar bereits gebildete Aggregate wieder auflösen können wurden entwickelt, sind jedoch oft aufgrund von schlechten Wasserlöslichkeiten nur unter Zusatz von Dimethylsulfoxid (DMSO) in Biotests einsetzbar. Durch das Design maßgeschneiderter Peptid-Polyethylenglykol (PEG)-Konjugate war die spezifische Bindung und anschließende Freisetzung ausgewählter potentieller anti-AD-Wirkstoffe in DMSO-freien Biotests möglich. Für den Entwurf der Wirkstoff-Transporter wurden Peptidbibliotheken mit Raman- und Fluoreszenz-Mikroskopie-basierten Methoden hinsichtlich der Anreicherung der Wirkstoffe an Peptiden mit hoher Wirkstoff-Bindekapazität getestet. Mithilfe von Matrix-unterstützter Laser-Desorption/Ionisation (MALDI)-Massenspektrometrie (MS/MS)-Fragmentierung konnten die Peptidsequenzen der positiven Treffer identifiziert werden. Die zugehörigen Konjugate wurden synthetisiert, mit den Wirkstoffen beladen und die entstehenden sehr gut wasserlöslichen Wirkstoff-Konjugat-Komplexe analysiert. Für biomedizinische Anwendungen sind kompakte und definierte Systeme von Vorteil. Zur Strukturaufklärung der Wirkstoff-Konjugat-Komplexe konnten zahlreiche Untersuchungen erfolgreich durchgeführt werden. Viele Komplexe wurden zudem in DMSO-freien Biotests der Tau-Protein-Aggregation eingesetzt. Die Bioverfügbarkeit der schwerlöslichen anti-AD-Wirkstoffe konnte durch die Solubilisierung mit maßgeschneiderten Peptid-PEG-Konjugaten enorm verbessert werden. Die auf Raman-aktive Substanzen erweiterte Screeningprozedur kann wahrscheinlich auf eine Großzahl von Wirkstoffen mit ungünstigen pharmakologischen Eigenschaften angewendet werden. / Considerable efforts are devoted in Alzheimer Disease (AD) research to develop disease modifying drugs. Various studies have demonstrated that abnormal aggregation of Tau protein probably interrupts communication between cells. Tau protein aggregation can be inhibited and even preformed aggregates can be redissolved by small-molecule compounds. Unfortunately, these molecules often can only be applied in limited biotests using dimethyl sulfoxide (DMSO) as co-solvent due to their poor water solubility and bioavailability. The solubilization of selected potential anti-AD drugs by tailored peptide-poly(ethylene glycol) (PEG) conjugates enabled the specific binding und subsequent release of these drugs in DMSO-free biotests. For the design of the drug conjugate carriers, large peptide libraries have been screened using Raman or fluorescence microscopy-based methods to follow drug enrichment on certain peptide library beads which exhibit high drug affinity. Identification of peptide sequences of positive hits was performed by Matrix-assisted Laser Desorption/Ionization (MALDI)-mass spectrometry (MS/MS) fragmentation. The corresponding conjugates were synthesized; loaded with the potential drugs and the resulting highly water-soluble drug transporter complexes were analyzed. Compact and defined complexes are desirable with regard to biomedical applications. Various studies on drug-peptide interactions, specifity of drug binding and influence of the different parts of the conjugates for drug capacities were performed successfully. Generated drug transporter complexes were finally tested in DMSO free bioassays. Depending on drug and peptide structures, the complexes could reach effects comparable to the drugs solubilized by DMSO. The bioavailability of poor water-soluble anti-AD compounds was largely improved. Presumably, the new developed Raman-screening procedure can be expanded to a great extent of compounds suffering from unfavorable pharmacological characteristics.