Development of novel chiral capillary electrophoresis methods for the serotonin receptor (5-HT2A) antagonist MDL 100,907 (volinanserin) and for its key intermediate compound

Enantioselective capillary electrophoretic methods were elaborated for the determination of the enantiomeric purity of (R)-MDL 100,907 and its preparatively resolved key intermediate compound during the synthesis route. The pKa values of the intermediate compound and the end product determined by CE were 10.5±0.1 and 9.0±0.1, respectively. The enantiopurity of the intermediate compound can be monitored in fully protonated state by applying 15mM sulfobutylether-β-cyclodextrin at pH 5 when the peak belonging to the impurity migrates before the main component. The fact that the consecutive steps of the synthesis do not affect the enantiomeric purity was verified by the other, newly developed CE method. The enantiomers of rac-MDL 100,907 were resolved by 15mM carboxymethyl-γ-cyclodextrin at pH 3. The applicability (selectivity, LOD, LOQ, repeatability, precision and accuracy) of the methods was studied as well

Consensus Virtual Screening Identified [1,2,4]Triazolo[1,5-b]isoquinolines As MELK Inhibitor Chemotypes

Maternal Embryonic Leucine-zipper Kinase (MELK) is a current oncotarget involved in a diverse range of human cancers, with the usage of MELK inhibitors being explored clinically. Here, we aimed to discover new MELK inhibitor chemotypes from our in-house compound library with a consensus-based virtual screening workflow, employing three screening concepts. After careful retrospective validation, prospective screening and in vitro enzyme inhibition testing revealed a series of [1,2,4]triazolo[1,5-b]isoquinolines as a new structural class of MELK inhibitors, with the lead compound of the series exhibiting a sub-micromolar inhibitory activity. The structure-activity relationship of the series was explored by testing further analogs based on a structure-guided selection process. Importantly, the present work marks the first disclosure of the synthesis and bioactivity of this class of compounds. © 2021 The Authors. ChemMedChem published by Wiley-VCH Gmb

Új szintézismódszerek kidolgozása és alkalmazása célzott hatásterületen aktív heterociklusos molekulák szintézisére = Elaboration and application of new synthetic methodologies for the synthesis of heterocyclic molecules of aimed biological activity

Pályázati kutatásunk alapvető célja az volt, hogy néhány, a legutóbbi időkben felismert új szintézis-lehetőséget laboratóriumunkban meghonosítsunk, saját magunk új módszereket dolgozzunk ki, és mindezek segítségével felfedező kutatásokat végezzünk kiemelten fontos területen ható biológiailag aktív molekulák megtalálására és szintézisére. Beszámolhatunk arról, hogy palládium-katalizált C-C és C-N keresztkapcsolások segítségével új gyűrűvázakhoz jutottunk, és alapvető új átalakulásokat kezdeményeztünk az organokatalízis és fluoros technika területén. Módszereink segítségével főként a multidrog-rezisztenciát gátló vegyületek családjában értünk el figyelemre méltó eredményt. Kimutattuk, hogy néhány újszerűen szubsztituált fenotiazin-származék hatása meghaladja a kontrollként vizsgált verapamil hatását. A rezisztencia gátlása különösen a mikróbás fertőzések és tumoros betegségek leküzdésében kiemelt jelentőségű. A leghatékonyabb származékokat egy jövőbeli gyógyszerfejlesztés lead-molekulájaként tekintjük. Munkánk elvégzésébe nagy számban vontunk be graduális és posztgraduális hallgatókat. A kutatási eredményekből 7 PhD értekezés született, ezek közül 4 már sikeres védésre került, emellett két egyetemi záródolgozat is elkészült. Munkánk tudományos értékét a megjelent 18 közlemény fémjelzi, összesített hatástényezőjük 57.5. | The basic aim of the present project activity was to establish recently recognized new synthetic methodologies in our laboratory, to elaborate new procedures, and to apply these novel approaches for identification and synthesis of compounds exhibiting biological activity in important areas of drug research. It is to be emphasized that application of palladium-catalyzed C-C and C-N cross coupling reactions allowed the synthesis of new ring systems, whereas basically new transformations have been initiated in the areas of organocatalysis and fluorous techniques.. The new methods provided the most outstanding reaults in the area of multidrug resistance inhibition. Results of some phenothiazines with unusual substitution pattern exceeded the effect of verapamil used as a reference compound. Resistance inhibition is of primary importance in treatment of microbial infections and tumor diseases. Those synthesized compounds exhibiting the highest effectivity can be regarded as lead compounds for the future drug development. Great number of MSc and PhD students were involved into accomplishment of the project. Seven PhD dissertations were born, four of these have already been successfully defended and, furthermore, two master theses have also been finalized. The scientific value of the research activity is coined by the 18 scientific publications with a cumulative impact factor of 57.5

New Facile Tandem Route to Oxo- and Thioxo[1,2,4]triazolo[1,5-a]pyridinium Salts

2-Arylsulfanyl- and benzylsulfanylpyridinium N-arylimides (2), easily available from tetrazolo[1,5-b]pyridinium salts (1), participate in 1,3-dipolar cycloaddition with aryl isothiocyanates and aryl isocyanates to result in formation of fused thioxo- and oxo[1,2,4]triazolium salts (5 and 12), respectively. This transformation is interpreted as a regular 1,3-cycloaddition followed by spontaneous elimination of the aryl- or benzylsulfanyl group. Formation of these triazolium salts can be followed - under appropriate reaction conditions - by ring-opening reactions to afford some new triazolyldienes (6). Recognition of the intermediate participation of the thiolate anion along the pathway 1 ? 5 allowed elaboration of a simple procedure to 5 implying a tandem reaction sequence

Transformation of zwitterionic pyridine derivatives to a spiro fused ring system: azoniabenzo[de]fluorine. Synthesis and mechanistic rationalization

Reaction of aryl- and benzylsulfanopyridinium amidates bearing a methyl group in position 6 with two equivalents of diphenylketene afforded a spiro fused ring system: azoniabenzo[de]fluorine. By use of excess amount of ketene, a distinct reaction was observed via which a 1H-pyrrolo[3,2- b]pyridin-2(3H)-one derivative was furnished. Structure of the tetracyclic spiro-fused ring system was unambiguously confirmed by X-ray diffraction and its formation was rationalized by DFT calculations