A straightforward synthesis of indazolo[3,2-a]isoquinolin-6-amines

4-Substituted 1-bromoisoquinolin-3-amines were subjected to Suzuki coupling with o-nitrophenylboronic acid to yield 1-(2-nitrophenyl) isoquinolinamines, which participated in Cadogan cyclization with triethyl phosphite under microwave irradiation in a sealed vial to yield fluorescent indazolo[3,2-a] isoquinolin-6-amines. The new compounds were also functionalized by transformation of the amino group. © 2013 Elsevier Ltd. All rights reserved

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 kondenzált nitrogén-heterociklusok. Szintézis és reakciókészség. = New fused N-heterocycles. Synthesis and reactivity

A pályázati kutatás fő célja új heterociklusos gyűrűvázak szintézise és reakciókészségének feltárása volt, emellett a biológiai hatás feltárása is a program részét képezte. A kutatások során öt egymással rokon területen sikerült eredményeket elérni. A Suzuki-Gronowitz protokoll felhasználásával hat új, piridazinnal és indollal kondenzált gyűrűváz szintézisét oldottuk meg. Ikerionos jellegű piridinium-amidátok és izotiocianátok reakciójával gyűrűtranszformációs átalakítást valósítottunk meg, mellyel jól járható szintézisutat dolgoztunk ki oxo- és tioxo-triazolopiridiniumsók előállítására. Kondenzált triazinvázú vegyületek körében kétféle átalakítást tanulmányoztunk: a) új triazolo-benzotriazin vázú azometin-imineket szintetizáltunk, melyek cikloaddíciójával kondenzált tetraciklusok keletkeztek; b) flash-vákuum pirolízis technikával a [1,3,4]triazolo[5,1-c]benzotriazin gyűrűváz gyűrűizomerizációját mutattuk ki. Cinnolil-ketonokhoz vezető eljárás kidolgozásával oxidatív ciklizáció segítségével egy új gyűrűváz: az [1,2,3]triazolo[1,5-b]cinnoliniumsó első képviselőjét izoláltuk. Hetaril-triéneket állítottunk elő, melyeket Wittig reagenssel reagáltatva új ciklizációkat figyeltünk meg. A pályázati munka során szintetizált vegyületek köréből multidrog-rezisztenciagátló származékokat ismertünk fel. | The main purpose of the project activity was the study of synthesis and reactivity of new heterocycles. Besides this aim, efforts have also been done for recognition of biological activity. Results have been achieved in five related areas. Six new fused pyridazines and indoles have been synthesized by application of the Suzuki-Gronowitz protocol. Ring transformations have been elaborated by reaction of zwitterionic pyridinium amidates and isocyanates which allowed well working methodology for the synthesis of oxo and thioxotriazoliumpyridinium salts. Two types of transformations have been carried out with fused triazines: a) new azomethine imines with triazolobenzotriazine skeletone have been synthesized and subjected to cycloadditions reactions to yield novel fused tetracycles; ring transformation of [1,3,4]triazolo[5,1-c]benzotriazines have been detected by flash vacuum pyrolytic technique. Well applicable synthetic pathway has been elaborated to cinnolyl ketones and transformation of these compounds by oxidative cyclization led to the synthesis of the first representative of the [1,2,3]triazolo[1,5-b]cinnolinium ring system. Hetaryltrienes have been synthesized and reacted with Wittig reagents to result in new cyclizations. Multidrug resistance inhibitory compounds have been recognized among the derivatives synthesized in the frame of the present projec

Synthesis and pharmacological investigation of new N-hydroxyalkyl-2-aminophenothiazines exhibiting marked MDR inhibitory effect

Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g. 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicit

Activity of the efflux pump inhibitor SILA 421 against drug-resistant tuberculosis

Organosilicon compounds are efflux pump inhibitors with potency as an antituberculosis drug. Of the organisilicon compounds tested, SILA 421 has been shown to have a highest potency as an antituberculosis drug (1). It shares the common pathways for antimycobacterial killing with other efflux pump inhibitors: it revealed direct in vitro activity against M. tuberculosis (1), it has been shown to modify resistance by inhibiting mdr-1 efflux pumps and has shown to enhance killing of M. tuberculosis by macrophages (1)

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

Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin

Background:Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way.Methodology/Principal Findings:Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the μM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro.Conclusions/Significance:These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax. © 2013 Beitzinger et al

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