8-[2-Chloro-5-(trifluoromethyl)phenyl]-4H-[1,2,4]oxadiazolo-[3,4-c][1,4]benzoxazin-1-one

8-Bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one 1 (NS2028) reacts with [2-chloro-5-(trifluoromethyl)phenyl]boronic acid 2 (2 equiv), Pd(OAc)2 (10 mol%) and KOAc (4 equiv) in acetonitrile heated to ca. 110 °C (sealed tube) for 12 hours to give 8-[2-chloro-5-(trifluoromethyl)phenyl]-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one 4 in 64% yield

Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones : very strong correlation to pleurotin and thioredoxin reductase inhibition

The thioredoxin (Trx)-thioredoxin reductase (TrxR) system plays a key role in maintaining the cellular redox balance with Trx being over-expressed in a number of cancers. Inhibition of TrxR is an important strategy for anti-cancer drug discovery. The natural product pleurotin is a well-known irreversible inhibitor of TrxR. The cytotoxicity data for benzo[1,2,4]triazin-7-ones showed very strong correlation (Pearson correlation coefficients ~0.8) to pleurotin using National Cancer Institute COMPARE analysis. A new 3-CF3 substituted benzo[1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo[1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo[1,2,4]triazin-7-ones exhibited different types of reversible inhibition of TrxR, and cyclic voltammetry showed characteristic quasi-reversible redox processes. Cell viability studies indicated strong dependence of cytotoxicity on substitution at the 6-position of the 1,3-diphenylbenzo[1,2,4]triazin-7-one ring.F.A. thanks the Irish Research Council (IRC) for a Government of Ireland Postgraduate Scholarship for Martin Sweeney and College of Science, National University of Ireland Galway (NUI Galway) for a postgraduate scholarship for Robert Coyle. We thank the National Cancer Institute (USA), Development Therapeutic Program for providing us with a small quantity of pleurotin. P.A.K. thanks the Cyprus Research Promotion Foundation [Grants: NEAYPODOMH/NEKYP/0308/02 and YGEIA/BIOS/0308(BIE)/13], the University of Cyprus (Medium Sized Grant), and the following organizations in Cyprus for generous donations of chemicals and glassware: the State General Laboratory, the Agricultural Research Institute, the Ministry of Agriculture, Medochemie Ltd and Biotronics Ltd. Furthermore, P.A.K. thanks the A. G. Leventis Foundation for helping to establish the NMR facility in the University of Cyprus.2018-05-3

The suppression of Columnar π-Stacking in 3-Adamantyl-1-phenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl

3-Adamantyl-1-phenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl (4) crystallizes as chains of radicals where the spin bearing benzotriazinyl moieties are isolated from each other. Magnetic susceptibility studies in the 5–300 K temperature region indicate that radical 4 demonstrates typical paramagnetic behavior stemming from non-interacting S = ½ spins

1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors

Tetra­kis(1,3,4,6,7,9-hexa­aza-1H-phen­alen-6-ium) sodium(I) penta­kis(tetra­fluorido­borate)

In the title compound, Na+·4C7H5N6 +·5BF4 −, the Na+ ion lies on a fourfold rotation axis and one of the tetra­fluoridoborate ions lies on a site of symmetry . Each Na+ ion is surrounded by four symmetry-related tetra­fluoridoborate ions, and is eight-coordinated by F atoms, the Na⋯F separation being 2.3956 (15) or 2.4347 (17) Å. The hexa­azaphenalenium ring system is essentially planar. In the crystal structure, the cations and anions are linked into a three-dimensional network by N—H⋯N and C—H⋯F hydrogen bonds

Regioselective fluorination of 7-oxo-1,2,4-benzotriazines using selectfluor

7-Oxo-1,2,4-benzotriazines (benzo[1,2,4]triazin-7-ones) are reversible thioredoxin reductase inhibitors that exhibit very strong correlations to pleurotin. In this article, we provide the first synthesis of fluorinated derivatives. Fluorination using Selectfluor of benzo[1,2,4]triazin-7-ones occurs regioselectively and in high yield at the enamine-activated position. This electron N-lone pair activation overrides the activation/deactivation effects of some other substituents. The reaction time was significantly reduced with the use of microwave irradiation at 120 °C and 7 bar. The cytotoxicity and cyclic voltammetry measurements for 8-fluoro-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (2) are presented and compared with its synthetic precursor, 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (1a)

Anti-cancer activity of phenyl and pyrid-2-yl 1,3-substituted benzo[1,2,4]triazin-7-ones and stable free radical precursors

Cell viability studies for benzo[1,2,4]triazin-7-ones and 1,2,4-benzotriazinyl (Blatter-type) radical precursors are described with comparisons made with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). All of the stable free radicals were several orders of magnitude less cytotoxic than the benzo[1,2,4] triazin-7-ones. The synthesis and evaluation of two new pyrid-2-yl benzo[1,2,4] triazin-7-ones are described, where altering the 1,3-substitution from phenyl to pyrid-2-yl increased cytotoxicity against most cancer cell lines, as indicated using National Cancer Institute (NCI) one-dose testing. COMPARE analysis of five-dose testing data from the NCI showed very strong correlations to the naturally occurring anti-cancer compound pleurotin. COMPARE is program, which analyzes similarities in cytotoxicity data of compounds, and enables quantitative expression as Pearson correlation coefficients. Compounds were also evaluated using the independent MTT assay, which was compared with SRB assay data generated at the NCI