One-pot synthesis and negative ion mass spectrometric investigation of a densely functionalized cinnoline, 3-amino-5,7,8-trichloro-6-hydroxycinnoline-4-carbonitrile

Known densely substituted 3-amino-5,7,8-trichloro-6-hydroxycinnoline-4-carbonitrile was synthesized using a new synthetic protocol involving chloranil and malonitrile via quinone methide formation. This one-pot synthesis occurs under base mediated conditions in a polar medium. The method involves condensation of excess malononitrile with chloranil in ethanol at reflux to 2-(2,4,5-trichloro-3-hydroxy-6-oxocyclohexa-2,4-dien-1-ylidene) malononitrile. This is an atom efficient, simple and effective procedure for the preparation of a highly substituted cinnoline that can serve as a relay to antimalarial prototypes

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor in vivo Using Fluorinated Bisquinolines

Antimalarials can interact with heme covalently, by - interactions or hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen due to electronic rather than steric factors. In gas phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF3 group occupied the 7-position. Hence, trifluromethyl groups buttressing quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/6- 31+G*) and crystal structure of (±)-trans-N1,N2-bis-(2,8-ditrifluoromethylquinolin-4- yl)cyclohexane-1,2-diamine were used to reveal preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III)state which has important implications for the future rational design of 4- aminoquinoline antimalarials

Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials

A series of novel, homologous compounds possessing the general formula N1‐Nn‐bis(2,6‐dinitro‐4‐trifluormethylphenyl)‐1,n‐diamino alkanes (where n=4, 6, 10 or 12), were designed to probe inter‐ and intra‐ binding site dimensions in malarial parasite (Plasmodium) tubulin. Various crystal structures, including chloralin and trifluralin, an isopropyl dimer, and 2,6‐dinitro‐4‐trifluoromethyl‐phenylamine, were determined. Dinitroanilines, when soluble, were evaluated both in culture and in vivo. Trifluralin was up to 2‐fold more active than chloralin against cultured parasites. The isopropyl dimer was water soluble (>5 mM) and revealed activity superior to that of chloralin in culture. The effects of selected dinitroanilines upon the mitotic microtubular structures of Plasmodium, the putative target of these dinitroanilines, were also determined. Electronic properties of the molecules were calculated using DFT (B3LYP/6‐31+G* level) to ascertain whether incorporation of such a pharmacophore could allow both QSAR and rational development of more selectively toxic antiparasitic agents

Purpurogallin-A heme binding component of oak galls

Recently, it has been shown that Purpurogallin (PPG), an orange benztropolone constituent of oak galls and its derivative, CU-CPT22, can compete with the binding of the specific lipoprotein ligand to toll-like receptors (TLRs), which are type I transmembrane proteins. These recognize pathogen-derived macromolecules that play a key role in the innate immune system. This system provides an attractive target for the treatment of various immune disorders. Notably, PPG also interacts with various metals and its mode of action against HIV in vitro may involve inhibition of metal containing integrases. In the current study, an optimised synthesis of PPG is presented together with its gas phase behaviour (probed by mass spectrometry) as well as its redox behaviour with porphyrins such as heme. This interaction may also explain its effects at metal containing integrases within HIV in vitro as well as its action during processing of iron complexes within Plasmodia. This compound could serve as a novel prototype for the synthesis of novel redox active antimalarials

Trapping virtual pores by crystal retro-engineering

Stable guest-free porous molecular crystals are uncommon. By contrast, organic molecular crystals with guest-occupied cavities are frequently observed, but these cavities tend to be unstable and collapse on removal of the guests—this feature has been referred to as ‘virtual porosity’. Here, we show how we have trapped the virtual porosity in an unstable low-density organic molecular crystal by introducing a second molecule that matches the size and shape of the unstable voids. We call this strategy ‘retro-engineering’ because it parallels organic retrosynthetic analysis, and it allows the metastable two-dimensional hexagonal pore structure in an organic solvate to be trapped in a binary cocrystal. Unlike the crystal with virtual porosity, the cocrystal material remains single crystalline and porous after removal of guests by heating

Anion selectivity properties of ruthenium(II) tris(5,5 '-diamide-2,2 '-bipyridine) receptors dictated by solvent and amide substituent

The ratio of the dichloromethane-methanol solvent mixture medium and nature of the receptor amide substituent critically dictates chloride vs. nitrate selectivity properties of new ruthenium(II) tris(5,5′-diamide-2,2′-bipyridine) receptors

Alkali metal cation cooperative anion recognition by heteroditopic bis(calix[4]arene) rhenium(I) bipyridyl and ferrocene receptor molecules

New heteroditopic bis(calix[4]arene) rhenium(i) bipyndyl (L 1, L 2) and ferrocene (L 4) receptor molecules have been prepared and shown to bind a variety of anions at the upper rim and alkali metal cations at the lower rim. Proton NMR anion titration studies reveal the strength and selectivity of anion binding was dependent upon the presence of the calix[4]arene moieties and nature of the bridging group with the preorganised receptors L 1 and L 2 forming strong complexes in deuterated DMSO solutions. With L 1, L 2 and L 4 co-bound lithium, sodium and potassium cations were found to significantly enhance the strength of iodide binding in acetonitrile solutions with the largest positive cooperative binding efTect observed with L 2 and sodium cations. Cyclic voltammetric investigations revealed L 4 to electrochemically recognise carboxylate and halide anions. In the presence of lithium cations the electrochemical response of L 4 to bromide anions was significantly amplified. © The Royal Society of Chemistry 2000

Metal-directed assembly of polyferrocenyl transition metal dithiocarbamate macrocyclic molecular boxes

Novel redox-active polyferrocenyl transition metal dithiocarbamate macrocyclic molecular boxes (10a-c), (11) and (12a-c) are synthesised by reaction of the respective ferrocenyl secondary amines, namely, N,N′-bis(ferrocenemethyl)-1,3-bis(aminomethyl)benzene (4), 1,1′-bis(benzylaminomethyl)ferrocene (8) and 1,1′-bis((ferrocenylmethyl)aminomethyl)ferrocene (9) with carbon disulfide, potassium hydroxide and transition metal (zinc, copper, nickel) acetate in high yields (52-82%) and characterised by spectroscopic and electrochemical techniques. The single-crystal X-ray structure of 10a shows that each zinc atom is in tetrahedral geometry, being bonded to two dithiocarbamate ligands with Zn-S distances 2.32(1)-2.44(1) Å. © 2001 Elsevier Science B.V