Gordana Pavlović

Novel cyano- and amidinobenzothiazole derivatives: synthesis, antitumor evaluation, and X-ray and quantitative structure-activity relationship (QSAR) analysis.

Synthesis of a series of novel cyano- and amidinobenzothiazole derivatives 3-31 is described. All studied amidino derivatives showed noticeable antiproliferative effect on several tumor cell lines. Cyano derivatives 11-17 showed considerably less pronounced activity because of their poor solubility in aqueous cell culture medium, which was confirmed by the principal components (PC) analysis. Compounds 21, 22, 28, and 29 were tested for their effects on the cell cycle and apoptosis, whereby 22 and 29, having methyl group at the C-6 position in pyridine ring, showed drastic cell cycle perturbations that were both concentration- and time-dependent and induced apoptosis. The QSAR modeling, based on the physicochemical descriptors and on the measured biological activities, indicated the relevance of molecular polarizability and particular distribution of pharmacophores on the molecular surface for activity. In conclusion, benzothiazoles containing either isopropylamidino or imidazolyl groups will be considered as starting compounds for further investigation on lead identification.

Mercury(II) complexes of heterocyclic thiones. Part 1. Preparation of 1:2 complexes of mercury(II) halides and pseudohalides with 3, 4, 5, 6-tetrahydropyrimidine-2-thione. X-ray, thermal analysis and NMR studies

A series of complexes HgX_2(H_4pymtH)_2 (X = Cl, Br, I, SCN, CN ; H_4pymtH = 3, 4, 5, 6-tetrahydropyrimidine-2-thione) has been obtained by the reaction of H_4pymtH with mercury(II) halides and pseudohalides in the 2:1 molar ratio. X-ray diffraction studies revealed tetrahedral coordination of mercury with S-bound H4pymtH. The exception is Hg(CN)_2(H_4pymtH)_2 where the coordination is 2+2 with two strongly bound CN� {; ; ; ; ; ligands and weaker Hg� {; ; ; ; ; S bonds with H4pymtH. One- and twodimensional 1^H and 13^C NMR measurements in dimethylsulfoxide solution confirmed the complexation of mercury to sulphur. The greatest complexation effects on chemical shifts were detected for the C-2, C-5 and H-1, 3 atoms i.e. two, four and five bonds away from mercury atom. The complexation effects in Hg(SCN)_2(H_4pymtH)_2 and Hg(CN)_2(H_4pymtH)_2 are in agreement with the strongest intramolecular H-bonding in the former and the weakest Hg-S bonds in the latter as compared to other complexes here.

Benzimidazole derivatives related to 2,3-acrylonitriles, benzimidazo[1,2-a]quinolines and fluorenes: Synthesis, antitumor evaluation in vitro and crystal structure determination

A synthesis and biological evaluation of new benzimidazole derivatives, related to 2,3-disubstituted acrylonitriles, benzimidazo[1,2-a]quinoline-6-carbonitriles and heteroaromatic fluorenes was described. The molecular and crystal structures of three compounds 4, 16 and 17 reveal that non-fused fluoro derivative, 4, deviates from planarity by 13.11(2) degrees, while fused methyl, 16, and fluoro, 17, derivatives are planar within 4 degrees exhibiting a planar aromatic surface capable to intercalate into double-stranded DNA. Compound 4 exists as E-isomer. The crystal structures confirmed that hydrogen bonding patterns are characterized dominantly by the weak C-H...N(F) bonds, except in the case of 4 where the presence of ethanol molecule of crystallization resulted in the N-H...O and O-H...N hydrogen bonds formation. In the crystal structures of 16 and 17 cyano group participates in hydrogen bonding formation, while in 4 this is not the case. All compounds, except 16 and 14 exerted pronounced antiproliferative activity on five tumor cell lines, whereby 2-benzimidazolyl-3-N-methylpyrolyl-acrylonitrile 13 and its fused analogue 23 exerted the highest activity on all cell lines (IC50=0.8-30 microM) and showed a special selectivity toward HeLa cells. There is no major difference in the biological activity between non-fused and fused analogues. Similarly, all compounds showed significant interaction with ct-DNA, supporting the fact that their antitumor activity could partially be the consequence of DNA-binding. The cyano moiety is important for the activity, but not the selectivity of tested compounds.

Mercury(II) compounds with 1,3-imidazole-2-thione and its 1-methyl analogue. Preparative and NMR spectroscopic studies. The crystal structures of di-μ-iodo-bis[iodo(1,3-imidazolium-2-thiolato-S)mercury(II)], bis[bromo(1,3-imidazolium-2-thiolato-S)]mercury(II) and bis[μ-(1-N-methyl-1,3-imidazole-2-thiolato-S)]mercury(II)

Abstract A series of mercury(II) compounds of the empirical formulae HgX2L, and HgX2L2 (X=Cl−, Br−, I−, SCN−; L=imtH2, meimtH; imtH2=1,3-imidazole-2-thione, meimtH=1-methyl-1,3-imidazole-2-thione) has been obtained by the reaction of mercury(II) salts and 1,3-imidazole-2-thione and 1-methyl-1,3-imidazole-2-thione, respectively. Mercury(II) acetate yields HgL2 complexes where L=imtH−, meimt−. The isolated compounds have been characterised by elemental chemical analysis, IR and 1H and 13C NMR spectroscopy. Complexation effects on chemical shifts in 1H and 13C spectra were shown to be a reliable probe for distinguishing HgX2L and HgX2L2 complexes. In the former molecules the thione carbon (C-2) is shielded up to 3.0 ppm and the thioamide protons (NH) are deshielded up to 0.5 ppm, as compared to the corresponding atoms in the latter molecules. In all complexes the 13C complexation shift at C-2 decreases with decreasing electronegativity of the halogen atom (X), indicating the corresponding increase in π-character of the C-2–S bond. The crystal structures of HgI2(imtH2), HgBr2(imtH2)2 and Hg(meimt)2 have been determined by X-ray diffractometry and revealed S-bound imtH2 in the iodo and bromo complex, while in Hg(meimt)2 the ligand acts as bridging with stronger S and weaker N bonds.

The first example of coexistence of the ketoamino–enolimino forms of diamine Schiff base naphthaldimine parts: the crystal and molecular structure of N,N′-bis(1-naphthaldimine)-o-phenylenediamine chloroform (1/1) solvate at 200 K

Abstract The N,N′-bis(1-naphthaldimine)-o-phenylenediamine chloroform (1/1) solvate was prepared from 2-hydroxy-1-naphthaldehyde and 1,2-phenylenediamine in a 2:1 molar ratio and characterized in solution and in the solid state using X-ray single crystal diffractometry, IR and NMR spectroscopy. The structure consists of three structural fragments: two planar, but not coplanar naphthaldimine moieties linked by phenyl ring that derived from o-phenylenediamine. The naphthaldimine fragments contain, along with naphthalene rings, six-membered pseudoaromatic chelate rings, formed by O H⋯N or N H⋯O intramolecular hydrogen bonds that retain planarity of the aldimine fragments. This structure is the first example of the coexistence of two different hydrogen bond types within Schiff base molecule, i.e. the one naphthaldimine part exists in the enolimino form (O H⋯N hydrogen bond of 2.5487(17) A), while the other exists in the ketoamino form (N H⋯O hydrogen bond of 2.5706(19) A). The different hydrogen bond types are related to the different π-electron density distribution within two parts. The amino hydrogen atom forms three-center intramolecular hydrogen bond, which includes the N H⋯O hydrogen bond of 2.5706(19) A within the ketoamino part and also the N H⋯N bond of 2.7238(18) A linking two naphthaldimine fragments of the molecule. IR and 1H and 13C NMR spectral data are consistent with revealed molecular structure in the solid state.

Ferrocene compounds ☆: Part XXXIII. Synthesis and characterization of amino acids containing skeletal 1,1′-ferrocenylene unit

Abstract The syntheses of 1′-(3-aminopropyl)ferrocene-1-carboxylic acid (7), 1′-amino-1-ferrocenebutyric acid (14) and their derivatives are reported. Reactions of 1′-methoxycarbonyl-1-ferrocenebutyric acid (3) or methyl 1′-carboxy-1-ferrocenebutyrate (10) with ethyl chloroformate/triethylamine/sodium azide gave methyl 1′-(3-azidocarbonylpropyl)ferrocene-1-carboxylate (4) and methyl 1′-azidocarbonyl-1-ferrocenebutyrate (11). These azides were rearranged by heating in acetic anhydride and hydrolyzed into N-acetyl derivatives of 7 and 14. The crucial intermediates 4 and 11 were transformed by the action of t-BuOH into Boc-7 and Boc-14. The crystal and molecular structures of the intermediates methyl 1′-(3-acetamidopropyl)ferrocene-1-carboxylate (5) and tert-butyl 1′-(3-methoxycarbonylpropyl)-1-ferrocenecarbamate (15) have been determined by the single crystal X-ray analysis. Compound 5 crystallizes in two polymorphic forms (5a and 5b); one of them (5b) contains two crystallographically independent molecules. The molecules 5a and 5b differentiate only in the conformation of (CH2)3NHAc part of the molecules exhibiting conformational polymorphism. The crystal structure is dominated by the intermolecular hydrogens bonds of NH⋯O type (2.820(1)–2.840(2) A) linking molecules into endless chains in all three structures. The chains are further interconnected by the CH⋯O hydrogen bonds (3.483(1)–3.267(2) A) in 5a and 15, but not in 5b.The structural features of 5 and 15 determined by the single crystal X-ray analysis, reveal existence of intermolecular hydrogens bonds of NH⋯O type (2.820(1)–2.840(2) A).

Preparation and characterization of the 1:1 adducts of mercury(II) halides with N-benzyl- and N-p-tolyl-2-oxo-1-naphthylideneamine. The crystal and molecular structures of two isostructural di-μ-halo-bis[halo(N-benzyl-2-oxo-1-naphthylideneamine)mercury(II)] adducts (halo=chloro, bromo)

Abstract A series of adducts of the type HgX2(C18H15NO) [X=Cl−, Br−, I−; C18H15NO=N-benzyl-2-oxo-1-naphthylideneamine (bznapH), N-p-tolyl-2-oxo-1-naphthylideneamine (tolnapH)] was obtained by refluxing the solution of the corresponding mercury(II) salt and the related naphthylideneamine in absolute ethanol in a 1:1 molar ratio. The adducts di-μ-chloro-bis[chloro(N-benzyl-2-oxo-1-naphthylideneamine)mercury(II)], HgCl2(bznapH) (1) and di-μ-bromo-bis[bromo(N-benzyl-2-oxo-1-naphthylideneamine)mercury(II)], HgBr2(bznapH) (2) are isostructural with the effective coordination of mercury being 2+2. The HgX2 moieties are retained in the adducts and contain two covalently linked chlorine [2.321(3) and 2.299(3) A in 1] or bromine atoms [2.446(1) and 2.422(1) A in 2]. These moieties are linked mutually by additional contacts of bridging halogen atoms [Hg⋯μX 3.189(2) and 3.298(1) A in 1 and 2, respectively], forming non-planar dimeric Hg2X4 units. Each Schiff-base ligand has a strong contact with mercury through the oxygen atom [Hg⋯O 2.392(5) and 2.410(5) A in 1 and 2, respectively]. The Schiff-base ligand in 1 and 2 exists as the ketoamino (quinoid) tautomeric structure with an intramolecular hydrogen bond of the NH⋯O type [2.58(1) and 2.59(1) A in 1 and 2, respectively]. On the contrary, in DMSO solution, due to dissociation of adducts 1–6, the enolimino (benzenoid) tautomeric form of the Schiff bases was established by NMR spectroscopy.

Transition metal complexes with the thiosemicarbazide-based ligands—XVII. The complexes of MoO2(II) with salicylaldehyde S-methylisothiosemicarbazone (H2L), MoO2(L)S (S Py, MeOH, EtOH). Crystal structures of Py and MeOH complexes

Abstract The reaction of MoO2(acac)2 with salicylaldehyde S-methylisothiosemicarbazone (H2L) yielded the complexes MoO2(L)S [S  Py (A), MeOH (B), EtOH (C)]. All of these complexes have the cis-dioxo octahedral configuration, which for complexes A and B has been confirmed by X-ray analysis. Crystal data for A are: C14H14MoN4O3S, Mr = 414.29, triclinic, P 1 , Z = 2, a = 7.826(3), b = 10.798(3), c = 11.261(2) A, α = 116.55(2)°, β = 104.56(1)°, γ = 80.55(2)°, V = 822.4(4) A3, Dx = 1.67 g cm−3, μ(Mo-Kα) = 9.174 cm−1, F(000) = 416, final R = 0.0332 for 3092 reflections. Crystal data for B: C10H13MoN3 O4S, Mr = 367.23, triclinic, P 1 , Z = 2, a = 9.553(5), b = 8.217(3), c = 9.551(2) A, α = 104.74(2)°, β = 107.90(2)°, γ = 90.72(2)°, V = 686.6(5) A3, Dx = 1.78 g cm−3, μ(Mo-Kα) = 10.898 cm−1, F(000) = 368, final R = 0.0221 for 3448 reflections. The octahedral coordination about each Mo atom consists of two cis oxo-oxygen atoms, one oxygen and two nitrogen atoms from the dianion meridional chelate ligand (L2−) and a nitrogen or oxygen atom from Py and MeOH, respectively. The compounds have been characterized by elemental analysis, IR spectra and molar conductivity.

Purification of electroplating wastewaters utilizing waste by-product ferrous sulfate and wood fly ash.

Abstract A new procedure for electroplating wastewater treatment using waste by-product (ferrous-sulfate) and waste (wood fly ash) is presented. Ferrous-sulfate was employed for Cr(VI) reduction whereas neutralization and heavy metal removal from electroplating wastewaters was performed using wood fly ash. Heavy metal removal efficiency varied from 97.5% for Cu to 99.973% for Zn. Satisfying results can be achieved already at the pH 8. The method is suitable for the purposes of wastewater treatment and disposal in compliance with environmental laws. Furthermore, it is technically simple, cost-efficient and requires less space compared to the classical methodology. According to the composition of its water extractable fraction remaining waste ash could be safely deposited on domestic waste repositories.

Mercury(II) Complexes with Heterocyclic Thiones- Preparation and Characterization of the 1:1 and 1:2 Mercury(II) Complexes with Benzo-1, 3-imidazole-2-thione

A series of complexes HgX2 (bzimtH_2 ) and HgX_2 (bzimtH2)_2 (X =Cl^- , Br^- , I^- , SCN^- ; bzimtH_2 = benzo-1, 3-imidazole-2-thione) was obtained by reaction of the mercury(II) salts with benzo-1, 3-imidazole-2-thione in the appropriate molar ratio(1:1 or 1:2). Hg(bzimtH)_2 was obtained by the deprotonation of bzimtH_2 with mercury(II) acetate (irrespective of the molar ratio of the reactants). The complexes were characterised by chemical and thermal analysis, IR, 1^H, and 13^C NMR spectroscopy, and some [HgX_2(bzimtH_2), X =I^- and HgX_2(bzimtH_2)_2 , X =I^- and SCN^-] by X-ray single crystal diffractometry. 1^H and 13^C NMR spectroscopic measurements in dimethyl sulphoxide revealed that the sulphur atom is coordinated to the mercury centre. The greatest complexation effects on the chemical shifts were observed for the thione carbon atom and thioamide proton. The crystal structures of HgI_2(bzimtH_2)_2 and Hg(SCN)_2 (bzimtH_2)_2 ˇC_2H_5OH consist of discrete monomeric molecules with halide or pseudohalide donor atoms and thione sulphur atoms tetrahedrally coordinated to the mercury atom. The structure of HgI2 (bzimtH2 )is polymeric with a trigonal bipyramidal 3 + 2 coordination geometry around the mercury atom. Polymerisation occurs through HgˇˇˇI interactions with neighbouring molecules. The distribution of the pi-electron density in bzimtH_2 corresponds to the thioketo tautomeric form in the solid state, and also in the DMSO solution of the complexes. Intermolecular hydrogen bonds of the type N-HˇˇˇN, N-HˇˇˇS and N-HˇˇˇI are observed.