Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines)

In continuing our search of potent antimalarials based on 8-aminoquinoline structural framework, three series of novel bis(8-aminoquinolines) using convenient one to four steps synthetic procedures were synthesized. The bisquinolines were evaluated for in vitro antimalarial (Plasmodiumfalciparum), antileishmanial (Leishmaniadonovani), antimicrobial (a panel of pathogenic bacteria and fungi), cytotoxicity, ??-hematin inhibitory and methemoglobin (MetHb) formation activities. Several compounds exhibited superior antimalarial activities compared to parent drug primaquine. Selected compounds (44, 61 and 79) when tested for in vivo blood-schizontocidal antimalarial activity (Plasmodiumberghei) displayed potent blood-schizontocial activities. The bisquinolines showed negligible MetHb formation (0.2-1.2%) underlining their potential in the treatment of glucose-6-phosphate dehydrogenase deficient patients. The bisquinoline analogues (36, 73 and 79) also exhibited promising in vitro antileishmanial activity, and antimicrobial activities (43, 44 and 76) against a panel of pathogenic bacteria and fungi. The results of this study provide evidence that bis(8-aminoquinolines), like their bis(4-aminoquinolines) and artemisinin dimers counterparts, are a promising class of antimalarial agents.     

Synthesis, structure, spectroscopic properties, and electrochemical behavior of mixed ligand bis(β-ketoesterato)zirconium (IV) and -hafnium (IV) phthalocyaninates

The synthesis of new zirconium and hafnium mixed ligand phthalocyanine complexes PcM(β-ketoester)₂, where M-Zr (IV), Hf (IV); Pc - the dianion of phthalocyanine, and β-ketoester - the out planed ligand, is reported. The obtained complexes are characterized by ¹H NMR, IR, UV-Vis spectroscopy and cyclic voltammetry. ¹H NMR and elemental analysis confirm the substitution of two Cl atoms for two β-ketoester fragments to the central atom of the macrocycle. The data of ¹H NMR, UV-Vis spectroscopy have allowed us to conclude that two β-ketoester ligands are in the cis geometry to the phthalocyanine plane. X-ray crystallography for bis(isopropyl 3-oxobutanoato)hafnium(IV)phthalocyanine confirms this conclusion. The central macrocycle of the phthalocyanine ligand is not exactly planar (deviations from the least-square plane exceed 0.15 Å) and has the conformation of an essentially flattened crown. The Hf(1) atom is 1.349(3) above this least-square plane. Cyclic voltammetry investigation shows that the introduction of two β-ketoester ligands to the central atom of phthalocyanine complex leads to both chemical and electrochemical stabilization of the whole Pc system.     

Molecular structure,spectroscopic (FT-IR,FT-Raman,UV–vis), NBO,thermochemistry analysis of bis(thiourea)zinc(II) chloride crystals

The experimental and theoretical studies on the molecular structure and vibrational spectra of bis(thiourea)zinc(II) chloride (BTZC) crystals were investigated. The Fourier transform infrared, Fourier transform Raman and UV–vis spectra of BTZC were recorded. The molecular geometry and vibrational frequencies of BTZC in the ground state were calculated by using B3LYP with LANL2DZ as basis set. Comparison of the observed structural parameters of BTZC with single-crystal X-ray studies yields a good agreement. Vibrational analysis of the simultaneous IR and Raman activation of the Zn–Cl stretching mode in the molecule provides the evidence for the charge transfer interaction taking place within the molecule. The energy and oscillator strength are calculated by time-dependent density functional theory. The simulated spectra satisfactorily coincide with the experimental spectra.     

Ligand substitution reactions of bis(μ-acetato)dichlorodicarbonyldiiridium(II)

Seven diiridium(II) complexes were synthesized by ligand substitution reactions of [Ir₂(μ-O₂CMe)₂Cl₂(CO)₂] (1) and [Ir₂(μ-O₂CMe)₂Cl₂(CO)₂(py)₂] (2).The reaction of 2 with the silver salt of a less coordinating anion, AgSbF₆, gave a cationic complex [Ir₂(μ-O₂CMe)₂Cl(CO)₂(py)₃]SbF₆ (3).A tricarbonyl cationic complex [Ir₂(μ-O₂CMe)₂(CO)₃Cl(py)₂]SbF₆ (4) was obtained under a CO atmosphere.Complex 2 reacted with AgO₂CCF₃ to give [Ir₂(μ-O₂CMe)₂Cl(O₂CCF₃)(CO)₂(py)₂] (5) in toluene.[Ir₂(μ-hiq)₂(CO)₂Cl₂] (Hhiq = 1-hydroxyisoquinoline, 6) was synthesized by the bridging-ligand substitution of 1 with Hhiq.Its axial adducts [Ir₂(μ-hiq)₂Cl₂(CO)₂L₂] (L = Mepy (4-methylpyridine), 7 or PPh₃, 8) were synthesized by addition of the ligands to a suspension of 6.In the structures of 7 and 8, two iridium atoms are bridged by two hiq ligands in a head-to-tail arrangement.The reaction of 1 with Hmhp (2-hydroxy-4-methylpyridine) led to triply bridged [Ir₂(μ-mhp)₃(CO)₂Cl(Hmhp)] (9).In complex 9, all the mhp ligands bridge between the Ir atoms in a head-to-head manner.The Ir-Ir distances of 3, 4, 5, 7 and 8 are 2.6047(7), 2.6216(9), 2.5899(9), 2.5933(5) and 2.634(2) Å, respectively, which are similar to those observed in[Ir₂(μ-O₂CMe)₂Cl₂(CO)₂L₂]. The Ir-Ir distance of 2.5512(4) Å in 9 is shorter than in the other complexes.     

Ruthenium PCP–bis(phosphinite) pincer complexes

The reactions of [RuHCl(CO)(PPh₃)₃] with resorcinol bis(phosphinite) pincer ligands lead to complexes of the general formula [RuCl(PCP)(CO)(PPh₃)]; the crystal structure of one example has been determined. The structures of the bulky resorcinol 2-methyl-4,6-di-tert-butyl resorcinol and its mono-diisopropylphosphinite derivative were also determined. Reactions of [RuCl₂(PPh₃)₃] with resorcinol bis(phosphinite) ligands yield complexes of the type [RuCl(PCP)(PPh₃)], while the reaction of C₆H-2-Me-4,6-^tBu₂-1,3-(OPPh₂) with [RuHCl(CO)(PPh₃)₃] provides a PCP–pincer complex in which the ligand has undergone 2-methyl C–H activation.     

Interaction of ruthenium(III) chloride with bis(3,5-dimethylpyrazol-1-yl)methane oxyanions, potential κ-N,N,O scorpionates

When RuCl₃ was set to react with both bis(3,5-dimethylpyrazol-1-yl)acetate (bdmpza) and bis(3,5-dimethylpyrazol-1-yl)methane sulfonate (bdmpzsa) new ruthenium(II) complexes were obtained. The reduction of ruthenium(III) was studied by the NMR Evans method and spectrophotometrically, for 1:1 (Ru:L) molar ratios. Using the Evans method pseudo first-order constants of 2.5 × 10⁻³ s⁻¹ (bdmpzsa) and 3.9 × 10⁻³ s⁻¹ (bdmpza) were obtained in DMSO-d₆ (2% t-butanol) solutions. Spectrophotometrically the corresponding constants were also calculated: 1.1 × 10⁻³ s⁻¹ for bdmpzsa, and 1.6 × 10⁻³ s⁻¹, for bdmpza. Both ligands behave as κ³-N,N,O scorpionates but with a weak oxyanionic coordination to the metal, susceptible to be substituted with NEt₃ for a 1:1 molar ratio.     

DNA binding by Ru(II)–bis(bipyridine)–pteridinyl complexes

The interactions of five bis(bipyridyl) Ru(II) complexes of pteridinyl-phenanthroline ligands with calf thymus DNA have been studied. The pteridinyl extensions were selected to provide hydrogen-bonding patterns complementary to the purine and pyrimidine bases of DNA and RNA. The study includes three new complexes [Ru(bpy)(2)(L-pterin)](2+), [Ru(bpy)(2)(L-amino)](2+), and [Ru(bpy)(2)(L-diamino)](2+) (bpy is 2,2'-bipyridine and L-pterin, L-amino, and L-diamino are phenanthroline fused to pterin, 4-aminopteridine, and 2,4-diaminopteridine), two previously reported complexes [Ru(bpy)(2)(L-allox)](2+) and [Ru(bpy)(2)(L-Me(2)allox)](2+) (L-allox and L-Me(2)allox are phenanthroline fused to alloxazine and 1,3-dimethyalloxazine), the well-known DNA intercalator [Ru(bpy)(2)(dppz)](2+) (dppz is dipyridophenazine), and the negative control [Ru(bpy)(3)](2+). Reported are the syntheses of the three new Ru-pteridinyl complexes and the results of calf thymus DNA binding experiments as probed by absorption and fluorescence spectroscopy, viscometry, and thermal denaturation titrations. All Ru-pteridine complexes bind to DNA via an intercalative mode of comparable strength. Two of these four complexes-[Ru(bpy)(2)(L-pterin)](2+) and [Ru(bpy)(2)(L-allox)](2+)-exhibit biphasic DNA melting curves interpreted as reflecting exceptionally stable surface binding. Three new complexes-[Ru(bpy)(2)(L-diamino)](2+), [Ru(bpy)(2)(L-amino)](2) and [Ru(bpy)(2)(L-pterin)](2+)-behave as DNA molecular "light switches."     

Synthesis,Bioactivation and Anti-HIV Activity of 4-Acyloxybenzyl bis(Nucleosid-5′-yl) Phosphates

Abstract

4-Acyloxybenzyl bis(nucleosid-5′-yl) phosphates 7a-c and 9a-c were prepared as potential prodrugs of the anti-HIV nucleosides 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxyinosine (ddI) or their 5′-monophosphates.

The anti-HIV activities of these triesters were determined in two T-cell lines. In a C8166 cell line they displayed activities comparable to and in some cases superior to AZT, but they also exhibited an increase in cytotoxicity. In a thymidine kinase deficient JM T-cell line the activity was reduced but was still superior to AZT. In the presence of porcine liver carboxyesterase (PLCE), triester 7b biodegrades to the diester 10 which, with phosphodiesterase, gives initially AZT monophosphate 3 and AZT.     

Pleconax Rafin. — eine bis heute unbeachtete Silenoideen-Gattung (Caryophyllaceae)

Zusammenfassung Die zwischen den Arten der SektionConoimorpha Otth (UntergattungConocalyx Willk.) der GattungSilene und den übrigen Arten derselben Gattung sowie aller übrigen Gattungen der TribusLychnideae A. Br. existierenden Unterschiede berechtigen zur Abtrennung dieser Sektion (Untergattung) als selbständige GattungPleconax Rafin. Nach bisherigen Untersuchungen gehören in diese Gattung folgende Arten und Unterarten:Pleconax ammophila (Boiss.)ourková mit subsp.ammophila und subsp.carpathae (Chowdhuri)ourková,P. amphorina (Pomel)ourková,P. conica (L.)ourková mit subsp.conica und subsp.conomaritima (D.Jord. et P.Pan.)ourková,P. coniflora (Nees)ourková,P. conoidea (L.)ourková,P. lydia (Boiss.)ourková,P. macrodonta (Boiss.)ourková,P. multinervia (Wats.)ourková,P. sartorii (Boiss. etHeldr.)ourková,P. subconica (Friv. emend. D.Jord. et P.Pan.)ourková mit subsp.subconica und subsp.grisebachii (David.)ourková sowieP. tempskyana (Freyn etSint.)ourková. Die angeführten nomenklatorischen Umkombinationen werden hier zum ersten Male veröffentlicht.     

Structure–anti-MRSA activity relationship of macrocyclic bis(bibenzyl) derivatives

We synthesized a series of macrocyclic bis(bibenzyl) derivatives, including riccardin-, isoplagiochin- and marchantin-class structures, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The structure–activity relationships and the results of molecular dynamics simulations indicated that bis(bibenzyl)s with potent anti-MRSA activity commonly have a 4-hydroxyl group at the D-benzene ring and a 2-hydroxyl group at the C-benzene ring in the hydrophilic part of the molecule, and an unsubstituted phenoxyphenyl group in the hydrophobic part of the molecule containing the A–B-benzene rings. Pharmacological characterization of the bis(bibenzyl) derivatives and 2-phenoxyphenol fragment 25, previously proposed as the minimum structure of riccardin C 1 for anti-MRSA activity, indicated that they have different action mechanisms: the bis(bibenzyl)s are bactericidal, while 25 is bacteriostatic, showing only weak bactericidal activity.     

Synthesis, crystal structures and magnetic properties of two bis(μ-phenoxido)dicopper(II) complexes derived from reduced Schiff base ligands

Two phenoxido bridged dinuclear Cu(II) complexes, [Cu₂(L¹)₂(NCNCN)₂] (1) and [Cu₂(L²)₂(NCNCN)₂]·2H₂O (2) have been synthesized using the tridentate reduced Schiff-base ligands 2-[1-(2-dimethylamino-ethylamino)-ethyl]-phenol (HL¹) and 2-[1-(3-methylamino-propylamino)-ethyl]-phenol (HL²), respectively. The complexes have been characterized by X-ray structural analyses and variable-temperature magnetic susceptibility measurements. Both the complexes present a diphenoxido bridging Cu₂O₂ core. The geometries around metal atoms are intermediate between trigonal bipyramid and square pyramid with the Addison parameters (τ) = 0.57 and 0.49 for 1 and 2, respectively. Within the core the Cu–O–Cu angles are 99.15° and 103.51° and average Cu–O bond distances are 2.036 and 1.978 Å for compounds 1 and 2, respectively. These differences have marked effect on the magnetic properties of two compounds. Although both are antiferromagnetically coupled, the coupling constants (J = −184.3 and −478.4 cm⁻¹ for 1 and 2, respectively) differ appreciably.     

A new insulin-mimetic bis(allixinato)zinc(II) complex: structure–activity relationship of zinc(II) complexes

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)₂, exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)₂ as the leading compound, we examined the in vitro and in vivo structure–activity relationships of Zn(ma)₂ and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)₂, exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (logP) of the ligand, indicating that the activity of Zn(ma)₂-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)₂ and Zn(ma)₂ were then compared, and both complexes were found to normalize hyperglycemia in KK-A^y mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)₂ improved glucose tolerance in KK-A^y mice much more than did Zn(ma)₂, indicating that Zn(alx)₂ possesses greater in vivo anti-diabetic activity than Zn(ma)₂. In addition, Zn(alx)₂ improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK-A^y mice. On the basis of these observations, we conclude that the Zn(alx)₂ complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00775-004-0590-8     

Evolution alpiner Populationen vonEuphrasia (Scrophulariaceae): Die mittel- bis kleinblütigen,drüsenhaarigen Arten

A more precise taxonomic concept ofE. hirtella and its infraspecific synonymy is presented. Its diploid nature (2n = 22) is confirmed. Within the European area ofE. hirtella five different races may be recognised: typical, brandisii, capitulata, Rofan and Bretagne. Taxonomic rank is not yet attributed to these races. The heterogeneous taxonomic assembly E. drosocalyx is disentangled. The type refers to products of hybrid introgression ofE. rostkoviana-characters (long glandular hairs) intoE. minima.

Former contributions of this series areEhrendorfer & Vitek (1984) andGreilhuber & al. (1984).     

ESEEM and Mössbauer studies of the ferriheme model compound bis(3-aminopyrazole)tetraphenylporphyrinatoiron(III) chloride, [TPPFe(NH2PzH)2]Cl

A model heme complex, bis(3-aminopyrazole)tetraphenylporphinatoiron(III) chloride, [TPPFe (NH₂PzH)₂]Cl, for which the EPR g-values lead to a rhombicity V/Δ=1.2 if g _zz is the largest g-value, have been investigated by electron spin echo envelope modulation (ESEEM) and Mössbauer spectroscopies. The ESEEM studies focus on the proton sum frequency peaks at near twice the proton Larmor frequency. Analysis of the distant proton peak (mainly due to the pyrrole-H) at exactly twice the proton Larmor frequency shows conclusively that g _zz is aligned along the normal to the porphyrin plane, and thus the electron configuration is (d _xy )²(d _xz ,d _yz )³, with g _zz >g _yy >g _xx . This system is thus another violation to Taylor's "proper axis system" rule. The near proton (the α-H and N-H of the axial ligands) peaks provide distance information for those protons from the metal. Magnetic Mössbauer studies of the same complex confirm the (d _xy )²(d _xz ,d _yz )³ ground state and indicate that, as is the case for cytochrome P450_cam, A _xx is the largest magnitude A-value, and is negative in sign. Other low-spin iron(III) porphyrinates also have A _xx of negative sign, but usually the magnitude is only about half that of A _zz , which is always positive in sign.     

Isomer distribution and structure of (2,2′-biphenyldiolato)bis(β-diketonato)titanium(IV) complexes: A single crystal X-ray, solution NMR and computational study

Novel dichlorobis(β-diketonato)titanium(IV) Ti(C₆H₅COCHCOR)₂Cl₂ and (2,2′-biphenyldiolato)bis(β-diketonato)titanium(IV) Ti(C₆H₅COCHCOR)₂biphen complexes with R = CH₃, C₆H₅ and CF₃, are synthesized and characterized by X-ray crystallography and further physical methods. There is a good agreement between DFT calculated and experimental structural data. A configurational analysis gives a calculated isomer distribution that is in agreement with the experimental data derived from low temperature ¹H NMR spectroscopy. The Ti(C₆H₅COCHCOR)₂biphen complexes exhibit high hydrolytic stability.     

Biodistribution of bis[β-(N,N,N-trimethylamino)ethyl]selenide-75Se diiodide,a potential articular cartilage imaging agent

In an effort to develop a specific radiodiagnostic agent for articular cartilage imaging, we have investigated the biodistribution of bis[β-(N,N,N-trimethylamino)ethyl]selenide-⁷⁵Se diiodide (⁷⁵Se BISTAES) in rabbits. At an intravenous dose of 5 mg/kg, the greatest localization of the compound occurred in articular cartilage 15 min after injection. The compound was excreted rapidly in the urine. The results suggest that ⁷⁵Se BISTAES has potential clinical use as an articular cartilage imaging agent.