Dicationic Compounds Research Articles

Novel Ionic Liquid Compound Act as Sweet Corrosion Inhibitors for X-65 Carbon Tubing Steel: Experimental and Theoretical Studies

Three novel ionic liquid-based imidazolium gemini dicationic compounds (I, II and III) synthesized, characterized by FTIR and 1HNMR spectroscopic techniques and were evaluated as corrosion inhibitors for X-65 carbon tubing steel in oil well formation water under sweet environment by electrochemical techniques. The inhibition effect was found effected by the inhibitor concentration and the spacer length in their chemical structure. Adsorption of the investigated inhibitors obeyed Langmuir isotherm which shows a mixed type of adsorption mechanism. SEM and EDX techniques investigate the surface morphology and show less damage for inhibited sample. Finally, theoretical calculations study the influence of inhibitors structure on the inhibition efficacy to give a hypothetical interpretation about inhibitors performance.

In Vitro , Ex Vivo , and In Vivo Activities of Diamidines against Trypanosoma congolense and Trypanosoma vivax

African animal trypanosomosis (AAT) is caused by the tsetse fly-transmitted protozoans Trypanosoma congolense and T. vivax and leads to huge agricultural losses throughout sub-Saharan Africa. Three drugs are available to treat nagana in cattle (diminazene diaceturate, homidium chloride, and isometamidium chloride). With increasing reports of drug-resistant populations, new molecules should be investigated as potential candidates to combat nagana. Dicationic compounds have been demonstrated to have excellent efficacy against different kinetoplastid parasites. This study therefore evaluated the activities of 37 diamidines, using in vitro and ex vivo drug sensitivity assays. The 50% inhibitory concentrations obtained ranged from 0.007 to 0.562 μg/ml for T. congolense and from 0.019 to 0.607 μg/ml for T. vivax On the basis of these promising results, 33 of these diamidines were further examined using in vivo mouse models of infection. Minimal curative doses of 1.25 mg/kg of body weight for both T. congolense- and T. vivax-infected mice were seen when the diamidines were administered intraperitoneally (i.p.) over 4 consecutive days. From these observations, 15 of these 33 diamidines were then further tested in vivo, using a single bolus dose for administration. The total cure of mice infected with T. congolense and T. vivax was seen with single i.p. doses of 5 and 2.5 mg/kg, respectively. This study identified a selection of diamidines which could be considered lead compounds for the treatment of nagana.

Redox Potential and Electronic Structure Effects of Proximal Nonredox Active Cations in Cobalt Schiff Base Complexes.

Redox inactive Lewis acidic cations are thought to facilitate the reactivity of metalloenzymes and their synthetic analogues by tuning the redox potential and electronic structure of the redox active site. To explore and quantify this effect, we report the synthesis and characterization of a series of tetradentate Schiff base ligands appended with a crown-like cavity incorporating a series of alkali and alkaline earth Lewis acidic cations (1M, where M = Na+, K+, Ca2+, Sr2+, and Ba2+) and their corresponding Co(II) complexes (2M). Cyclic voltammetry of the 2M complexes revealed that the Co(II/I) redox potentials are 130 mV more positive for M = Na+ and K+ and 230-270 mV more positive for M = Ca2+, Sr2+, and Ba2+compared to Co(salen-OMe) (salen-OMe = N,N'-bis(3-methoxysalicylidene)-1,2-diaminoethane), which lacks a proximal cation. The Co(II/I) redox potentials for the dicationic compounds also correlate with the ionic size and Lewis acidity of the alkaline metal. Electronic absorption and infrared spectra indicate that the Lewis acid cations have a minor effect on the electronic structure of the Co(II) ion, which suggests the shifts in redox potential are primarily a result of electrostatic effects due to the cationic charge.

Synthesis and potent antiprotozoal activity of mono/di amidino 2-anilinobenzimidazoles versus Plasmodium falciparum and Trypanosoma brucei rhodesiense

A series of mono and dicationic new 2-anilinobenzimidazole carboxamidines were prepared in a four step process starting from 4-amino-3-nitrobenzonitrile and corresponding o-phenylenediamines. Their antiparasitic activity against Plasmodium falciparum (P. falciparum) and Trypanosoma brucei rhodesiense (T.b. rhodesiense) were evaluated in vitro. Some of the dicationic compounds (10,12,14) showed equal or very close activity against T.b. rhodesiense with melarsoprol and also showed promising activity against P. falciparum as compared to chloroquine. Among the monocationic derivatives compound 21 exhibited best inhibitory activity against P. falciparum.

Using Dicationic Ion-Pairing Compounds To Enhance the Single Cell Mass Spectrometry Analysis Using the Single-Probe: A Microscale Sampling and Ionization Device.

A unique mass spectrometry (MS) method has been developed to determine the negatively charged species in live single cells using the positive ionization mode. The method utilizes dicationic ion-pairing compounds through the miniaturized multifunctional device, the single-probe, for reactive MS analysis of live single cells under ambient conditions. In this study, two dicationic reagents, 1,5-pentanediyl-bis(1-butylpyrrolidinium) difluoride (C5(bpyr)2F2) and 1,3-propanediyl-bis(tripropylphosphonium) difluoride (C3(triprp)2F2), were added in the solvent and introduced into single cells to extract cellular contents for real-time MS analysis. The negatively charged (1- charged) cell metabolites, which form stable ion-pairs (1+ charged) with dicationic compounds (2+ charged), were detected in positive ionization mode with a greatly improved sensitivity. We have tentatively assigned 192 and 70 negatively charged common metabolites as adducts with (C5(bpyr)2F2) and (C3(triprp)2F2), respectively, in three separate SCMS experiments in the positive ion mode. The total number of tentatively assigned metabolites is 285 for C5(bpyr)2F2 and 143 for C3(triprp)2F2. In addition, the selectivity of dicationic compounds in the complex formation allows for the discrimination of overlapped ion peaks with low abundances. Tandem (MS/MS) analyses at the single cell level were conducted for selected adduct ions for molecular identification. The utilization of the dicationic compounds in the single-probe MS technique provides an effective approach to the detection of a broad range of metabolites at the single cell level.

Inhibition of Spinal Ca(2+)-Permeable AMPA Receptors with Dicationic Compounds Alleviates Persistent Inflammatory Pain without Adverse Effects.

Upregulation of Ca2+-permeable AMPA receptors (CP-AMPARs) in the dorsal horn (DH) neurons of the spinal cord has been causally linked to the maintenance of persistent inflammatory pain. Therefore, inhibition of CP-AMPARs could potentially alleviate an, otherwise, poorly treatable chronic pain. However, a loss of CP-AMPARs could produce considerable side effects because of the crucial role of CP-AMPARs in synaptic plasticity. Here we have tested whether the inhibition of spinal CP-AMPARs with dicationic compounds, the open-channel antagonists acting in an activity-dependent manner, can relieve inflammatory pain without adverse effects being developed. Dicationic compounds, N1-(1-phenylcyclohexyl)pentane-1,5-diaminium bromide (IEM-1925) and 1-trimethylammonio-5-1-adamantane-methyl-ammoniopentane dibromide (IEM-1460) were applied intrathecally (i.t.) as a post-treatment for inflammatory pain in the model of complete Freund’s adjuvant (CFA)-induced long-lasting peripheral inflammation. The capability of dicationic compounds to ameliorate inflammatory pain was tested in rats in vivo using the Hargreaves, the von Frey and the open-field tests. Treatment with IEM-1460 or IEM-1925 resulted in profound alleviation of inflammatory pain. The pain relief appeared shortly after compound administration. The effects were concentration-dependent, displaying a high potency of dicationic compounds for alleviation of inflammatory hyperalgesia in the micromolar range, for both acute and long-lasting responses. The period of pain maintenance was shortened following treatment. Treatment with IEM-1460 or IEM-1925 changed neither thermal and mechanical basal sensitivities nor animal locomotion, suggesting that inhibition of CP-AMPARs with dicationic compounds does not give rise to detectable side effects. Thus, the ability of dicationic compounds to alleviate persistent inflammatory pain may provide new routes in the treatment of chronic pain.

High-Resolution Ambient MS Imaging of Negative Ions in Positive Ion Mode: Using Dicationic Reagents with the Single-Probe.

We have used the Single-probe, a miniaturized sampling device utilizing in-situ surface microextraction for ambient mass spectrometry (MS) analysis, for the high resolution MS imaging (MSI) of negatively charged species in the positive ionization mode. Two dicationic compounds, 1,5-pentanediyl-bis(1-butylpyrrolidinium) difluoride [C5(bpyr)2F2] and 1,3-propanediyl-bis(tripropylphosphonium) difluoride [C3(triprp)2F2], were added into the sampling solvent to form 1+ charged adducts with the negatively charged species extracted from tissues. We were able to detect 526 and 322 negatively charged species this way using [C5(bpyr)2F2] and [C3(triprp)2F2], respectively, including oleic acid, arachidonic acid, and several species of phosphatidic acid, phosphoethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and others. In conjunction with the identification of the non-adduct cations, we have tentatively identified a total number of 1200 and 828 metabolites from mouse brain sections using [C5(bpyr)2F2] and [C3(triprp)2F2], respectively, through high mass accuracy measurements (mass error <5 ppm); MS/MS analyses were also performed to verify the identity of selected species. In addition to the high mass accuracy measurement, we were able to generate high spatial resolution (~17 μm) MS images of mouse brain sections. Our study demonstrated that utilization of dicationic compounds in the surface microextraction with the Single-probe device can perform high mass and spatial resolution ambient MSI measurements of broader types of compounds in tissues. Other reagents can be potentially used with the Single-probe device for a variety of reactive MSI studies to enable the analysis of species that are previously intractable.

Differential influence of 7 cations on 16 non-competitive NMDA receptor blockers.

The specific binding of the NMDA receptor (NR) channel ligand [(3)H]MK-801 to rat brain membranes is sensitive to positively charged buffer ingredients as to tris(hydroxymethyl)aminomethane (Tris), to Na(+), or to protons. Here we demonstrate that 16 non-competitive NR antagonists, including 5 long-chain diamines, classical NR channel blockers and several less known compounds, differ widely in their sensitivities to cationic buffer constituents. Although chemically distinguished either as extended di-cationic or as compact mono-cationic, their sensitivities to cationic buffer ingredients did not suggest this grouping. While the di-cationic compounds are known for their sensitivity to spermine (polyamine inverse agonists), also some of the mono-cationic blockers exhibited this feature. They might share as common target a recently described negatively charged extracellular GluN1/GluN2B interface.

Fluorescent Pyrene‐Based Bis‐azole Compounds: Synthesis and Photophysical Analysis

A rational synthetic procedure for the preparation of a series of pyrene-based neutral and dicationic bis-azole compounds is reported. The method allows the tailored design of pyrene-based azoles with different substituents at the nitrogen atoms of the heterocycles, for which the relative conformation of the resulting bis-azoles can be easily controlled. The bis-azoliums were used for the preparation of the related diplatinum complexes by reaction with [{Pt(ppy)(μ-Cl)2 }2 ] (ppy=2-phenylpyridinate). The X-ray molecular structure of one of the resulting compounds, a diplatinum(II) bis(N-heterocyclic carbene) complex, is described. Studies on the photophysical properties of all new species are described. The emission of the bis-azole-based compounds seems to be independent of their substitution patterns, which basically indicates that physical properties such as solubility, melting point, and viscosity can be fine-tuned while maintaining the luminescence properties. Finally, the energies associated with the HOMO and LUMO levels suggest that this family provides versatility to match the energy levels of a wide range of host materials, which is important for the preparation of organic light-emitting devices.

Structural features of neutral and cationic cyclams

Dicationic compounds of general formula [1,8-R2-1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane]X2, where R = H, Me or Bn' and X is a halogen counterion were obtained by reactions of 1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane with different electrophiles. The solid-state molecular structures of the compounds reveal that the hydrogen, methyl or benzyl groups are located on the nitrogen atoms that are not only the less sterically hindered but also have the electron lone pair pointing out of the macrocycle backbone. In all compounds it is observed a bond shortening between the N-Caminal and the two other C–N bonds that may be attributed to an inductive effect. These compounds afford the corresponding trans-N,N'-disubstituted cyclams upon hydrolysis in basic medium.

Mono- and di-cationic hydrido boron compounds.

Brønsted acid HNTf2 (Tf = SO2CF3) mediated dehydrogenative hydride abstraction from (L(1))BH3 () and (L(2))BH3 () (L(1) = IPrCH2 = 1,3-(2,6-di-isopropylphenyl)imidazol-2-methylidene (); L(2) = SIPrCH2 = 1,3-(2,6-di-isopropylphenyl)imidazolidin-2-methylidiene ()) affords thermally stable hydride bridged mono-cationic hydrido boron compounds [{(L(1))BH2}2(μ-H)](NTf2) () and [{(L(2))BH2}2(μ-H)](NTf2) (). Furthermore, hydride abstraction yields di-cationic hydrido boron compounds [{(L(1))BH}2(μ-H)2](NTf2)2 () and [{(L(2))BH}2(μ-H)2](NTf2)2 (). Unique cationic boron compounds with CH2BH2(μ-H)BH2CH2 ( and ) and CH2BH(μ-H)2BHCH2 ( and ) moieties feature a 3c-2e bond and have been fully characterized. Interesting electronic and structural features of compounds are analysed using spectroscopic, crystallographic, and computational methods.

Investigation of the binding modes between AIE-active molecules and dsDNA by single molecule force spectroscopy.

AIE (aggregation-induced emission)-active molecules hold promise for the labeling of biomolecules as well as living cells. The study of the binding modes of such molecules to biomolecules, such as nucleic acids and proteins, will shed light on a deeper understanding of the mechanisms of molecular interactions and eventually facilitate the design/preparation of new AIE-active bioprobes. Herein, we studied the binding modes of double-stranded DNA (dsDNA) with two types of synthetic AIE-active molecules, namely, tetraphenylethene-derived dicationic compounds (cis-TPEDPy and trans-TPEDPy) and anthracene-derived dicationic compounds (DSAI and DSABr-C6) using single molecule force spectroscopy (SMFS) and circular dichroism (CD) spectroscopy. The experimental data indicate that DSAI can strongly intercalate into DNA base pairs, while DSABr-C6 is unable to intercalate into DNA due to the steric hindrance of the alkyl side chains. Cis-TPEDPy and trans-TPEDPy can also intercalate into DNA base pairs, but the binding shows strong ionic strength dependence. Multiple binding modes of TPEDPy with dsDNA have been discussed. In addition, the electrostatic interaction enhanced intercalation of cis-TPEDPy with dsDNA has also been revealed.

Sustainable design for environment-friendly mono and dicationic cholinium-based ionic liquids

Cholinium-based ionic liquids are receiving crescent interest in diverse areas of application given their biological compatibility and potential for industrial application. In this work, mono and dicationic cholinium ionic liquids as well as cholinium derivatives were synthesized and their toxicity assessed using the luminescent bacteria Vibrio fischeri. A range of cholinium derivatives was synthesized, using different amines and the correspondent brominated derivatives, through the alkylation of the amine with the halide in MeCN. The results indicate that their toxicity is highly dependent on the structural modifications of the cholinium cation, mainly related to the alkyl side or linkage chain length, number of hydroxyethyl groups and insertion of carbon–carbon multiple bonds. The data indicated that it is possible to perform environmentally advantageous structural alterations, namely the addition of double bonds, which would not negatively affect V. fischeri. Moreover, the dicationic compounds revealed a significantly lower toxicity than the monocationic counterparts. The picture emerging from the results supports the idea that cholinium derivatives are promising ionic liquids with a low environmental impact, emphasizing the importance of a careful and directed design of ionic liquid structures.

The use of dicationic ion-pairing compounds to enhance the ambient detection of surface lipids in positive ionization mode using desorption electrospray ionisation mass spectrometry

Lipids are typically analysed in negative ionisation mode in desorption electrospray ionisation mass spectrometry (DESI-MS), which can result in reduced sensitivity. In this study we examine the use of dicationic compounds as reactive DESI-MS agents to detect a range of lipid standards from the surface in positive ionisation mode. Nine dicationic compounds were tested for their ability to detect seven representative lipid species (palmitoleic acid, linoleic acid, phosphatidic acid (34:1), phosphoethanolamine (34:2), phosphatidylglycerol (34:1), phosphatidylserine (36:1), and phosphoinositol (34:2)) with a 2D DESI source on hydrophobic surfaces. Two different solvent systems (methanol/chloroform (1:1) and methanol) were tested with each dicationic compound, with the DESI-MS analysis performed in the positive ionisation mode. Most of the dications tested were able to form stable ion-pairs with the negatively charged lipid species when analysed from the surface with DESI-MS, and were detected readily in positive ionisation electrospray mode as singly charged species. The optimal solvent system was found to be methanol. The dicationic compound [C6(C1Pyrr)2][Br]2 was found to enhance the detection of palmitoleic acid (638%), linoleic acid (304%) and phosphoethanolamine (269%) compared with the negative ionisation mode. We demonstrate the first successful application of dicationic compounds in DESI-MS for the ambient surface detection of model lipids in positive electrospray ionisation mode. Dicationic compounds could potentially be used as reactive DESI-MS agents to improve the ambient detection of a number of negatively charged analytes.

The position of imidazopyridine and metabolic activation are pivotal factors in the antimutagenic activity of novel imidazo[1,2-a]pyridine derivatives

The antimutagenic activity of eight novel imidazo[1,2-a]pyridine derivatives (I-VIII) against sodium azide (NaN3) and benzo[a]pyrene (B[a]P) was evaluated using the Salmonella reverse mutation assay. At non-toxic concentrations (12.5–50µM), imidazopyridines I, II, III, and V with a terminal imidazopyridine group were mutagenic, while derivatives VII and VIII with a central imidazopyridine group were not mutagenic. Compounds IV, VII, and VIII exerted a moderate antimutagenic activity against NaN3 under pre-exposure conditions, and a strong activity (>40%) against B[a]P in the presence of S9 under both pre- and co-exposure conditions and mostly independent on the dose. Imidazopyridines possibly inhibited the microsomal-dependent activation of B[a]P. The demethylated derivative VII was the most active antimutagen. All imidazopyridines had a low to moderate antioxidant activity. The antibacterial activity of imidazopyridines was sporadic and moderate probably due to the failure of bacteria to convert imidazopyridines into active metabolites. The position of imidazopyridine was a pivotal factor in the mutagenic/antimutagenic activity. The strong antimutagenic compounds were dicationic planar compounds with a centered imidazo[1,2-a]pyridine spacer. With LD50 of 60mg/kg in mice for both derivatives VII and VIII, it is safe to investigate the anticancer activity of these derivatives in animal models.

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

Polyamine Transport by the Polyspecific Organic Cation Transporters OCT1, OCT2, and OCT3

Polyamines are ubiquitous organic cations implicated in many physiological processes. Because they are positively charged at physiological pH, carrier-mediated systems are necessary for effective membrane permeation, but the identity of specific polyamine transporter proteins in eukaryotic cells remains unclear. Polyspecific organic cation transporters (OCTs) interact with many natural and xenobiotic monovalent cations and have been reported to transport dicationic compounds, including the short polyamine putrescine. In this study, we used Xenopus oocytes expressing mammalian OCT1 (SLC22A1), OCT2 (SLC22A2), or OCT3 (SLC22A3) to assess binding and transport of longer-chain polyvalent polyamines. In OCT-expressing oocytes, [(3)H]MPP(+) uptake rates were 15- to 35-fold higher than in noninjected oocytes, whereas those for [(3)H]spermidine increased more modestly above the background, up to 3-fold. This reflected up to 20-fold lower affinity for spermidine than for MPP(+); thus, K(0.5) for MPP(+) was ~50 μM in OCT1, ~170 μM in OCT2, and ~60 μM in OCT3, whereas for spermidine, K(0.5) was ~1 mM in OCT1, OCT2, and OCT3. J(max) values for MPP(+) and spermidine were within the same range, suggesting that both compounds are transported at a similar turnover rate. To gain further insight into OCT substrate specificity, we screened a selection of structural polyamine analogues for effect on [(3)H]MPP(+) uptake. In general, blocking potency increased with overall hydrophobic character, which indicates that, as for monovalent cations, hydrophobicity is a major requirement for recognition in polyvalent OCT substrates and inhibitors. Our results demonstrate that the natural polyamines are low affinity, but relatively high turnover, substrates for OCTs. The identification of OCTs as polyamine transport systems may contribute to further understanding of the mechanisms involved in polyamine homeostasis and aid in the design of polyamine-like OCT-targeted drugs.

Mesomorphic [2]Rotaxanes: Sheltering Ionic Cores with Interlocking Components

Two types of liquid crystalline [2]rotaxanes based on a conventional tetracatenar motif (a rod-shaped molecule with two side chains at each end) have been prepared. Dicationic compounds with ester stoppers and tetracationic materials with pyridinium stoppers are compared to each other and their dumbbell shaped analogs. Since the ionic core contributes about 70% to the overall length and molecular weight of the molecules, sheltering the ionic cores with an interlocked neutral macrocycle has considerable effect on the mesomorphism and thermal stability of the materials. The influence of the sheltering macrocycle, the numbers of charges on the core and the size and nature of the side chains (aliphatic vs siloxane) were probed. [2]Rotaxanes with linear side chains and minimum ratios of chain-to-core volumes of about 0.35 and 0.30 for tetra- and dicationic compounds, respectively, display smectic liquid crystal phases. Larger ratios increase the temperature range of the smectic A phases beyond the decomposition temperatures; a disadvantage for processing because no stable isotropic liquid phase is available. The change from tetra- to dicationic [2]rotaxanes increased not only the fluidity of their smectic A phases but also their thermal and chemical stability. Branched side chains (2-hexyldecyl) disfavor the formation of lamellar mesophases and, instead, induce higher ordered soft crystal phases. No liquid crystal phases but soft crystal phases are observed for the analogous di- and tetracationic compounds without an ion sheltering interlocked macrocycle (dumbbells).

Photodynamic inactivation of Candida albicans sensitized by a series of novel axially di-substituted silicon (IV) phthalocyanines

The photodynamic activities against Candida albicans have been evaluated for seven silicon (IV) phthalocyanines modified axially by different functional groups. The effects of the axial substituents on the spectroscopic, photochemical, cellular uptake, and photobiological properties of these silicon phthlaocyanines have been revealed. The dicationic compounds 2 and 4 , having two quaternary ammonium groups at the axial positions, exhibit the highest antifungal photocytotoxicity with an IC 90 of 61–66 μM, which can be ascribed to their high singlet oxygen quantum yield , non-aggregation nature, effective cellular uptake, and intracellular distribution pattern (localizing preferentially in the mitochondria). By comparison, compounds 2 and 4 show a higher photodynamic inactivation of C. albicans cells than methylene blue (MB), a known antifungal photosensitizer . The IC 90 values against C. albicans for 2 and 4 are ca. 8 times lower than that for MB. These results indicate that the dicationic silicon phthalocyanines 2 and 4 are interesting candidates as antifungal photosensitizers for future studies. ► Photodynamic inactivation of Candida albicans by a series of SiPcs was studied. ► The structure–activity relationship of these silicon phthalocyanines was discussed. ► The dicationic SiPcs 2 and 4 exhibit the highest antifungal photocytotoxicity. ► 2 and 4 show ca. 8 times higher photoactivities than methylene blue.

The adaptive potential of a survival artist: characterization of thein vitrointeractions ofToxoplasma gondiitachyzoites with di-cationic compounds in human fibroblast cell cultures

The impact of di-cationic pentamidine-analogues against Toxoplama gondii (Rh- and Me49-background) was investigated. The 72 h-growth assays showed that the arylimidamide DB750 inhibited the proliferation of tachyzoites of T. gondii Rh and T. gondii Me49 with an IC(50) of 0·11 and 0·13 μM, respectively. Pre-incubation of fibroblast monolayers with 1 μM DB750 for 12 h and subsequent culture in the absence of the drug also resulted in a pronounced inhibiton of parasite proliferation. However, upon 5-6 days of drug exposure, T. gondii tachyzoites adapted to the compound and resumed proliferation up to a concentration of 1·2 μM. Out of a set of 32 di-cationic compounds screened for in vitro activity against T. gondii, the arylimidamide DB745, exhibiting an IC(50) of 0·03 μM and favourable selective toxicity was chosen for further studies. DB745 also inhibited the proliferation of DB750-adapted T. gondii (IC(50)=0·07 μM). In contrast to DB750, DB745 also had a profound negative impact on extracellular non-adapted T. gondii tachyzoites, but not on DB750-adapted T. gondii. Adaptation of T. gondii to DB745 (up to a concentration of 0·46 μM) was much more difficult to achieve and feasible only over a period of 110 days. In cultures infected with DB750-adapted T. gondii seemingly intact parasites could occasionally be detected by TEM. This illustrates the astonishing capacity of T. gondii tachyzoites to adapt to environmental changes, at least under in vitro conditions, and suggests that DB745 could be an interesting drug candidate for further assessments in appropriate in vivo models.