Dibasic Compounds Research Articles

Optimization of generic conditions for electromembrane extraction of basic substances of moderate or low polarity.

Generic electromembrane extraction (EME) methods were developed and optimized for basic analytes of moderate or low polarity, employing prototype conductive vial EME equipment. Two generic methods, B1 and B2, were devised for mono- and dibasic compounds with distinct polarity windows: 2.0<log P<6.0 for B1 and 1.0<log P<4.5 for B2. In B1, 10μL of 2-nitrophenyl octyl ether served as the liquid membrane, while B2 utilized 10μL of 2-undecanone. Both methods involved the acidification of 125μL of human plasma samples with 125μL of sample diluent (0.5M HCOOH for B1 and 1.0M HCOOH for B2). The acceptor phase consisted of 250μL of 100mM HCOOH. Extraction was conducted for 30 min with agitation at 800rpm, employing an extraction potential of 100V for B1 and 50V for B2. A set of 90 pharmaceutical compounds was employed as model analytes. Both B1 and B2 demonstrated high recoveries (40%-100%) for the majority of model analytes within their respective polarity windows. Intra-day precision was within 2.2% and 9.7% relative standard deviation. Both extraction systems exhibited stability in terms of current, matrix effect values were between 90% and 109%.

Estimating the Bias of Model Compounds for the Determination of Species-Specific Protonation Constants.

The previously unknown extent of the goodness of using model compounds for the microspeciation of polyprotic systems was studied. Mirror-symmetric dibasic compounds and their monosubstituted derivatives were investigated to quantify how the derivatives are appropriate models of the minor microspecies to be mimicked in various microspeciation systems. The results were analyzed using statistical methods. It was found that the respective O-methyl and S-methyl derivatives of phenols and thiols as well as the methyl esters of carboxylic acids are sufficiently good derivatives for microspeciation. It was also found that the methyl esters are superior to the carboxylic amides for modeling the -COOH moiety.

Extraction and Determination of Nicotine in Tobacco from Selected Local Cigarettes Brands in Iraq

Tobacco smoke contains more than 3,800 different compounds, where all could harm the exposed humans to different degrees. Among them, nicotine (3-(1-methyl-2-pyrrolidinyl) pyridine) is considered the most toxic compound. In many countries, tobacco smoking is considered a severe health hazard and a significant factor in death and several common diseases. Because of that, knowing the toxicity of nicotine is important to help understand tobacco-induced human diseases and identify the potential risks associated with the therapeutic use of nicotine as an aid in smoking cessation. Thereby, estimating the nicotine amount is very crucial in tobacco production. As this work aims to extract and determine nicotine, which is the highest toxic component in tobacco plant leaves, several methods were carried out to extract the nicotine. All extracting methods were based on water extraction as a polar solvent and the other non-polar solvents. Water shows a limited extraction activity for nicotine from tobacco leaves. Since nicotine is a dibasic compound, an alkaline solution (40% NaOH) was used to extract nicotine from tobacco leaves for the selected samples. Further, solvent extraction by non-polar solvents was conducted to extract nicotine from the alkaline solution and prepare it for the spectrometric analysis. FT-IR and UV analysis show that the oily substance, which was extracted from tobacco leaves, is nicotine. Results were confirmed by microscopic examination for the extracted nicotine after the addition of mercuric chloride, where flowery shape crystals of nicotine liganded with mercuric chloride complex were formed.

Bis(2-aminoimidazolines) and Bisguanidines: Synthetic Approaches, Antiparasitic Activity and DNA Binding Properties.

Parasitic diseases caused by protozoan parasites of the genus Trypanosoma and Plasmodium cause some of the deadliest and disabling human infections in tropical and subtropical areas. Diphenyl-based bis(2-phenylimino)imidazolidines and bisguanidines are extremely potent antiparasitic agents against Trypanosoma brucei (etiological agent of African trypanosomiasis) and Plasmodium falciparum (etiological agent of severe malaria). Many of these compounds are also curative in mouse models of stage 1 African trypanosomiasis representing promising leads for the development of antitrypanosomal drugs. In addition, different classes of bis(2-iminoimidazolidines) and bisguanidines have been shown to have antimicrobial activity against other pathogens (e.g. bacteria, fungi, parasitic worms). Due to their structural and physicochemical properties, these dibasic compounds, which are dications at physiological pH, are prone to bind to the minor groove of DNA at AT-rich sites. In several cases, such interaction is thought to be responsible for their antimicrobial activity. In this review, we give a comprehensive view of the synthetic methods used to introduce the 2-aminoimidazoline scaffold in a molecule. Synthetic routes that give access to these cyclic guanidines (i.e. unsubstituted, 1-, 4-, and 5-substituted 2-aminoimidazolines) are detailed. The in vitro and in vivo antiprotozoal activity of bis(2-aminoimidazolines) and bisguanidines against kinetoplastid parasites (T. brucei, T. cruzi, Leishmania), Plasmodium spp. and other pathogens (e.g. ESKAPE bacteria, Candida spp., M. tuberculosis, E. multilocularia) is also reviewed. Finally, the targets that are involved in the antimicrobial activity (e.g. DNA) or other biological activities (e.g. α-adrenergic receptors, imidazoline binding sites, kinases) of this class of dicationic compounds are discussed.

Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani

Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study, we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately, this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable antileishmanial compound, MetRS remains an attractive antileishmanial drug target.

Reducing the Hygroscopicity of the Anti-Tuberculosis Drug (S,S)-Ethambutol Using Multicomponent Crystal Forms

Ethambutol (ETB) is a chiral dibasic compound formulated and marketed as the (S,S)-ethambutol dihydrochloride, (S,S)-EDH, to treat tuberculosis. It is administered orally in a solid formulation composed of isoniazid, rifampicin, and pyrazinamide as a fixed-dose combination tablet. Because of its high hygroscopicity, (S,S)-EDH is known for catalyzing the degradation of isoniazid by rifampicin to yield isonicotinyl hydrazone. In order to avoid or even minimize these mutual drug–drug interactions, in this work we have focused on the development of less hygroscopic multicomponent solid forms of ETB. Four salts of this drug, namely, oxalate (ETBOXA), maleate, terephthalate, and trichloroacetate, were prepared via supramolecular synthesis by the slow evaporation method and characterized by X-ray diffraction (single crystal X-ray diffraction, powder X-ray diffraction), spectroscopic (Fourier transform-infrared), and thermal (thermogravimetric analysis, differential scanning calorimetry, hot stage microscopy) techniques. The hygroscopic nature of these salts, including (S,S)-EDH, were evaluated, and all of them were found to be hygroscopic, with the exception of ETBOXA.

Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds

The challenge of defining the concentration of unbound drug at the lung target site after inhalation limits the possibility to optimize target exposure by compound design. In this study, a novel rat lung slice methodology has been developed and applied to study drug uptake in lung tissue, and the mechanisms by which this occurs. Freshly prepared lung slices (500 μm) from drug-naive rats were incubated with drugs followed by determination of the unbound drug volume of distribution in lung (Vu,lung), as the total concentration of drug in slices divided by the buffer (unbound) concentration. Vu,lung determined for a set of inhaled drug compounds ranged from 2.21 mL/g for salbutamol to 2970 mL/g for dibasic compound A. Co-incubation with monensin, a modulator of lysosomal pH, resulted in inhibition of tissue uptake of basic propranolol to 13%, indicating extensive lysosomal trapping. Partitioning into cells was particularly high for the cation MPP+ and the dibasic compound A, likely because of the carrier-mediated transport and lysosomal trapping. The results show that different factors are important for tissue uptake and the presented method can be used for profiling of inhaled compounds, leading to a greater understanding of distribution and exposure of drug in the lung.

Limiting the Number of Potential Binding Modes by Introducing Symmetry into Ligands: Structure-Based Design of Inhibitors for Trypsin-Like Serine Proteases.

In the absence of X-ray data, the exploration of compound binding modes continues to be a challenging task. For structure-based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin-like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties. This results in several possible orientations within the active site, complicating the binding mode prediction of such compounds by docking tools. Therefore, we introduced symmetry in bi- and tribasic compounds to reduce conformational space in docking calculations and to simplify binding mode selection by limiting the number of possible pocket occupations. Asymmetric bisbenzamidines were used as starting points for a multistage and structure-guided optimization. A series of 24 final compounds with either two or three benzamidine substructures was ultimately synthesized and evaluated as inhibitors of five serine proteases, leading to potent symmetric inhibitors for the pharmaceutical drug targets matriptase, matriptase-2, thrombin and factor Xa. This study underlines the relevance of ligand symmetry for chemical biology.

Exploration of Salts and Cocrystals of 2,2′,6,6′-Tetracarboxybiphenyl with Acetic Acid, Monobasic and Dibasic N-Heterocycles, and N-Oxides

Several complexes of 2,2′,6,6′-tetracarboxybiphenyl (H41) with various N-containing heterocycles and N-oxides were synthesized and their crystal structures were analyzed in terms of salt/cocrystal, deprotonation, synthons, and network geometries. The tetra carboxylic acid, H41, was found to act as a host for the inclusion of acetic acid dimers. For complexation reactions with bases, the mono basic compounds such as pyridine, quinoline, and acridine; the dibasic compounds such as 9,10-phenanthrolene, 4,4′-bipyridylethane, 4,4′-bipyridyldisulfide, phenazine, and 1,4-diazabicyclooctane (dabco); and N-oxides of 4,4′-bipyridine and dabco are considered. In the crystal structures of these complexes, the H41 was found to exist as H21 (double deprotonation of H41), H31 (mono deprotonation of H41), or H41 (cocrystals) forms depending on the basicity of the complexing agent and other factors. Out of 13 complexes studied here the more probable acid-pyridine synthon was observed in one complex, the COO–···HOOC– synth...

Rapid Determination of Ionization Constants (pK a) by UV Spectroscopy Using 96-Well Microtiter Plates.

We have developed a methodology that enables for the rapid measurement of ionization constants (pK a) of series of compounds by UV spectrophotometry. This protocol, which is straightforward to set up, takes advantage of the sensitivity of UV spectroscopy and the throughput enabled by the 96-well microplate (as opposed to the use of 1 cm quartz cuvette). The compounds, in stock solutions in DMSO, are dissolved in several aqueous buffer solutions directly in the microtiter plate, allowing the simultaneous determination of the UV spectra as a function of pH. Further treatment of the data provides the pK a values in a medium-throughput manner. The pK a values of 11 new antitrypanosomal dibasic compounds were determined using this methodology.

From libraries to candidate: The discovery of new ultra long-acting dibasic β2-adrenoceptor agonists

Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.

The Synthesis and Study on Optical Characteristics of the Asymmetrical Polymerizable Fluorescent Brighteners

A novel type of asymmetrical polymerizable fluorescent brighteners was synthesized using 4-nitro-4-aminostilbene-2,2′-disulfonic acid (ANSD) and cyanuric chloride as raw materials, through reduction reaction of sodium hydrosulfide and condensation reaction of variant amine compounds replacing the chlorine of triazine rings, containing another dibasic triazine compound grafted polyaminamide. The ultraviolet absorption and fluorescence emission properties, photoinduced isomerization phenomena and application properties of the asymmetrical polymerizable fluorescent brighteners, asymmetrical and symmetrical fluorescent brighteners in aqueous solutions, tetrahydrofuran(THF) N,N-dimethyl formamide (DMF) were particularly investigated. The fluorescence quantum yield was determined using quinine sulfate in 0.5 mol/l H2SO4(ΦF = 0.55) as the fluorescence standard. The effect of concentration and polarity of solvents on fluorescence properties was observed. Results show that the ultraviolet absorption and dyeing properties as well as light stability of the prepared asymmetrical polymerizable fluorescent brighteners increased obviously compared with asymmetrical and symmetrical FBs with the phenomena of photoinduced isomerization decreasing. It was found that the polarity of the solvents influences the quantum yield of fluorescence and has only a small effect upon the positions of the absorption and fluorescence maxima of FBs. Meanwhile, concentration of trans- and cis-isomers depends on the nature of the substituents.

Synthesis and structure–activity relationships for biphenyl H 3 receptor antagonists with moderate anti-cholinesterase activity

The combination of antagonism at histamine H 3 receptors and inhibition of acetylcholinesterase has been recently proposed as an approach to devise putative new therapeutic agents for cognitive diseases. The 4,4′-biphenyl fragment has been reported by us as a rigid scaffold leading to potent and selective non-imidazole H 3-antagonists. Starting from these premises, the current work presents an expanded series of histamine H 3 receptor antagonists, characterized by a central 4,4′-biphenyl scaffold, where the structure–activity profile of both mono-basic and di-basic compounds is further explored and their ability to inhibit rat brain cholinesterase activity is determined. The steric properties and basicity of the terminal groups were modulated in symmetrical compounds, carrying identical substituents, and in asymmetrical compounds, having a piperidine ring at one end and different groups at the other. The length of the linker connecting the biphenyl scaffold to the terminal groups was also modulated. Binding studies at rat and human H 3 receptors evidenced the highest binding affinities for di-basic compounds, in the order of nM concentrations, and that the steric requirements for the two terminal groups are different. Many potent compounds showed good selectivity profiles over the other histamine receptors. Interestingly, some derivatives displayed a moderate ability to inhibit rat brain cholinesterase, for example compound 12 (1-[2-(4′-piperidinomethyl-biphenyl-4-yl)ethyl]piperidine) has a pIC 50 = 5.96 for cholinesterase inhibition and high H 3 receptor binding affinity and antagonist potency (p K i = 8.70; p K B = 9.28). These compounds can be considered as rigid analogs of a recently reported class of dual-acting compounds and as a promising starting point for the design of new H 3-antagonists with anti-cholinesterase activity.

Quantitative modeling of selective lysosomal targeting for drug design

Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick-Nernst-Planck equation. The cell model considers the diffusion of neutral and ionic molecules across biomembranes, protonation to mono- or bivalent ions, adsorption to lipids, and electrical attraction or repulsion. Based on simulation results, high and selective accumulation in lysosomes was found for weak mono- and bivalent bases with intermediate to high log K (ow). These findings were validated with experimental results and by a comparison to the properties of antimalarial drugs in clinical use. For ten active compounds, nine were predicted to accumulate to a greater extent in lysosomes than in other organelles, six of these were in the optimum range predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation. This demonstrates that the cell model can be a useful tool for the design of effective lysosome-targeting drugs with minimal off-target interactions.

Inhibition of secretion by 1,3-Cyclohexanebis(methylamine), a dibasic compound that interferes with coatomer function.

We noted previously that certain aminoglycoside antibiotics inhibit the binding of coatomer to Golgi membranes in vitro. The inhibition is mediated in part by two primary amino groups present at the 1 and 3 positions of the 2-deoxystreptamine moiety of the antibiotics. These two amines appear to mimic the epsilon-amino groups present in the two lysine residues of the KKXX motif that is known to bind coatomer. Here we report the effects of 1, 3-cyclohexanebis(methylamine) (CBM) on secretion in vivo, a compound chosen for study because it contains primary amino groups that resemble those in 2-deoxystreptamine and it should penetrate lipid bilayers more readily than antibiotics. CBM inhibited coatomer binding to Golgi membranes in vitro and in vivo and inhibited secretion by intact cells. Despite depressed binding of coatomer in vivo, the Golgi complex retained its characteristic perinuclear location in the presence of CBM and did not fuse with the endoplasmic reticulum (ER). Transport from the ER to the Golgi was also not blocked by CBM. These data suggest that a full complement of coat protein I (COPI) on membranes is not critical for maintenance of Golgi integrity or for traffic from the ER to the Golgi but is necessary for transport through the Golgi to the plasma membrane.

Phloem translocation of strong acids—glyphosate, substituted phosphonic and sulfonic acids—in Ricinus communis L

AbstractThe mobility in phloem of several substituted phosphonic acids and a sulfonic acid was studied in the castor bean plant, Ricinus communis L. For a series of14C‐labelled phosphonate mono‐esters applied to the petioles of mature leaves, phloem transport was modest, becoming poor over longer distances in the plant. Substituted phenylphosphonic acids were more efficiently moved in phloem; uptake from the petiole and subsequent redistribution were slow, but these dibasic compounds were very stable in plants and substantial amounts reached the roots after 72 to 120 h. Glyphosate was very efficiently transported to phloem sinks even within 24 h, with high concentrations in phloem sap. Toluene‐4‐sulfonic acid moved predominantly in the xylem to the mature leaves and its phloem transport was poor. Transport patterns are considered in relation to the physico‐chemical properties of the compounds. Ion trapping appears to play little part in the phloem transport of these strong acids, though the good accumulation and transport in phloem of the complex molecule glyphosate cannot at present be explained.

Release of polyionizable compounds from submicrometer oil‐in‐water emulsions

AbstractA novel, general, theoretical equation that describes the release of polyionizable compounds from submicrometer emulsions was derived and evaluated. The model accounts for simultaneous partitioning, interfacial activity, and adsorption to surfactant for n independent drug species and j surfactant species in a single emulsion system. Under the appropriate conditions, this model collapses to a previously described model for submicrometer emulsions. The model was tested for submicrometer emulsions containing a model dibasic compound (quinine sulfate). Drug release behavior was observed at pH 3.00, 5.07, and 7.50 in the presence and absence of an anionic surfactant (sodium lauryl sulfate). At each pH, the proposed theory describes the observed release behavior. At all pHs studied, a substantial amount of quinine was adsorbed to the surface of the oil droplet. Presumably, this behavior was largely the result of electrostatic attraction between ionized drug and sodium lauryl sulfate at the oil—water interface. Adsorption constants were evaluated for complexation of cationic and dicationic species of quinine to sodium lauryl sulfate, and the adsorption constant of the cationic species was larger, presumably because of the ionic nature of the surfactant.

Interaction of basic compounds with coated vesicles.

The effect of poly- and dibasic amines, including chloroquine and quinacrine, on the dissociation of coated vesicles at pH 7.4 in 0.01 M 2-(N-morpholino)ethanesulfonic acid has been evaluated by light scattering and sucrose gradient centrifugation. The degree of inhibition of dissociation by the polybases is proportional to the number of amine groups in each compound. However, very little difference in effectiveness was found in a series of dibasic compounds, NH2(CH2)2-5NH2. Chloroquine and quinacrine contain dibasic aliphatic chains as well as aromatic ring systems. These two antimalarials are more effective in inhibiting dissociation of coated vesicles than the dibasic aliphatic amines. The ring systems therefore appear to be contributing, independently, to the free energy of stabilization of the coat structure of coated vesicles. It is suggested that the interaction of poly- or dibasic compounds with clathrin or coated vesicles could influence the turnover of ligands in receptor-mediated endocytosis.

Acylation of dibasic compounds containing amino amidine and aminoguanidine functions

Acylation of dibasic compounds containing amino amidine and aminoguanidine functions

Babesicidal Effect of Basically Substituted Carbanilides: I: Activity against Babesia rodhaiui in Mice

SUMMARY The babesicidal effect of a large number of di-basic compounds was tested in experimental Babesia rodhaini injection in mice. Compound No. 3, which can be designated as 3,3’-bis-(2-imidazolin-2-yl)carbauilide, or 1,3-bis [m-(2-imidazolin-2-yl) phenyl] urea, was the most effective.