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PubMed2006

Inhibitory effect of carboxylic acid group on hERG binding.

Drug-induced QT prolongation arising from drugs' blocking of hERG channel activity presents significant challenges in drug development. Many, but not all, of our benzamidine-containing factor Xa inhibitors were found to have high hERG binding propensity. However, incorporation of a carboxylic acid group into these benzamidine molecules generally leads to hERG inactive compounds regardless where the carboxyl group is tethered within the molecules. The inhibitory effect of a carboxylic acid group on hERG binding has also been observed in many series of diverse structural scaffolds (including non-amidines). These findings suggest that the negatively charged carboxylate group causes unfavorable interaction within hERG channel binding cavity by electrostatic interaction.

Benzamidines↗
PubMed2005

Separation of atropisomeric 1,4,5,6-tetrahydropyrimidinium salts by chiral HPLC and determination of their enantiomerization barriers.

Chiral HPLC separation of a series of novel atropisomeric quaternary (1) and ternary (2) 1,2-disubstituted 1,4,5,6-tetrahydropyrimidinium salts bearing disymmetric aryl groups in positions 1 and/or 2 is described. A screening of different polysaccharide stationary phases (OD-R, OJ-R and AD-RH) and chromatographic conditions allowed for partial or baseline resolution of 16 over 26 compounds. When a semi-preparative separation was achieved, the corresponding enantiomerization barriers were determined employing the off-column method. The experimental data were compared inter se in order to establish the factors influencing the magnitude of the barriers and with those corresponding to the parent amidines.

Chromatography, High Pressure Liquid↗
PubMed2004

Synthesis and cytotoxic effect of carbocyclic potential minor groove binders.

New carbocyclic potential minor groove binders were synthesised, using 3-nitrobenzoyl chloride and aliphatic alpha,omega-diamines with three, four and five methylene fragments. The half structures, compounds IV-VI can be compared to bis-amidines, compounds X-XII to bis-netropsin. All of the compounds were investigated antiproliferative and cytotoxic effects in the standard cell line of mammalian tumour MCF-7.

Acids, Carbocyclic↗
PubMed2005

Biochemical and molecular modeling analysis of the ability of two p-aminobenzamidine-based sorbents to selectively purify serine proteases (fibrinogenases) from snake venoms.

Snake venoms contain several trypsin-like enzymes with equivalent physicochemical characteristics and similar inhibition profiles. These are rather difficult to separate by classical purification procedures and therefore constitute a good model for affinity chromatography analysis. Some of these trypsin homologues present fibrinogenase activity, mimicking one or more features of the central mammalian coagulation enzyme, thrombin. It was previously demonstrated that a number of amidine derivatives are able to interact specifically with some of these serine proteases. To understand the enzyme-sorbent interactions we have investigated the ability of two commercially available benzamidine affinity matrices to purify thrombin-like serine proteases (TLSP) with similar biological properties from two snake venoms (Bothrops jararacussu and Lachesis muta rhombeata). Curiously, each sorbent retained a single but distinct TLSP from each venom with high yield. Molecular modeling analysis suggested that hydrophobic interactions within a specific region on the surface of these enzymes could be generated to explain this exquisite specificity. In addition, it was demonstrated that a specific tandem alignment of the two benzamidine sorbents enables the purification of three other enzymes from B. jararacussu venom.

Amino Acid Sequence↗
PubMed2004

Effect of cell physicochemical characteristics and motility on bacterial transport in groundwater.

The influence of physicochemical characteristics and motility on bacterial transport in groundwater were examined in flow-through columns. Four strains of bacteria isolated from a crystalline rock groundwater system were investigated, with carboxylate-modified and amidine-modified latex microspheres and bromide as reference tracers. The bacterial isolates included a gram-positive rod (ML1), a gram-negative motile rod (ML2), a nonmotile mutant of ML2 (ML2m), and a gram-positive coccoid (ML3). Experiments were repeated at two flow velocities, in a glass column packed with glass beads, and in another packed with iron-oxyhydroxide coated glass beads. Bacteria breakthrough curves were interpreted using a transport equation that incorporates a sorption model from microscopic observation of bacterial deposition in flow-cell experiments. The model predicts that bacterial desorption rate will decrease exponentially with the amount of time the cell is attached to the solid surface. Desorption kinetics appeared to influence transport at the lower flow rate, but were not discernable at the higher flow rate. Iron-oxyhydroxide coatings had a lower-than-expected effect on bacterial breakthrough and no effect on the microsphere recovery in the column experiments. Cell wall type and shape also had minor effects on breakthrough. Motility tended to increase the adsorption rate, and decrease the desorption rate. The transport model predicts that at field scale, desorption rate kinetics may be important to the prediction of bacteria transport rates.

Bacterial Physiological Phenomena↗
PubMed2005

Role of an active site adenine in hairpin ribozyme catalysis.

The hairpin ribozyme is a small catalytic RNA that accelerates reversible cleavage of a phosphodiester bond. Structural and mechanistic studies suggest that divalent metals stabilize the functional structure but do not participate directly in catalysis. Instead, two active site nucleobases, G8 and A38, appear to participate in catalytic chemistry. The features of A38 that are important for active site structure and chemistry were investigated by comparing cleavage and ligation reactions of ribozyme variants with A38 modifications. An abasic substitution of A38 reduced cleavage and ligation activity by 14,000-fold and 370,000-fold, respectively, highlighting the critical role of this nucleobase in ribozyme function. Cleavage and ligation activity of unmodified ribozymes increased with increasing pH, evidence that deprotonation of some functional group with an apparent pK(a) value near 6 is important for activity. The pH-dependent transition in activity shifted by several pH units in the basic direction when A38 was substituted with an abasic residue, or with nucleobase analogs with very high or low pK(a) values that are expected to retain the same protonation state throughout the experimental pH range. Certain exogenous nucleobases that share the amidine group of adenine restored activity to abasic ribozyme variants that lack A38. The pH dependence of chemical rescue reactions also changed according to the intrinsic basicity of the rescuing nucleobase, providing further evidence that the protonation state of the N1 position of purine analogs is important for rescue activity. These results are consistent with models of the hairpin ribozyme catalytic mechanism in which interactions with A38 provide electrostatic stabilization to the transition state.

Adenine↗
PubMed2004

Factors that influence the prevalence of acaricide resistance and tick-borne diseases.

This manuscript provides a summary of the results presented at a symposium organized to accumulate information on factors that influence the prevalence of acaricide resistance and tick-borne diseases. This symposium was part of the 19th International Conference of the World Association for the Advancement of Veterinary Parasitology (WAAVP), held in New Orleans, LA, USA, during August 10-14, 2003. Populations of southern cattle ticks, Boophilus microplus, from Mexico have developed resistance to many classes of acaricide including chlorinated hydrocarbons (DDT), pyrethroids, organophosphates, and formamidines (amitraz). Target site mutations are the most common resistance mechanism observed, but there are examples of metabolic mechanisms. In many pyrethroid resistant strains, a single target site mutation on the Na(+) channel confers very high resistance (resistance ratios: >1000x) to both DDT and all pyrethroid acaricides. Acetylcholine esterase affinity for OPs is changed in resistant tick populations. A second mechanism of OP resistance is linked to cytochrome P450 monooxygenase activity. A PCR-based assay to detect a specific sodium channel gene mutation that is associated with resistance to permethrin has been developed. This assay can be performed on individual ticks at any life stage with results available in a few hours. A number of Mexican strains of B. microplus with varying profiles of pesticide resistance have been genotyped using this test. Additionally, a specific metabolic esterase with permethrin-hydrolyzing activity, CzEst9, has been purified and its gene coding region cloned. This esterase has been associated with high resistance to permethrin in one Mexican tick population. Work is continuing to clone specific acetylcholinesterase (AChE) and carboxylesterase genes that appear to be involved in resistance to organophosphates. Our ultimate goal is the design of a battery of DNA- or ELISA-based assays capable of rapidly genotyping individual ticks to obtain a comprehensive profile of their susceptibility to various pesticides. More outbreaks of clinical bovine babesisois and anaplasmosis have been associated with the presence of synthetic pyrethroid (SP) resistance when compared to OP and amidine resistance. This may be the result of differences in the temporal and geographic patterns of resistance development to the different acaricides. If acaricide resistance develops slowly, herd immunity may not be affected. The use of pesticides for the control of pests of cattle other than ticks can affect the incidence of tick resistance and tick-borne diseases. Simple analytical models of tick- and tsetse-borne diseases suggest that reducing the abundance of ticks, by treating cattle with pyrethroids for example, can have a variety of effects on tick-borne diseases. In the worst-case scenario, the models suggest that treating cattle might not only have no impact on trypanosomosis but could increase the incidence of tick-borne disease. In the best-case, treatment could reduce the incidence of both trypanosomosis and tick-borne diseases Surveys of beef and dairy properties in Queensland for which tick resistance to amitraz was known were intended to provide a clear understanding of the economic and management consequences resistance had on their properties. Farmers continued to use amitraz as the major acaricide for tick control after the diagnosis of resistance, although it was supplemented with moxidectin (dairy farms) or fluazuron, macrocyclic lactones or cypermethrin/chlorfenvinphos.

Acaricides↗
PubMed1998

Physico-chemical characterization of a double long-chain cationic amphiphile (Vectamidine) by microelectrophoresis.

We recently synthesized a novel cationic amphiphile (N-t-butyl-N'-tetradecyl-3-tetradecylaminopropionamidine or Vectamidine (previously described as diC14-amidine)) that associates with DNA and RNA and facilitates their entry and expression into eukaryotic cells. Among several parameters that have been shown to influence the transfection process, the surface charge density plays a key role. Quantitative information about that charge density associated to the cationic amphiphiles organized in liposomal structure is not yet available. We provide here evidence by titration and microelectrophoresis measurements that an evaluation of the intrinsic acidity constants, the surface pH and the counterion binding constants allows to determine the charge density at physiological pH of Vectamidine liposomes. The knowledge of this superficial charge is a prerequisite to a molecular understanding of the DNA-cationic amphiphile complex formation. The method described could be extended to any kind of cationic amphiphile.

Cations↗
PubMed1992

Formation of nitric oxide by cytochrome P450-catalyzed oxidation of aromatic amidoximes.

Rat liver microsomes catalyze the oxidation of para-hexyloxy-benzamidoxime 1 to the corresponding arylamide 2 and NO2-, by NADPH and O2. Involvement of cytochromes P450 as catalysts of this reaction was shown by the strong inhibitory effects of CO and miconazole and the spectacular increase of the activity upon treatment of rats with dexamethasone, a specific inducer of cytochromes P450 of the 3A subfamily. Formation of NO during oxidation of 1 was shown by detection of the formation of cytochrome P450- and cytochrome P420-Fe(II)-NO complexes by visible and EPR spectroscopy. The formation of these complexes should be responsible, at least in part, for the fast decrease of the rate of microsomal oxidation of 1 with time. These results suggest that exogenous compounds containing amidine or amidoxime functions could act as precursors of NO in vivo after in situ oxidation by cytochromes P450.

Animals↗
PubMed1986

Evidence of binary complex formations between cytochrome P-450, cytochrome b5, and NADPH-cytochrome P-450 reductase of hepatic microsomes.

Water-soluble carbodiimide-catalyzed cross-linking of purified cytochrome P-450 LM2, cytochrome b5, and NADPH-cytochrome P-450 reductase was used to identify stable complexes formed between these proteins. High yields of P-450-b5 and P-450 reductase-b5 dimers, and lower yields of P-450 reductase-LM2 dimers were obtained. Substitution of native b5 and P-450 reductase with fully amidinated derivatives showed that LM2 and b5 were cross-linked exclusively through their respective amino and carboxyl groups. However, there appeared to be two complexation sites on the reductase which cross-link to b5 through amino groups and to LM2 through carboxyl groups respectively. A heterotrimer could not be identified following incubation of all three proteins together with EDC.

Animals↗
PubMed2002

Synthesis and biological evaluation of trehalose analogs as potential inhibitors of mycobacterial cell wall biosynthesis.

Analogs of trehalose are reported that were designed to interfere with mycolylation pathways in the mycobacterial cell wall. Several derivatives of 6,6'-dideoxytrehalose, including N,N'-dialkylamino and 6,6'-bis(sulfonamido) analogs, were prepared and evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37)Ra and a panel of clinical isolates of Mycobacterium avium. 6,6'-Diaminotrehalose and its diazido precursor were both inactive, but significant activity apparently related to aliphatic chain length was found among the sulfonamides, N-alkylamines, and one of the amidines.

Antitubercular Agents↗
PubMed2002

Amidinobenzisothiazole derivatives with antidegenerative activity on cartilage.

N-(Benzo[d]isothiazol-3-yl)amidines were synthesised and evaluated for their antiinflammatory activity. Encouraging results led us to evaluate these derivatives on the prevention of cartilage destruction in articular disease. Antidegenerative activity was assayed on culture of porcine nasal cartilage and diarthroidal joint human cartilage in the presence of interleukin-1beta (IL-1beta). The amount of glycosaminoglycans (GAGs) and the production of nitric oxide (NO) in the culture medium were determined. The obtained results showed that all the compounds, in the presence of IL-beta, blocked the cartilage breakdown, with different behaviour. The antidegenerative activity is more evident in human cartilage.

Amides↗
PubMed2001

Interactions between organic flocculant PAN-DCD and dyes.

Organic flocculant polyacrylonitrile-dicyandiamide (PAN-DCD) was characterized by IR, 1H NMR and 13C NMR spectra. Polar groups, such as triazine, carboxyl, amidine, carbonamide and non-polar groups, such as methylene were identified in the macromolecular chain of PAN-DCD. The flocculant effectively decolorized the examined dyes in their aqueous solutions under acid condition. By comparing the IR spectra of dyes with that of PAN-DCD and that of flocs formed, weak chemical interactions between amino in PAN-DCD side chain and sulfonic acid group in the dye molecules were observed through the formation of -NH3+ SO3(-)-, NH2+ SO3(-)- or/and =NH+ SO3(-)-. By using equilibrium dialysis technique, the hydrophobic interactions between PAN-DCD and the dyes in the binding process were also observed from the experimental results. The binding extent of PAN-DCD to dye KN-R was greater than that of MO. The addition of urea into the binding system of KN-R by PAN-DCD reduced the first binding constant K from 12.2 x 10(5) (without urea) to 3.48 x 10(5) (with urea).

Acrylic Resins↗
PubMed1997

Characterization of macromolecular transport pathways in malaria-infected erythrocytes.

We have previously provided evidence for a pathway in Plasmodium falciparum-infected erythrocytes, coined the parasitophorous duct pathway, which provides serum (macro)molecules direct access to intraerythrocytic parasites . The present study addresses the purity of the fluorescent macromolecules used to define the duct pathway and provides ultrastructural evidence for its presence. The fluorescent tracers used to characterize transport remain intact during their incubation with infected erythrocytes. Transport of macromolecules in the external medium or host cell cytosol to the intracellular parasites is shown to occur by two distinct pathways. Fluorescent dextrans in the erythrocyte cytosol are ingested by the parasite via a specialized organelle, the cytostome, and are transported to the parasite food vacuole. Transport through this pathway occurs throughout the asexual life cycle. By contrast, fluorescent dextrans in the external medium bypass the erythrocyte cytosol, and are internalized by the parasite by a process resembling fluid-phase endocytosis. Serial sections of mature parasites fixed and stained by various methods for transmission electron microscopy reveal areas of apparent membrane continuity between the erythrocyte membrane and the parasitophorous vacuolar membrane that surrounds the parasite, that could leave the parasites exposed to the external medium. Using carboxylate and amidine-modified fluorescent latex spheres and laser scanning confocal microscopy, macromolecules up to 50-70 nm in diameter are found to have direct access to intraerythrocytic parasites. This size exclusion is consistent with the dimensions of the parasitophorous duct pathway revealed by electron microscopy. This investigation reports for the first time the existence of two, distinct macromolecular transport pathways in malaria-infected erythrocytes.

Animals↗
PubMed2003

Microspheres based on inulin for the controlled release of serine protease inhibitors: preparation, characterization and in vitro release.

The pharmacological activity of serine protease inhibitors, potential drugs for the treatment of thrombosis, is often linked to the presence of amidine functions. With the aim of developing a suitable formulation for these compounds, inulin and inulin acetate associated or not with 1,12-dodecanedicarboxylic acid, were chosen to prepare microspheres. Using a coacervation method, these biocompatible polymers led to microspheres of about 0.5-5 microm. The encapsulation of a water-soluble model drug (E,E)-bis(amidinobenzylidene)cycloheptanone [(E,E)-BABCH] in these microspheres was studied. In this investigation, factorial designs were used to determine the joint influence of several variables (drug mass, speed and time of formulation stirring, centrifugation time) for an optimum encapsulation efficiency. Results revealed that encapsulation efficiency reached 65% whatever the nature of the biopolymer, by using a stirring time of 30 min, a high stirring speed and a centrifugation time of 15 min. (E,E)-BABCH release from microspheres was examined in an in vitro model. The profiles were characterized by three phases strongly dependent on the microspheres and the diacid association displayed a crucial role. With inulin and inulin acetate, the initial phase was a rapid 'drug burst'. Within the first 5 min, 58-62% of the drug were delivered. Microspheres of inulin acetate associated with 1,12-dodecanedicarboxylic acid, showed a slower release with only 32% of the drug delivered after 15 min. After a slow diffusion phase (33 h), an increasing rate until complete drug release was observed for 2.5 days.

Delayed-Action Preparations↗
PubMed1997

Structural analogues of ZAPA as GABAA agonists.

Structural analogues of ZAPA, Z-3-[(aminoiminomethyl)thio]prop-2-enoic acid, an isothiouronium analogue of GABA, are potent GABAA agonists as seen in the isolated guinea-pig ileum and in the facilitation of [3H]diazepam binding to rat brain membranes. Compounds with guanidino or amidine groups replacing the amino functionality of GABA were also found to be active. The highest activity was displayed by the isothiouronium salts in which the conformational flexibility of the molecule is restricted by a Z-substituted carbon-carbon double bond. A series of bis-isothiouronium compounds was prepared from aliphatic alpha, omega-bis-thioureas as mixtures of E and Z adducts. Maximum GABAA agonist activity for this series was found with a C6-C8 carbon chain, and the results were consistent with an interaction at the GABAA receptor with only one end of the molecule, rather than the more potent effect expected of a molecule bridging two active sites. GABAA antagonist/partial agonist activity was observed on the guinea pig isolated ileum for a number of different analogue types, with the most potent being bis-isothiouronium derivatives. None of the substituted derivatives of ZAPA was as active as ZAPA itself, and maximum GABAA activity was found in the n-pentyl and n-hexyl analogues.

Acrylates↗
PubMedDate not supplied

Synthesis and anti-Pneumocystis carinii pneumonia activity of novel dicationic dibenzothiophenes and orally active prodrugs.

Dicationic carbazoles have been found to be highly active against a rat model of Pneumocystis carinii pneumonia (PCP). Unfortunately, amidoxime derivatives, designed as prodrugs, were inactive against PCP even though the corresponding amidines were highly active. In the present work, a series of 2,8- and 3,7-bis cationic dibenzothiophenes was synthesized and assayed for anti-PCP activity. Three of the compounds proved to be more potent and less toxic than a standard anti-PCP drug (pentamidine) when given intravenously. Unlike the carbazoles, a dibenzothiophene amidoxime prodrug given orally reduced the parasite load by more than 99%. While no quantitative correlation was seen between anti-PCP activity and DNA binding, a strong level of DNA binding was found to be necessary for antimicrobial activity.

Animals↗
PubMed2001

Quantum chemical calculations of infrared spectra for the identification of unknown compounds by GC/FTIR/MS in exobiological simulation experiments.

Gas chromatography/Fourier transform IR spectroscopy/mass spectrometry (GC/FTIR/MS) is a powerful tool for the separation and unambiguous identification of complex mixtures of organic compounds, where the use of two kinds of spectra allows to significantly increase identification reliability. The simplest situation is when acquired spectra can be found in IR and MS databases, or appropriate standards are available; but this is not always the case. Some simulation experiments related to the origins of life and exobiology (e.g., simulation of amino acid pyrolysis during atmospheric entry of space bodies) can be a typical example when one encounters with numerous unknown compounds. To assist their identification by GC/FTIR/MS, recently we suggested quantum chemical calculations of infrared spectra in order to compare them to IR spectra acquired experimentally. The present work summarizes the results obtained by semi-empirical and ab initio methods, discusses their advantages and limitations, considering as test compounds some cyclic amides and amidines derived from amino acids, saturated and unsaturated nitriles (including those of interest for the Titan atmospheric chemistry), acetylenes and some other nitrogen compounds.

Amino Acids↗