Design, synthesis, and testing of potential antisickling agents. 4. Structure-activity relationships of benzyloxy and phenoxy acids

In this paper we further establish the activity of two classes of small molecules, benzyloxy and phenoxy acids, as potent inhibitors of hemoglobin S (HbS) gelation. Structural modifications with a large number of each class confirm our earlier work that the highest activity is observed with compounds that contain dihalogenated aromatic rings with attached polar side chains. We have also found a halogenated aromatic malonic acid derivative to be quite active. Compounds reported in this paper are compared with other antigelling agents studied in our laboratory. Comments are made concerning the antigelling activity and binding sites of four derivatives and their effect on the allosteric mechanism of hemoglobin (Hb) function.     

Studies on novel 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives as potential analgesic and anti-inflammatory agents

In this study, a series of (7-acyl-5-chloro-2-oxo-3H-benzoxazol-3-yl)alkanoic acid derivatives were synthesized and evaluated for their analgesic and anti-inflammatory activities by using the p-benzoquinone-induced writhing test and the carrageenan hind paw edema model, respectively. Acetic acid-induced peritoneal capillary permeability test and serotonin-induced hind paw edema test were also employed for the most active compounds. The test results indicated that (7-acyl-2-oxo-3H-benzoxazol-3-yl)alkanoic acids (Compounds 6 a-c, 8 a-c, 10 a-c) were equally or more potent analgesic and anti-inflammatory agents than aspirin and indomethacin respectively. The compounds 8a and 8c, but not 8b have the longest carbon chain on alkanoic acid moiety did not induce gastric lesion in mice.     

The significance of the relative effects of loop diuretics and anti-brain edema agents on the Na+, K+, Cl− cotransport system and the Cl−/NaCO 3 − anion exchanger

Summary 3-Amino-5-sulfamoylbenzoic acids and several series of (aryloxy)alkanoic acids were evaluated for their inhibitory effects on two human erythrocyte ion transport systems — the Na⁺, K⁺ cotransport system and the DIDS-sensitive anion carrier.Several classic loop diuretics, including the (aryloxy)alkanoic acid-ethacrynic acid and several 3-amino-5-sulfamoylbenzoic acids, like bumetanide and furosemide, displayed relatively strong inhibitory activity versus the cotransport system with relatively weaker action versus the anion carrier. Furthermore, diuretic potency correlated with cotransport inhibitory potency.Another class of (aryloxy)alkanoic acids, namely the [(2,3-dihydro-1 H-inden-5-yl)oxy]acetic acids, such as indacrinone and MK-473, which exhibit less potent loop dacrinone and MK-473, which exhibit less potent loop diuretic activity, were less potent cotransport inhibitors and more effective inhibitors of the anion carrier.Still other (aryloxy)alkanoic acids, with little saliuretic activity, namely a sub-class of [(2,3-dihydro-1 H-inden-5-yl)oxy]alkanoic acids and a series of [(2,3,9,9a-tetrahydro-1 H-fluoren-7-yl)oxy]acetic acids displayed little or no inhibitory action on the cotransport system but enhanced inhibitory action on the anion carrier. Most interestingly, the relative anion carrier inhibitory potency correlated well with the relative inhibitory activity of each compound on bicarbonate-stimulated cell swelling in cat cerebrocortical slices.Abbreviations DIDS 4,4-diisothiocyanostilbene-2,2-disulfonate - SITS 4-acetamido-4-isothio-cyanostilbene-2,2-disulfonate - Tris tris(hydroxymethyl)aminomethane - MOPS 4-morpholinopropanesulphonic acid     

4-(3-Oxo-1,2-benzisothiazolin-2-yl)alkanoic, phenyl and phenoxyalkanoic acids: synthesis and anti-inflammatory, analgesic, and antipyretic properties

Based on previous observations, the preparation, some physicochemical (partition coefficient, pKa) and pharmacological properties of 4-(3-oxo-1,2-benzisothiazolin-2-yl)alkanoic, benzoic, phenyl, phenoxyalkanoic acids and of some of their functional derivatives are reported. All new compounds were biologically examined for their antiphlogistic, analgesic and antipiretic actions, in comparison with those of 1,2-benzisothiazolin-2-one and with those of ibuprofen as the antiphlogistic, analgesic, antipyretic arylalkanoic prototype. Structure-activity relationships showed that the 1,2-benzisothiazolin-2-one and its new alkanoic and arylalkanoic derivatives have strong actions which are however specific for some of the tested pharmacological properties. From this point of view, the synthesized substances have a narrow spectrum of activity, if compared with ibuprofen which is at the same time an antiphlogistic, analgesic and antipiretic substance. The antiphlogistic and antipyretic activities of 4-(3-oxo-1,2-benzisothiazolin-2-yl)benzoic, phenylacetic and phenylmethylacetic acids and the antipyretic and analgesic actions of 3-oxo-1,2-benzisothiazolin-2-ylacetic acid, which are comparable or higher in "potency" than those of ibuprofen, are noteworthy.     

Design, synthesis, and testing of potential antisickling agents. 7. Ethacrynic acid analogues

In search of a drug to treat sickle cell anemia, several analogues of the diuretic ethacrynic acid (ECA) have been synthesized and found equivalent in antigelling potency to ECA, but they have moderate or little diuretic activity. Structure-activity studies revealed that most of the highly active derivatives contain an acryloyl moiety. The latter functionality reacts covalently with protein sulfhydryl groups via a Michael addition reaction. Other derivatives, which lack the acryloyl moiety, showed notably lower antigelling activity. Since the antigelling assay is run under anaerobic conditions, activity implies a stereochemical inhibition of polymerization of deoxyhemoglobin S. The solubility ratios obtained from [HbS drug]/[HbS control] of several compounds (Table I) are near those expected for a drug with clinical potential (1.06-1.20 at tolerable doses in vivo).     

N-phosphonocarbonylpyrrolidine derivatives of guanine: a new class of bi-substrate inhibitors of human purine nucleoside phosphorylase

A complete series of pyrrolidine nucleotides, (3R)- and (3S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acids and (3S,4R)-, (3R,4S)-, (3S,4S)-, and (3R,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acids, were synthesized and evaluated as potential inhibitors of purine nucleoside phosphorylase (PNP) isolated from peripheral blood mononuclear cells (PBMCs) and cell lines of myeloid and lymphoid origin. Two compounds, (S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acid (2a) and (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid (6a), were recognized as nanomolar competitive inhibitors of PNP isolated from cell lines with K(i) values within the ranges of 16-100 and 10-24 nM, respectively. The low (MESG)K(i) and (Pi)K(i) values of both compounds for PNP isolated from PBMCs suggest that these compounds could be bisubstrate inhibitors that occupy both the phosphate and nucleoside binding sites of the enzyme.     

Muscarinic cholinergic agonists and antagonists of the 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridine type. Synthesis and structure-activity relationships

A series of 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyr idines (2a-q) were synthesized and tested for central muscarinic cholinergic receptor binding affinity by using [3H]oxotremorine-M and [3H]QNB as ligands and in a functional assay using guinea pig ileum. The analogues with unbranched C1-8-alkyl substituents (2a-g) were agonists, whereas the compounds with branched or cyclic substituents (2h-m) were antagonists. The alkyl ether analogues (2o-q) were also agonists but had lower receptor binding affinity than the corresponding alkyl analogues. The 3-(5-alkyl-1,2,4-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridi ne analogues had only ver low affinity for the central muscarinic receptors and were weak antagonists in the ileum assay. A few 3-(3-butyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyr idines substituted with methyl or hydrogen in the 1-, 5-, or 6-position were synthesized and tested. N-Desmethyl analogue 7 was a potent muscarinic agonist, whereas N-desmethyl-5-methyl analogue 11 and N-methyl-6-methyl analogue 13 both were antagonists with lower muscarinic receptor affinity. The 3-(3-butyl-1,2,4-oxadiazol-5-yl)quinuclidine (17) and tropane (15) analogues were both very potent antagonists with high affinity for central muscarinic receptors. The ratio [IC50(QNB)/IC50(Oxo-M)] x 0.162 proved to be a good indicator of the efficacy of the compounds in the guinea pig ileum assay.     

Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists

The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to β-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.     

4-(1,2-Benzisothiazol-3-yl)alkanoic and phenylalkanoic acids: synthesis and anti-inflammatory, analgesic and antipyretic activities.

Continuing their studies on benzisothiazolyl derivatives, Authors refer to the preparation and pharmacological properties of 4-(1,2-benzisothiazol-3-yl) alkanoic and phenylalkanoic acids. All substances were tested for anti-inflammatory, analgesic and antipyretic properties. As reference compounds, 1,2-benzisothiazolin-3-one and 4-(3-oxo-1,2-benzisothiazolin-3-yl) phenylacetic acid, as prototypes of benzisothiazolinonic derivation. Ibuprofen, as a prototype of substituted arylalkanoic acids, and Phenylbutazone were used. Analysis of the data leaded to the following conclusions. Introduction of the aryl moiety, passing from benzisothiazolylalkanoic to benzisothiazolyl-phenylalkanoic structures, produced a remarkable increase of activity. 2-[4-(1,2-benzisothiazol-3-yl)phenyl] propionic and 2-[4-(1,2-benzisothiazol-3-yl)phenyl]butyiric acids showed anti-inflammatory, analgesic and antipyretic properties comparable to those of Ibuprofen. Substantial differences in variations in activities were observed comparing the properties of benzisothiazolylphenylalcanoic acids with those of the benzisothiazolinonic series, object of preceding studies.     

Synthesis,antibacterial, antifungal and genotoxic activity of bis-1,3,4-oxadiazole derivatives

In the present investigation, four 1,3,4-bis-oxadiazole derivatives were synthesized as potential antimicrobial agents. The compounds are: 5,5'-dimercapto-bis-[1,3,4-oxadiazol-2-yl]propane (2a), 5,5'-dimercapto-bis-[1,3,4-oxadiazol-2-yl]butane (2b), 5,5'-dimercapto-bis-[1,3,4-oxadiazol-2-yl]octane (2c) and 5,5'-dibenzylthio-bis-[1,3,4-oxadiazol-2-yl]butane (3). The above newly synthesized compounds were investigated for their antibacterial, antifungal and mutagenic activities. The results of the biological activities revealed that the compounds 2a-c exhibited both antibacterial and antifungal activities against S. aureuss and B. subtilis. Compound 2a also showed activity against P. aeureoginosa. All the above compounds and compound 3 exhibited activity against C. albicans. Genotoxic studies showed that compound 2a had a weak base pair substitution mutagenicity but none of them exhibited a frameshift mutagenic action using Ames test.     

Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotection.

The isoxazole amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) (1), which is a highly selective agonist at the AMPA subtype of excitatory amino acid (EAA) receptors, has been used as a lead for the development of two novel EAA receptor antagonists. One of the compounds, 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid (AMOA, 7), was synthesized via O-alkylation by ethyl chloroacetate of the amino acid protected AMPA derivative 4. The other compound, 2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-+ ++oxoisoxazolin -4-yl]propionic acid (AMNH, 14) was synthesized with use of 4-(chloromethyl)-3-methoxy-5-methylisoxazole (8) as the starting material. The intermediate 4-(chloromethyl)-2-(3-methoxy-5-methylisoxazol-4-yl)methyl-5-me thylisoxazolin- 3-one (11) was converted into the acetamidomalonate (12), which was stepwise deprotected to give 14. Compounds 7 and 14 were stable in aqueous solution at pH values close to physiological pH. Neither 7 nor 14 showed detectable affinities for the receptor, ion channel, or modulatory sites of the N-methyl-D-aspartic acid (NMDA) receptor complex. Quantitative receptor autoradiographic and conventional binding techniques were used to study the affinities of 7 and 14 for non-NMDA receptor sites. Both compounds were inhibitors of the binding of [3H]AMPA (IC50 = 90 and 29 microM, respectively). Compounds 14 and 7 were both very weak inhibitors of the high-affinity binding of radioactive kainic acid [( 3H]KAIN). Compound 14, but not 7, was, however, shown to be an inhibitor of low-affinity [3H]KAIN binding (IC50 = 40 microM) as determined in the presence of 100 mM calcium chloride. In the rat cortical slice preparation, 7 was shown to antagonize excitation induced by 1 with some selectivity, whereas 14 proved to be a rather selective antagonist of KAIN-induced excitation. Both antagonists showed very weak effects on the excitatory effects of NMDA. Compound 7 was a poor antagonist of excitation by quisqualic acid (2), whereas 14 did not affect excitation by this nonselective AMPA receptor agonist. On cat spinal neurones, both 7 and 14 reduced excitations by 1 and KAIN, but, again, the excitatory effects of 2 were much less sensitive. Compound 14 and, in particular, 7 effectively protected rat striatal neurones against the neurotoxic effects of KAIN, whereas the toxic effects of 1 were reduced only by 7. Neither antagonist showed protection against the cell damage caused by intrastriatal injection of the NMDA agonist quinolinic acid.(ABSTRACT TRUNCATED AT 400 WORDS)     

2-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda6-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides as potent and selective peptide deformylase inhibitors

Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Escherichia coli peptide deformylase (PDF) were obtained by rational optimization of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural information, gathered from Ni-PDF complexed with 1, suggested the preparation of two series of related hydroxamic acid analogues, 2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-N-hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides (B), among which potent PDF inhibitors (37, 42, and 48) were identified. Moreover, two selected compounds, one from each series, 36 and 41, showed good selectivity for PDF over several endoproteases including matrix metalloproteases. However, these compounds showed only weak antibacterial activity.     

Discovery of novel antitumor antimitotic agents that also reverse tumor resistance

We have discovered a novel series of 7-benzyl-4-methyl-5-[(2-substituted phenyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amines, which possess antimitotic and antitumor activities against antimitotic-sensitive as well as resistant tumor cells. These agents bind to a site on tubulin that is distinct from the colchicine, vinca alkaloid, and paclitaxel binding sites and some, in addition to their antitumor activity, remarkably also reverse tumor resistance to antimitotic agents mediated via the P-glycoprotein efflux pump. The compounds were synthesized from N-(7-benzyl-5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide 11 or the corresponding 5-iodo analog 14 via Sonogashira couplings with appropriate iodobenzenes or phenylacetylene followed by reduction and deprotection to afford the target analogs. Sodium and liquid NH3 afforded the debenzylated analogs. The most potent analog 1 was one to three digit nanomolar against the growth of both sensitive and resistant tumor cells in culture. Compounds of this series are promising novel antimitotic agents that have the potential for treating both sensitive and resistant tumors.     

Cardiotonic agents. 3. Synthesis and biological activity of novel 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones

Several 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones were synthesized and evaluated for positive inotropic activity. The 1H-imidazol-4-yl regioisomers 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (25a) and 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (28a) were potent positive inotropic agents. By contrast, the corresponding 1H-imidazol-5-yl regioisomers 25b and 28b were only weak positive inotropic agents. Compounds 25a and 28a were also potent inhibitors of cardiac phosphodiesterase fraction III.     

Exploration of essential structure of malloapelta B for the inhibitory activity against TNF induced NF-κB activation

For the exploration of pharmacophoric moiety of malloapelta B (1) possessing the inhibitory activity of NF-kappaB activation, structural variation of alpha,beta-unsaturated carbonyl motif was attempted. 1 was reduced by catalytic hydrogenation, sodium borohydride, and lithium aluminumhydride. Catalytic hydrogenation with 30 psi or 15 psi of H2 gas of 1 generated 8-butyl-5,7-dimethoxy-2,2-dimethylchroman (2) and 1-(5,7-dimethoxy-2,2-dimethylchroman-8-yl)butan-1-one (3), respectively. Reduction with sodium borohydride occurred at the double bond of alpha,beta-unsaturated ketone of 1 to give 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)butan-1-one (4). Reduction of 1 with lithium aluminumhydride and then quenched with methanol and water produced unexpected products, 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)-3-methoxy-1-butene (5) and 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)-3-hydroxy-l-butene (6). These are formed from the isomerization of initial product 9 through the continuous conjugate carbocation intermediate 11. Addition of ethylmagnesium bromide and dimethyl malonate anion to 1 gave the conjugate adducts 7 and 8. Ethylmagesium bromide and sodium borohydride reduction unusually gave the conjugate addition due to steric congestion around carbonyl group of 1. Compound 2 exhibits the reduced inhibitory activity against NF-kappaB activation and the others do not show the activity. Therefore alpha,beta-unsaturated carbonyl group of 1 should be important for its inhibitory activity.     

Structure-activity studies of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder

A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N'-cyanoguanidino]propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.     

4-Substituted 1-phenyl-1H-indazoles with analgesic, antiinflammatory, antipyretic and local anesthetic activities

The synthesis of amides 3 and 4 starting from (1-phenyl-1H-indazol-4-yl)acetic and [(1-phenyl-1H-indazol-4-yl)oxy]acetic acids, respectively, as well as of 2-(1-phenyl-1H-indazol-4-yl)ethanamines 5 starting from 3, is described. Moreover, a number of 2-[(1-phenyl-1H-indazol-4-yl)oxy]ethanamines 7 and 3-[(1-phenyl-1H-indazol-4-yl)oxy]propanamines 8 were prepared starting from 1-phenyl-1H-indazol-4-ol. Some compounds 3, 4 and 7 showed an appreciable analgesic activity in mice, whereas compounds 4 were moderately active as antiinflammatory agents in rats. Some compounds 3, 4, 5, 7 and 8 showed also local anesthetic and a weak antipyretic activity in mice and rats, respectively.     

Effects of [(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]alkanoic acids, [(N-alkyl-1-oxo-1H,3H-isoindolin-5-yl)oxy]butanoic acids, and related derivatives on chloride influx in primary astroglial cultures

It has been shown that agents that inhibit chloride influx and therefore lower intracellular chloride levels in a major cell type in cerebral gray matter, the astrocyte, inhibit astrocytic swelling in vitro and in vivo. In our laboratories, 4-[(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]alkanoic acids and related derivatives have been synthesized and tested for ability to lower intracellular astrocytic chloride levels in an established in vitro cultured rat astrocyte model. In general, derivatives with nitrogen substituents such as relatively small alkyl groups are active at 0.1 mM and/or 0.5 mM levels whereas larger substituents such as cyclopentyl and cyclohexyl are less active. Halogen substitution on the aromatic ring did not enhance activity. Derivatives with acid side chains of four carbons demonstrated superior activity to those of two carbons.     

Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents

Toxoplasma gondii is an opportunistic pathogen responsible for toxoplasmosis. T. gondii is a purine auxotroph incapable of de novo purine biosynthesis and depends on salvage pathways for its purine requirements. Adenosine kinase (EC.2.7.1.20) is the major enzyme in the salvage of purines in these parasites. 6-Benzylthioinosine and analogues were established as "subversive substrates" for the T. gondii, but not for the human adenosine kinase. Therefore, these compounds act as selective anti-toxoplasma agents. In the present study, a series of N(6)-benzyladenosine analogues were synthesized from 6-chloropurine riboside with substituted benzylamines via solution phase parallel synthesis. These N(6)-benzyladenosine analogues were evaluated for their binding affinity to purified T. gondii adenosine kinase. Furthermore, the anti-toxoplasma efficacy and host toxicity of these compounds were tested in cell culture. Certain substituents on the aromatic ring improved binding affinity to T. gondii adenosine kinase when compared to the unsubstituted N(6)-benzyladenosine. Similarly, varying the type and position of the substituents on the aromatic ring led to different degrees of potency and selectivity as anti-toxoplasma agents. Among the synthesized analogues, N(6)-(2,4-dimethoxybenzyl)adenosine exhibited the most favorable anti-toxoplasma activity without host toxicity. The binding mode of the synthesized N(6)-benzyladenosine analogues were characterized to illustrate the role of additional hydrophobic effect and van der Waals interaction within an active site of T. gondii adenosine kinase by induced fit molecular modeling.     

Anticholinesterasic, nematostatic and anthelmintic activities of pyridinic and pyrazinic compounds

In the search for acetylcholinesterase inhibitors as a potential target for the discovery of anthelmintic drugs, a series of 27 pyridinic and pyrazinic compounds have been designed on the basis of molecular hybridization of two known AChE inhibitors, namely, tacrine and (-)-3-O-acetylspectaline, and on the concept of isosterism. The synthesized compounds generally presented moderate anticholinesterasic activities when compared with the positive control physostigmine, but one compound (ethyl 2-[(6-chloropyrazin-2-yl)sulfanyl] acetate) exhibited an in vitro ability to immobilize the root-knot nematode Meloidogyne incognita that was highly comparable to that of the positive control Temik. Moreover, in anthelmintic assays against the gastrointestinal parasitic nematode Nippostrongylus brasiliensis (L4), some of the compounds, such as (6-chloropyrazin-2-yl)sulfanyl ethanol (32, EC?? = 33 nM), presented activities that were considerably stronger than that of the positive control albendazole (EC?? = 340 nM). In the light of the positive results obtained in the anthelmintic evaluations, the acute oral toxicity of the representative compound diethyl 2,2'-[(3-nitropyridine-2,6-diyl) bissulfanediyl] diacetate was determined in rats, and the drug was shown to be non-toxic at a dose of 2000 mg/kg. These results, allied with the relatively simple structures of the active compounds and their facile synthesis, highlight their potential use as anthelmintic or nematicidic agents.