Synthesis and receptor binding studies of 3-substituted piperazine derivatives

In order to find novel receptor ligands various substituents were introduced into the side chain in position 3 of the piperazine 5. During nucleophilic substitution of the hydroxy group of 5 aziridinium ions were formed, resulting in rearranged 1,4-diazepanes and piperazines as side products. 1,2-anellated piperazines 15, 18 and 19 were prepared by hydrogenation of the alpha,beta-unsaturated ester 13 and by condensation of the primary amine 16b with formaldehyde, respectively. Receptor binding studies with radioligands revealed that the phenylacetamide 17b interacts with moderate affinity (K(i) = 181 nM) and considerable selectivity with sigma(1) receptors.     

DNA binding and biological studies of some novel water-soluble polymer-copper(II)-phenanthroline complexes

Some novel water-soluble polymer-copper(II)-phenanthroline complex samples, [Cu(phen)2(BPEI)]Cl(2).4H2O (phen=1,10-phenanthroline, BPEI=branched polyethyleneimine), with different degrees of copper complex content in the polymer chain have been prepared by ligand substitution method in water-ethanol medium and characterized by infrared, UV-visible, EPR spectral and elemental analysis methods. The binding of these complex samples with DNA has been investigated by electronic absorption spectroscopy, emission spectroscopy and gel retardation assay. Electrostatic interactions between DNA molecule and polymer-copper(II) complex molecule containing many high positive charges have been observed. Besides these ionic interactions, van der Waals interactions, hydrogen bonding and other partial intercalation binding modes may also exist in this system. The polymer-copper(II) complex with higher degree of copper complex content was screened for its antimicrobial activity and antitumor activity.     

Synthesis and antileishmanial profile of some novel terpenyl pyrimidines

Some novel terpenyl pyrimidine derivatives 2(a-d) and 6(a-b) have been synthesised from alpha/beta-ionone keteneacetals 1 and 5. The terpenyl pyrimidine 2e has been synthesised from beta-ionone 3 in two steps in quantitative yield. The pyrimidine derivatives were screened for in-vivo antilesihmanial activity. The compounds 2d, 2e, 6a and 6b showed promising in-vivo antileishmanial activity.     

Synthesis and antimicrobial activity of some novel dicationic sulphonophanes

The synthesis of some novel imidazole-based dicationic sulfonophanes incorporating various spacer units is described. All the sulphonophanes exhibit good antibacterial and antifungal activity against five bacterial strains Bacillus subtilis, Staphylococcus aureus, Vibrio cholera, Escherichia coli, Proteus vulgaris and human pathogenic fungus Candida albicans.     

Synthesis by microwave irradiation and binding properties of novel 5-HT(1A) receptor ligands.

This work reports the synthesis by microwave irradiation and the binding tests on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors of new substituted piperazines in order to identify selective ligands for 5-HT(1A) subtype receptor. Conventional heating and microwave irradiation of the reactions was compared. Synthesis by microwave irradiation gave the desired compounds in better yields than those obtained by conventional heating. The overall times for the syntheses were considerably reduced. Some resulting active compounds (29 and 39) were characterised by a good selectivity profile for the 5-HT(1A) subtype receptor. The more active compounds were selected and further evaluated for their binding affinities on D(1), D(2) dopaminergic and alpha(1), alpha(2) adrenergic receptors. The compound with higher affinity and selectivity for the 5-HT(1A) over all the considered receptors was the 3-[4-[4-(1,2,3,4-tetrahydronaphthyl)-1-piperazinyl]butan]-benzotriazinone (-)29 (5-HT(1A) K(i)=36 nM, other receptors not active).     

Synthesis and dopamine receptor binding of bridged tricyclic dopamine analogues

The bridged tricyclic dopamine analogues exo-2-(N-n-propylamino)-6,7-dihydroxybenzonorbornene, exo-2-(N,N-di-n-propylamino)-6,7-dihydroxybenzonorbornene, and exo-2-amino-6,7-dihydroxybenzobicyclo[2.2.2]octene have been synthesized and assayed for their effects on the binding of [³H]spiperone and [³H]apomorphine to rat striatal membranes. The inactivity of these compounds is rationalized on the basis of proposed topographical models of dopamine receptors.     

Synthesis and antimicrobial studies of novel dichlorofluorophenyl containing aminotriazolothiadiazines

Dichlorofluorophenyl containing aminotriazolothiadiazines (6) were synthesized by initial condensation of 2-chloro-N-(substituted phenyl) acetamides (4) with triazole (3) and further cyclization using POCl(3). The structures of newly synthesized compounds were confirmed by IR, NMR, mass and elemental analysis. All the compounds were screened for their antibacterial and antifungal activities. Compounds 5a, 5e, 5n, 5o, 6a, 6n, and 6o showed very good antibacterial and antifungal activities at 6.25 microg/ml concentrations.     

Synthesis of some novel imidazolinones as potent anticonvulsant agents

Imidazolinone derivatives of IIa-IIc, IIIa-IIIf and IVa-IVf have been synthesised by the condensation of some known sulpha drugs with 5-oxazolone derivatives, which were prepared by Erlenmeyer condensation of benzoyl glycine with different aldehydes in the presence of sodium acetate and acetic anhydride. The constitution of the products has been supported by elemental analysis and IR, 1H-NMR spectral data. The products have been screened for their (a) in vitro growth inhibitory activity against several microorganisms and (b) in vivo anticonvulsant activity.     

Synthesis, antitumor evaluation and DNA binding studies of novel amidino-benzimidazolyl substituted derivatives of furyl-phenyl- and thienyl-phenyl-acrylates, naphthofurans and naphthothiophenes

A series of amidino-substituted benzimidazoles, related to furyl-phenyl- and thienyl-phenyl-acrylates, naphthofurans and naphthothiophenes were prepared, their antitumor evaluation and interactions with ct-DNA have been investigated. All tested compounds show differential and strong antitumor activity without apparent difference depending on their structures. Interestingly, the MCF-7 tumor cell line is highly sensitive to all compounds. Compounds 6-9 showed noticeable selectivity in regard to normal fibroblasts (WI 38). Compounds 4-9 interact with ct-DNA by more binding modes, whose mutual distribution is dependent on the compound/DNA ratio. The "acyclic"4-6 and "cyclic" compound 7 interact mostly within the minor groove of DNA, although partial intercalation of 6 and 7 cannot be excluded. The "cyclic" compounds 8 and 9 intercalate between DNA base pairs at high excess of DNA over compounds.     

Effects of riboflavin deficiency upon age-related changes in beta-adrenergic and adenosine receptor binding in rat adipocytes

The binding of (-)(3H)dihydroalprenolol (DHA) and (-)-N6-(3H)phenyl-isopropyladenosine (PIA) to beta-adrenergic and adenosine receptors, respectively, was determined in membranes of adipocytes isolated from riboflavin-deficient rats and age-matched, pair-fed controls for feeding periods of three to forty weeks. In normal chow-fed animals, the binding of both ligands to receptors markedly decreased in older compared to that in younger animals. In young, riboflavin-deficient animals, DHA binding diminished compared to that in age-matched controls. No further decrease in binding of DHA occurred in older, aged-matched, riboflavin-deficient rats. Riboflavin deficiency did not have any effect on PIA binding in either young or old animals. Thus, in riboflavin deficiency, beta-adrenergic binding in adipocyte membranes from young animals is reduced and the normal age-related decrease in this receptor binding does not occur. By contrast, the binding of PIA to adenosine receptors is lower in older than in younger animals regardless of riboflavin nutriture.     

Synthesis and antimicrobial studies on novel chloro-fluorine containing hydroxy pyrazolines

A series of chloro-fluorine containing chalcones (3) were prepared by Claisen-Schmidt condensation. Chalcone dibromides (4) were obtained by the bromination of chalcones at room temperature. Treatment of chalcone dibromides (4) with aryloxy acid hydrazides (5) in the presence of triethylamine gave chloro-fluorine containing hydroxy pyrazolines (7) rather than the expected 1-aryloxy-3-aryl-5-aryl pyrazoles (6). The structures of the newly synthesized compounds were confirmed by IR, NMR, mass and elemental analysis. All the compounds were tested for their antibacterial and antifungal activities. Some compounds showed very good antibacterial activity and antifungal activity.     

Synthesis, potent anti-staphylococcal activity and QSARs of some novel 2-anilinobenzazoles

Synthesis and anti-staphylococcal activity of a number of substituted 2-anilinobenzimidazoles, benzothiazoles and benzoxazoles are reported. The anti-staphylococcal activities were evaluated in standard in vitro MIC assay method. While anilinobenzimidazole derivatives 11-45 showed very potent anti-staphylococcal activities (greatest activity with an MIC value of 0.095 microg/mL), none of the 2-anilinobenzothiazoles and benzoxazole derivatives exhibited inhibitory activity. QSAR analysis of the anilinobenzimidazoles was studied on the relationship between the anti-staphylococcal activity (MIC in mug/ml) and extrapolated log k(w) values.     

Synthesis and QSAR studies of novel 1-substituted-2-aminobenzimidazoles derivatives

A series of novel 1-substituted-2-aminobenzimidazole derivatives were synthesized. The structures of the synthesized compounds were confirmed by 1H-NMR spectra and by elemental analysis. Acute toxicities of these compounds were detected on mice via toxicity (logLD50). QSAR analysis of these chemicals was studied on the relationship between acute toxicity and the octanol/water partition coefficient (LogP). The products were identified by the results of elemental analysis and 1H-NMR spectra. The toxicity (logLD50) of 2-aminobenzimidazole 1-substituents were correlated well with the partition coefficient LogP, r=0.9243. The bioactivity (toxicity) of 2-aminobenzimidazoles can be predicted by the molecular structural parameter such as LogP.     

Gestodene: a novel synthetic progestin--characterization of binding to receptor and serum proteins

Gestodene, 17 alpha-ethinyl-13-ethyl-17 beta-hydroxy-4,15-gonadien-3-one, is a new orally active progestational agent, which is available for clinical use in oral contraceptives. The aim of the present study is to make a broad characterization of gestodene at the receptor level and to discuss the results in comparison to those of established progestogens. Kinetic studies of 3H-gestodene uptake show a rapid increase in the amount of specific binding during the first three hours. After saturation, the amount of specifically bound 3H-gestodene remained almost constant up to 24 hours at 4 degrees C. The dissociation of 3H-gestodene from the cytoplasmic myometrial progestone receptor, measured by displacement of labeled steroid with dextran-coated charcoal treatment at 4 degrees C at various times, showed a biphasic or two-component first order dissociation curve. As anticipated, sucrose gradient centrifugation analysis of the 3H-gestodene-labeled cytosol of human myometrial tissue showed that the gestodene binding components sedimented in the 4S and 8S region. A 200-fold molar excess of nonradioactive gestodene reduced only the 8S binding of 3H-gestodene. 4S binding of 3H-gestodene was not reduced, which indicate the existence of a second high capacity binding component. In biological test systems, such as the Clauberg test or Kaufmann test, gestodene has proved to be a very effective progestogen. Among nortestosterone derivatives it is one of the most potent and resembles progesterone biologically in its progestogenic effects. This biologically identical gestagenic activity of gestodene and progesterone is reflected by a very similar behavior in vitro in terms of binding to progesterone receptors of human uterus cytosol. Furthermore, competitive studies indicated that gestodene like other synthetic progestagens also displays some affinity for androgen and glucocorticoid receptors but no measurable affinity for the estrogen receptor. Remarkable is the high binding affinity of gestodene to the binding sites of the mineralocorticoid receptor of rat kidney with a RBA value of 350% compared to aldosterone.     

Synthesis of novel tetrahydroimidazole derivatives and studies for their biological properties

Ethylenediamine was reacted with suitable aromatic aldehydes in order to prepare their respective diSchiff bases. These compounds were then reduced to give the corresponding tetrahydrodiSchiff bases, which were low melting in nature. Finally, these derivatives were condensed with different aromatic aldehydes to give the desired tetrahydroimidazoles. The structures of all these compounds were established on the basis of spectral data. These novel tetrahydroimidazoles showed promising anti-inflammatory and analgesic activity. The compounds were also screened for their anti-bacterial property against Staphylococcus aureus and Escherichia coli.     

Synthesis of novel isoxazolidine derivatives and studies for their antifungal properties

A series of novel 5-substituted isoxazolidine derivatives 3a(i-viii), 3b(i-viii) and 3c(i-viii) have been prepared and their antifungal activity on Aspergillus flavus, Fusarium moniliforme and Botrydiplodia theobromae have been evaluated.     

Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors

With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measurements of a series of 4-(aryl)piperidin-3-one O-4-benzyl oxime hydrochlorides (1-10) of both E and Z configuration. E configuration compounds showed high SERT binding affinities (K_i = 10-98 nM) and high SERT selectivities over both NET and DAT. The molecular docking studies allowed a rationalization of the molecular basis of drug-SERT interactions both of the synthesized compounds and paroxetine and fluoxetine used as reference antidepressant drugs.     

Synthesis of some novel 2,4-disubstituted thiazoles as possible antimicrobial agents

A series of novel 4-aryl/chloroalkyl-2-(2,3,5-trichlorophenyl)-1,3-thiazoles (5a-g and 7a-e) were synthesized by condensing 2,3,5-trichlorobenzenecarbothioamide with phenacyl bromide/dichloroacetone. 2,3,5-Trichlorobenzaldehyde thiosemicarbazone on treatment with phenacyl bromide afforded 4-aryl-2-(2,3,5-trichlorophenylidenehydrazino)-1,3-thiazoles (10a-g) in good yield. The newly synthesized compounds are characterized by IR, (1)H NMR and mass spectral studies. These compounds were also screened for their antibacterial and antifungal activities. Preliminary results reveal that some of the synthesized compounds are showing promising antimicrobial activity.     

Synthesis and biological evaluation of some novel cyclic-imides as hypoglycaemic, anti-hyperlipidemic agents

Certain new halogenated cyclic-imides related to N-substituted phthalimide moiety were synthesized. Spacers of one or two carbon atom distances were inserted to connect the N-terminus of the cyclic-imide nuclei to the used heteroaryl groups to evaluate the effect of such alteration on biological activity. The synthesized compounds were subjected to hypoglycaemic and anti-hyperlipidemic evaluation. Some of the tested compounds proved to be more potent than the reference drugs glibenclamide and clofibrate. Compound 5e remarkably reduced serum glucose level by 55%; while 5c, 5e, 7d and 8e reduced total serum cholesterol by 58, 56, 54 and 53%, respectively. Those new cyclic-imides could be considered as useful template for future development to obtain more potent hypoglycaemic and anti-hyperlipidemic agents.     

Synthesis, SAR and antibacterial studies on novel chalcone oxazolidinone hybrids

With an intention to synergise the antibacterial activity of chalcones and oxazolidinones, several hybrid compounds possessing both chalcone and oxazolidinone moieties were synthesized and tested for antibacterial activity. The hybrid molecules containing heterocycles instead of aromatic ring were found to be active. A SAR study with various heterocycles resulted in a lead molecule 20, which was converted to one of the potent antibacterial compounds 27.