N, N -disubstituted piperazines and homopiperazines: synthesis and affinities at alpha4beta2* and alpha7* neuronal nicotinic acetylcholine receptors

A series of N, N- disubstituted piperazines and homopiperazines were prepared and evaluated for binding to natural alpha4beta2* and alpha7* neuronal nicotinic acetylcholine receptors (nAChRs) using whole brain membrane. Some compounds exhibited good selectivity for alpha4beta2* nAChRs and did not interact with the alpha7* nAChRs subtype. The most potent analogs were compounds 8-19 (K(i) = 10.4 microM), 8-13 (K(i) = 12.0 microM), and 8-24 (K(i) = 12.8 microM). Thus, linking together a pyridine pi-system and a cyclic amine moiety via a homopiperazine ring affords compounds with low affinity but with good selectivity for alpha4beta2* nAChRs.     

Design,synthesis and structure–activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression

A novel series of quinoxalin-2-carboxamides were designed based on the ligand-based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The obtained compounds’ structures were confirmed by spectral data. The target new chemical entities were evaluated for their 5-HT₃ receptor antagonisms in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT₃ agonist, 2-methyl-5-HT, which was expressed in the form of pA₂ value. All the synthesized compounds showed antagonism towards 5-HT₃ receptor; based on this result, a structure–activity relationship was derived, which reveals that the aromatic residue in 5-HT₃ receptor antagonists may have hydrophobic interaction with 5-HT₃ receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA₂ values exhibited good anti-depressant-like activity as compared to the vehicle-treated group.     

Synthesis and pharmacological evaluation of a novel series of 3-aryl-2-(2-substituted-4-methylthiazole-5-yl)thiazolidin-4-one as possible anti-inflammatory and antimicrobial agents

A new series of 3-aryl-2-(2-aryl/benzyl-4-methylthiazole-5-yl)thiazolidin-4-one was synthesized by condensation of 2-aryl/benzyl-4-methylthiazole-5-carbaldehyde, aromatic amines and thioglycolic acid in toluene. All the synthesized compounds are characterized by IR, NMR and elemental or mass analysis. Sixteen out of the newly synthesized compounds were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema method. Some of the synthesized compounds exhibited good anti-inflammatory activity compared with indomethacin. The synthesized compounds were also evaluated for their in vitro antimicrobial activity. Some of the compounds showed mild antibacterial activity while most of the compounds showed good antifungal activity.     

Design, synthesis, inhibitory activity, and SAR studies of pyrrolidine derivatives as neuraminidase inhibitors

A series of pyrrolidine derivatives were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus (H3N2). All compounds were synthesized in good yields starting from commercially 4-hydroxy-L-proline using a suitable synthetic strategy. These compounds showed potent inhibitory activity against influenza A neuraminidase. Within this series, five compounds, 6e, 9c, 9e, 9f, and 10e, have good potency (IC(50)=1.56-2.71 microM) which are compared to that the NA inhibitor Oseltamivir (IC(50)=1.06 microM), and could be used as lead compoundS in the future.     

Design, synthesis, inhibitory activity, and SAR studies of hydrophobic p-aminosalicylic acid derivatives as neuraminidase inhibitors

A series of hydrophobic p-aminosalicylic acid derivatives containing a lipophilic side chain at C-2 and an amino or guanidine at C-5 were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus (H3N2). All compounds were synthesized in good yields starting from commercially available p-aminosalicylic acid (PAS) using a suitable synthetic strategy. These compounds showed potent inhibitory activity against influenza A NA. Within this series, six compounds, 11, 12, 13e, 16e, 17c, and 18e, have the good potency (IC(50)=0.032-0.049 microM), which are compared to Oseltamivir (IC(50)=0.021 microM) and could be used as lead compounds in the future.     

Synthesis of the novel series of bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase

Six potential AChE reactivators were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by insecticide chlorpyrifos was tested in vitro. According to the results, (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide seems to be the most potent AChE reactivator. The reactivation potency of these compounds depends on structural factors such as constitution of the linking chain between both pyridinium rings, position of the oxime moiety at the pyridinium ring and presence of quaternary nitrogens.     

Synthesis and in vivo diuretic activity of some novel pyrimidine derivatives

A series of 1,6-dihydropyrimidine-2-amine derivatives and 1,6-dihydropyrimidine-2-thiol derivatives were synthesized by the reaction of substituted 1,3-diphenylprop-2-en-1-one (chalcones) with guanidine hydrochloride and thiourea, respectively. All the synthesized compounds were in good agreement with elemental and spectral data. The synthesized compounds were screened in vivo for diuretic activity. The four compounds 2d, 2e, 3d and 3e, which showed moderate to good diuretic activity, were evaluated for their toxicity studies and none of the compounds showed any toxicity of the liver as compared with control. However, compounds 3e and 3d showed diuretic properties more than that of standard (acetazolamide) and were long acting. Overall, compound 3e, 6-(2,6-dichlorophenyl)-4-(pyridin-2-yl)-1,6-dihydropyrimidine-2-thiol, was found to be the most promising candidate of the series.     

In vitro efficacy of new antiprotozoals against Philasterides dicentrarchi (Ciliophora, Scuticociliatida)

Philasterides dicentrarchi is a histiophagous ciliate that causes severe losses in turbot and sea bass farming. This study investigated the in vitro efficacy against P. dicentrarchi of 85 newly synthesized compounds and 12 commercial compounds, of which 2 are fluoroquinolones (norfloxacine and lomefloxacine) with known antibacterial activity. Seventeen of the newly synthesized compounds (2 naphthyridines, 2 pyridothienodiazines and 13 pyridothienotriazines) and the fluoroquinolone norfloxacin showed good activity. The most promising compound was the pyridothienotriazine 12k, with activity similar to that of the salicylanilides niclosamide and oxiclozanide (MLC 0.8 mg l(-1) in PBS, 1.5 mg l(-1) in seawater; MLC = minimum 24 h lethal concentration).     

Semantic and prosodic effects of Dutch linking elements

The studies presented here investigate the contribution of linking -en- and rhythm to a compound’s conceptual plurality. Participants were asked to estimate the conceptual plurality of the modifier constituents of Dutch compounds. In the first study, pseudo-compounds (compounds composed of pseudo-words, burb+en+tijpis) and novel compounds (novel combinations of existing nouns, aap+en+leraar, ‘monkey teacher’) with linking -en- were investigated. In study two, we examined written existing compounds that occur with and without -en- (bloem+bak or bloem+en+bak, ‘flower box’) and present a stress clash or not at the constituent boundaries. Finally, study three investigated the same question as study two for spoken existing compounds. The results reveal that existing compounds written or spoken with linking -en- are considered to bear more plural meaning than the ones without linking element. Furthermore, an effect of rhythm on plurality was observed in pseudo-compounds and in spoken existing compounds. When these compounds contain linking -en- to prevent a stress clash, they are considered to bear less plural meaning than those with linking -en- in a neutral context. These studies demonstrate that rhythm can affect the interpretation of linking elements. The fact that we only find a rhythmic effect in pseudo-compounds and spoken existing compounds but not in written existing compounds is explained in terms of processing.     

Synthesis of a novel series of bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase

Nine potential AChE reactivators were synthesized using a modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by insecticide chlorpyrifos was tested in vitro. 2,2'-Bis(hydroxyiminomethyl)-1,1'-(1,4-phenylenedimethyl)-bispyridinium dibromide seems to be the most potent AChE reactivator. The reactivation potency of these compounds depends on structural factors such as length of the linking chain between both pyridinium rings and position of the oxime moiety on the pyridinium ring.     

Synthesis, biological evaluation, and docking studies of 3-(substituted)-aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines as potent anti-inflammatory and antioxidant agents

A novel series of 3-(substituted)-aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines (5a-o) has been synthesized and the structures of newly synthesized compounds were characterized by IR, (1)H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their in vitro and in vivo anti-inflammatory activity, and also for their antioxidant activity. Compounds 5b, 5c, 5d and 5n were found to be selective COX-2 inhibitors. Compound 5c was found to potent inhibitor of the carrageenin induced paw edema in rats. Most of the compounds exhibited good DPPH and superoxide radical scavenging activity, while compounds 5c, 5d, 5i and 5k exhibited good hydroxyl radical scavenging activity. Molecular docking result, along with the biological assay data, suggested that compound 5c was a potential anti-inflammatory agent.     

Antitumor agents. 256. Conjugation of paclitaxel with other antitumor agents: evaluation of novel conjugates as cytotoxic agents

Sixteen different taxoid conjugates were prepared by linking various anticancer compounds, including camptothecin (CPT), epipodophyllotoxin (EP), colchicine (COL), and glycyrrhetinic acid (GA), at the 2'- or 7-position on paclitaxel (TXL, 1) through an ester, imine, amine, or amide bond. Newly synthesized conjugates were evaluated for cytotoxic activity against replication of several human tumor cell lines. Among them, TXL-CPT conjugates, 8-10, were more potent than TXL itself against the human prostate carcinoma cell line PC-3 (ED(50)=14.8, 3.1, 19.4nM compared with 55.5nM), and conjugate 10 was also 8-fold more active than TXL against the LN-CAP prostate cancer cell line. These compounds also possessed anti-angiogenesis ability as well as lower inhibitory effects against a normal cell line (MRC-5). Thus, conjugates 8-10 are possible antitumor drug candidates, particularly for prostate cancer.     

Synthesis and anticonvulsant activity of sulfonamide derivatives-hydrophobic domain

A series of sulphonamide derivatives (1-11) were synthesized in good yield and evaluated for their possible anticonvulsant activity and neurotoxic study. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Majority of the compounds were active in MES and scPTZ tests. All the compounds were less toxic than the standard drug phenytoin.     

Preparation of New Spiropyrazole,Pyrazole and Hydantoin Derivatives and Investigation of Their Antioxidant and Antibacterial Activities.

In this study, the synthesis of new spiropyrazoles, pyrazole and hydantoin heterocycles is reported by three component reactions of parabanic acids, hydrazine derivatives, and phenacyl bromides in the presence of triphenylphosphine as a nucleophile and triethylamine as a base in good to high yields (69–91 %). Evaluation of the synthesized compounds revealed a good to excellent antioxidant activities (37.6–96.2 %) using DPPH inhibitory potency. Among these compounds, hydantoin derivatives displayed higher antioxidant activities (93.7–96.2 %) comparing with spiropyrazoles and pyrazoles. The obtained results showed that Cl and Br substituents on the phenyl ring increased antioxidant activities of the related heterocycles. The antibacterial activities of the synthesized compounds were examined against two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. Among the synthesized heterocycles, 2-[1,3-dimethyl-2,5-dioxo-4-(2-oxo-2-phenylethyl)imidazolidin-4-yl]hydrazine-1-carbothioamide exhibited the excellent antibacterial activity against both Gram-positive and Gram-negative bacteria.     

A new benzoangelicin with strong photobiological activity

Benzoangelicins 4-6 were synthesized in good yields from 7-hydroxy-5-methoxy-4-methylcoumarin (1). In the absence of UVA radiation, compounds 5 and 6 were only weakly active against HL60 and HeLa tumour cells; in its presence, compound 6 was 10 times more active than the reference compound 8-methoxypsoralen. None of 4-6 exhibited cutaneous phototoxicity.     

Novel 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues as cytotoxic agents

A series of 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues were synthesized and evaluated for cytotoxic activity against eight human cancer cell lines. Compounds 18, 21, 28, 29, 30 and 31 showed cytotoxic activity with GI(50) values in the range of 2.1-8.1 microM concentration. Among these, compounds 21 and 28 exhibited good pharmacokinetic properties. These compounds were further evaluated for their in vivo efficacy in modified hollow fibre assay (HFA).     

Synthesis, biological active molecular design, and molecular docking study of novel deazaflavin-cholestane hybrid compounds

Novel deazaflavin-cholestane hybrid compounds, 3',8'-disubstituted-5'-deazacholest-2,4-dieno[2,3-g]pteridine-2',4'(3'H,8'H)-diones, have been synthesized by condensation reaction between 6-(monosubstituted amino)-pyrimidin-2,4(1H,3H)-diones and 2-hydroxymethylenecholest-4-en-3-one in presence of p-toluenesulfonic acid monohydrate and diphenyl ether. The antitumor activities against human tumor cell lines (CCRF-HSB-2 and KB cells) have been investigated in vitro, and many of these compounds showed promising antitumor activities. Furthermore, molecular docking study using LigandFit within the software package Discovery Studio 1.7 was done for lead optimization of these compounds as potential PTK inhibitors. In general, all of the synthesized steroid-hybrid compounds showed good binding affinities into PTK (PDB code: 1t46).     

Synthesis and biological evaluation of 2-thiopyrimidine derivatives

Various 2-thiopyrimidine derivatives have been synthesized by an efficient, one-pot reaction of functionalized amines with either 4-isothiocyanato-4-methyl-2-pentanone or 3-isothiocyanatobutanal. All the synthesized compounds were fully characterized by elemental analysis (CHN), FT-IR, (1)H NMR, and mass spectral data. One of the compounds, 7,7,8a-trimethyl-hexahydro-thiazolo[3,2-c]pyrimidine-5-thione (17) showed good anti-inflammatory (37.4% at 100 mg/kg p.o.) and analgesic activity (75% at 100 mg/kg p.o.). 7-(1-Mercapto-3,3,4a-trimethyl-4,4a,5,9b-tetrahydro-3H-pyrido[4,3-b]indol-7-yl)-3,3,4a-trimethyl-3,4,4a,5-tetrahydro-benzo[4,5]imidazo[1,2-c]pyrimidine-1-thiol (3) showed moderate activity against CDK-1 (IC(50)=5 microM). The other compounds showed moderate anti-inflammatory (5-20%), analgesic (25-75%) and protein kinase (CDK-5, GSK-3) inhibitory activities (IC(50)> 10 microM).     

Approach to dual-acting platelet activating factor (PAF) receptor antagonist/thromboxane synthase inhibitor (TxSI) based on the link of PAF antagonists and TxSIs

A series of compounds (22-36) which possess dual-acting PAF antagonist/TxSI have been generated by the approach of linking the known PAF antagonists and TxSIs, such as Ridogrel (1).     

Synthesis, characterization, and relaxivity of two linear Gd(DTPA)-polymer conjugates

Two linear polyamide conjugates of Gd(DTPA)2- were synthesized and characterized by high-resolution nuclear magnetic resonance (NMR) spectroscopy and size exclusion chromatography (SEC). DTPA was copolymerized with two different diamines, 1,6-hexanediamine and trans-1,4-cyclohexanediamine, yielding the polymers DTPA-HMD and DTPA-CHD, with low polydispersity. Their molecular flexibility in solution was studied using 13C spin-lattice relaxation time measurements, indicating that the cyclohexanediamine linking moiety of the DTPA-HMD polymer is more rigid than that of DTPA-CHD. The influence of the flexibility of the linking functionalities on the relaxivity of the Gd3+-DTPA-polymer conjugates was studied by water nuclear magnetic relaxation dispersion (NMRD). The relaxivity of the Gd(DTPA-CHD) polymer was only slightly higher than that of the Gd(DTPA-HMD) polymer, and only two times higher than the usual values for small Gd-DTPA-like chelates. The low relaxivities obtained for both polymers, much lower than expected from the polymer apparent molecular weights, result from their substantial residual flexibility, and also from a too long, nonoptimal, value of the inner-sphere water exchange rate. These polymeric compounds are also cleared very quickly from the blood of rats, indicating that they are of limited value as blood pool contrast agents for MRA.