A new class of arylpiperazine derivatives: the library synthesis on SynPhase lanterns and biological evaluation on serotonin 5-HT(1A) and 5-HT(2A) receptors

An efficient solid-supported method for the synthesis of a new class of arylpiperazine derivatives containing amino acid residues has been developed. A 72-membered library was synthesized on SynPhase Lanterns functionalized by a BAL linker. A one-pot cleavage/cyclization step of aspartic and glutamic acid derivatives yielded succinimide- and pyroglutamyl-containing ligands (chemsets 9 and 10). The library representatives under study showed different levels of affinity for 5-HT(1A) and 5-HT(2A) receptors (estimated K(i) = 24-4000 and 1-2130 nM, respectively). Several dual 5-HT(1A)/5-HT(2A) ligands were found, of which two (9(3,3) and 9(3,5)) displayed high 5-HT(2A) affinity comparable to that of the reference drug ritanserin. A set of individual fragment contributions for the prediction of 5-HT(1A) and 5-HT(2A) affinity of all the library members were defined on the basis of the Free-Wilson analysis of 26 compounds. An alkylarylpiperazine fragment had essentially the same impact on the affinity for both receptors, whereas different terminal amide fragments were preferred by 5-HT(1A) (chemset 17, R(2) = adamantyl) and 5-HT(2A) (chemset 9, R(2) = norborn-2-ylmethyl) binding sites.     

Arylpiperazine derivatives of diphenylsulfide:Synthesis and evaluation for dual 5-HT1A/SSRI activities

The design, synthesis and biological evaluation of a novel series of arylpiperazine derivatives of diphenylsulfide with dual 5- HT1A/SSRI activities are reported. The target compounds exhibit low to moderate 5-HT transporter affinity and moderate to high 5- HT1A affinity, Compound 13a shows moderate dual activities and is a promising lead compound for further structure-activity relationships studies.     

Molecular modeling studies focused on 5-HT7 versus 5-HT1A selectivity. Discovery of novel phenylpyrrole derivatives with high affinity for 5-HT7 receptors

The present study discusses the well-known 5-HT7/5-HT1A selectivity issue through a new series of phenylpyrrole derivatives. The first hits emerged from a virtual screening performed on a chemolibrary. Further study led to an optimization of a preliminary 5-HT7 pharmacophore model. The importance of each pharmacophoric feature is confirmed, but these characteristics have to be coupled to geometric constraints in order to achieve a 5-HT7 selectivity. Indeed, 5-HT1A affinity probably arises from extended conformations, whereas a bent one appears to be best suited for 5-HT7 selectivity.     

Synthesis,characterization, pharmacological,molecular modeling and antimicrobial activity evaluation of novel isomer quinoline derivatives

The structural and spectroscopic characteristics of the synthesized structurally novel compound 4-chloro-6-methylquinoline-2(1H)-one (4C6MQ) and its isomer 4-chloro-8-methylquinoline-2(1H)-one (4C8MQ) have been examined by means of experimental and computational quantum chemical methods like density functional theory (DFT). The crystal structure of the 4C6MQ compound has been brought to light by single-crystal x-ray diffraction (SCXRD) method which consists of two independent molecules (A and B) in the asymmetric unit with similar conformations. Both the isomer compounds are characterized spectroscopically by FTIR, FT-Raman, UV-Vis, and NMR spectrum and compared with DFT results. The geometries of the isomer compounds have been optimized by using DFT/B3LYP method with the 6-311G++(d,p) basis sets. From the optimized geometry of the compounds, geometric parameters (bond lengths, bond angles, and torsion angles); vibrational analysis; chemical shifts; and electronic absorption of the isomer compounds have been computed and compared with the experimental result. The detailed assignments of vibrational wave numbers have been prepared based on potential energy distribution (PED) which was carried out in the VEDA4 program. In addition, natural bonding orbital analysis, frontier molecular orbital, and molecular electrostatic potential have been explained theoretically. The in silico (absorption, distribution, metabolism, excretion and toxicity) studies were analyzed to identify the potential drug likeliness of the isomer compounds. The implications of the inhibitory activity of isomer compounds against DNA gyrase and lanosterol 14 α-demethylase enzyme by molecular docking are discussed. Further, the isomer compounds were screened for their antibacterial and antifungal activities.     

Synthesis,pharmacological evaluation,and molecular modeling studies of novel isatin hybrids as potential anticancer agents

A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N₄ piperazine was found to be the most active with the promising IC₅₀ (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.     

Synthesis,molecular modeling,and pharmacological evaluation of new 2-substituted benzoxazole derivatives as potent anti-inflammatory agents

Structural Chemistry - In the present work, 2-substituted benzoxazole derivatives were synthesized from 2-(benzo[d]oxazol-2-yl) aniline. All the synthesized compounds were purified and...     

1-[2-（2-Methoxyphenylthio） benzyl]-4-arylpiperazines derivatives： Synthesis and evaluation for dual 5-HT1A/SSRI activities

A series of 1-[2-（2-methoxyphenylthio） benzyl]-4-arylpiperazines derivatives was designed and synthesized based on 5-HT1A/ SSRI drugs design strategies. The synthesized compounds were evaluated for their dual 5-HT1A/5-HTT activities. 2007 Ai Jun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.     

Lower homologues (methyl, ethyl) of diorganotin derivatives of germyl (substituted) propanoic acids: spectroscopic elucidations and biological studies

Some novel lower homologues of diorganotin derivatives of germyl substituted propanoic acids with general formula [Ar(3)GeCH(R(1))CH(R(2))COO](2)SnR(2)(3), where Ar = p-CH(3)C(6)H(4), C(6)H(5), R(1) = p-CH(3)C(6)H(4), p-CH(3)OC(6)H(4), o-CH(3)OC(6)H(4), C(6)H(5), R(2) = H, CH(3), R(3) = CH(3), C(2)H(5) have been prepared by the condensation reaction of dialkyltin oxide and triarylgermyl(substituted) propanoic acid in 1 : 2 M ratio, respectively, and were characterized by IR, multinuclear ((1)H, (13)C, (119)Sn) NMR, (119 m)Sn M?ssbauer spectroscopy. The synthesized compounds were also screened for their toxicity and possible antibacterial, antifungal activities and found some encouraging results.     

SAR study of 1-aryl-4-(phenylarylmethyl)piperazines as ligands for both dopamine D2 and serotonin 5-HT1A receptors showing varying degrees of (Ant)agonism. Selection of a potential atypical antipsychotic

The syntheses of several 1-aryl-4-(arylpyridylmethyl)piperazines (4) and their affinities for dopamine D(2) and serotonin 5-HT(1A) receptors are described. The compounds were evaluated both in vitro and in vivo, resulting in the identification of the drug candidate SLV313 (4e) with equipotent and full D(2) receptor antagonism and 5-HT(1A) receptor agonism. Minor structural modifications in SLV313 revealed the possibility of designing compounds possessing varying degrees of partial agonism on one or both target receptors.     

Synthesis of novel 5-HT1A arylpiperazine ligands: Binding data and computer-aided analysis of pharmacological potency

Serotonin receptors modulate numerous behavioral and neuropsychological processes. Therefore, they are the target for the action of many drugs, such as antipsychotics, antidepressants, antiemetics, migraine remedies, and many others. The 5-HT1A receptors have been involved in the pathogenesis and treatment of anxiety and depression and represent a promising target for new drugs with reduced extrapyramidal side effects. In most antidepressants, a piperazine-based structural motif can be identified as a common moiety. Here we describe the synthesis, pharmacological, and in silico characterization of a novel arylpiperazines series with excellent 5-HT1A affinity. The final compounds, 4a, 8a, and 8b, were selected according to predictions of in silico pharmacokinetics, docking analysis, and molecular dynamics in conjunction with physical properties, and metabolic stability. The accentuated molecules could serve as a lead compound for developing 5-HT1A drug-like molecules for depression treatment.     

Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-ben zoazepine-1-carbonyl]benzanilide and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1- carbonyl]benzanilide derivatives

Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V1A and V2 receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl ]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinity compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahyd ro-1H-1 -benzoazepin-5-ylidene}acetamide (14) exhibited the most potent binding affinity and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2,3,4,5- tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V1A and V2 receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.     

New 3-(4-arylpiperazin-1-yl)-1-(benzo[b]thiophen-3-yl)-2-methylpropanol derivatives:Synthesis and evaluation for dual 5-HT1A/SSRI activities

A series of 3-(4-arylpiperazin-1-yl)-l-(benzo[b]thiopben-3-yl)-2-methylpropanol derivatives were designed and synthesized based on 5-HT1A/SSRI drugs design strategies.The synthesized compounds were evaluated for their dual 5-HT1A/5-HTT activities.     

Coplanarity in the backbones of ladder-type oligo(p-phenylene) homologues and derivatives

p-Tolyl-substituted ladder-type oligo(p-phenylene)s containing three, four, and five phenylene rings were readily synthesized. The uniform aryl substitution of these systems allowed us to determine the coplanarity of the pi-conjugated backbones crystallographically. The intramolecular annulations eliminate almost all of the conformational disorder and enhance the degree of pi-conjugation of the backbones, resulting in significant red shifts in the absorption and emission maxima and lower oxidation potentials in the higher homologues. [structure: see text]     

N-（2-（2-Methoxyphenylthio）benzyl）-2-aryloxyethylamines： Synthesis and evaluation for dual 5-HT1A/SSRI activities

The design, synthesis and biological evaluation of N-（2-（2-methoxyphenylthio） benzyl）-2-aryloxyethyl amines with dual 5-HT1A/SSR/activities are reported. Compound 8e displays the best dual activities and is a promising lead compound for further SAR studies.     

Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 1. The selection of naphthalene derivatives

The synthesis and design using molecular modeling techniques for non-peptide, low molecular weight novel fibrinogen receptor (glycoprotein IIb/IIIa: Gp IIb/IIIa) antagonists, is reported. We used a highly potent serine protease inhibitor, Nafamostat, having an amidinonaphthyl unit as the starting compound. The compounds 4-(6-amidino-2-naphthylaminocarbonyl)phenoxyacetic acid (5a) and 4-(6-amidino-2-naphthalenecarboxamido)phenoxyacetic acid (5b) inhibited adenosin-5'-diphospate (ADP)-induced aggregation of human platelet-rich plasma (PRP) with IC50 values of 0.05 and 0.07 microM, respectively, and had lost their ability to inhibit a variety of serine proteases, including thrombin, factor Xa, plasmin and trypsin.     

1-（N-（2-（2-Methoxyphenylthio）benzyl）-N-methylamino-3-aryloxypropan-2-ols： Synthesis and evaluation for dual 5-HT1A/SSRI activities

A series of 1-（N-（2-（2-methoxyphenylthio）benzyl）-N-methylamino-3-aryloxypropan-2-ols derivatives were designed and synthesized based on 5-HT1A/SSRI drugs design strategies. The synthesized compounds were evaluated for their dual 5-HT1A/ 5-HTT activities. 2007 Ai Jun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.     

Synthesis of 6-(4-methyl-1-piperazinyl)-7H-indeno[2,1-c]-quinoline derivatives as potential 5-HT receptor ligands

Two synthetic pathways for the achievement of the title compounds are reported. The key intermediate, namely 3-carboxy-4-phenyl-2(1H)-quinolinone 9 , was directly cyclized into the corresponding 6-chloro-7H-indeno[2,1-c]quinolin-7-one 10 or alternatively it was esterified, reduced to the alcohol, chlorinated and cyclized into the 6-chloro-7H-indeno[2,1-c]quinoline 8 . Further reaction of the chloroindenoquinoline derivatives with N-methylpiperazine afforded the piperazinyl derivatives 4a-c .     

Synthesis and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as potent sodium channel blockers for the treatment of stroke

In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.