5-Benzylidene-hydantoins: synthesis and antiproliferative activity on A549 lung cancer cell line.

Benzylidene hydantoins have been recently reported as a new class of EGFR inhibitors. We describe here a simple and efficient methodology for the parallel solution-phase synthesis of a library of 5-benzylidene hydantoins, which were evaluated for antiproliferative activity on the human lung adenocarcinoma A549 cell line. Various substituents at positions 1, 3 and 5 on the hydantoin nucleus were examined.

Synthesis and structure-activity relationships for biphenyl H3 receptor antagonists with moderate anti-cholinesterase activity.

The combination of antagonism at histamine H(3) receptors and inhibition of acetylcholinesterase has been recently proposed as an approach to devise putative new therapeutic agents for cognitive diseases. The 4,4'-biphenyl fragment has been reported by us as a rigid scaffold leading to potent and selective non-imidazole H(3)-antagonists. Starting from these premises, the current work presents an expanded series of histamine H(3) receptor antagonists, characterized by a central 4,4'-biphenyl scaffold, where the structure-activity profile of both mono-basic and di-basic compounds is further explored and their ability to inhibit rat brain cholinesterase activity is determined.

Synthesis and stability in biological media of 1H-imidazole-1-carboxylates of ROS203, an antagonist of the histamine H3 receptor.

A series of carbamate derivatives of the H(3) antagonist ROS203 (1) were prepared, and their lipophilicity and steric hindrance were modulated by introducing linear or branched alkyl chains of various lengths. In vitro stability studies were conducted to evaluate how structural modulations affect the intrinsic reactivity of the carbamoyl moiety and its recognition by metabolic enzymes. Linear alkyl carbamates were the most susceptible to enzymatic hydrolysis, with bioconversion rates being higher in rat liver and plasma.

Aryl azoles with neuroprotective activity--parallel synthesis and attempts at target identification.

A parallel synthesis of aryl azoles with neuroprotective activity is described. All compounds obtained were evaluated in an in vitro assay using a NMDA toxicity paradigm showing a neuroprotective activity between 15% and 40%. The potential biological target of the active compounds was investigated by extensive literature searches based around similar scaffolds with reported neuroprotective activity.

Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure.

Synthesis and structure-activity relationships of FAAH inhibitors: cyclohexylcarbamic acid biphenyl esters with chemical modulation at the proximal phenyl ring.

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the intracellular hydrolysis of fatty acid ethanolamides such as anandamide and oleoylethanolamide. Targeting this enzyme may have important therapeutic potentials owing to the multiple physiological roles of these amides. Cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) was one of the most promising FAAH inhibitors so far described.

5-benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity.

A series of 1,5-disubstituted hydantoins, whose structure was designed to interact at the ATP-binding site of EGFR, was synthesized and evaluated for inhibition of EGFR kinase activity and antiproliferative action. Some of these compounds, characterized by a 1-phenethyl and a 5-(E)-benzylidene substituent, inhibited EGFR autophosphorylation and polyGAT phosphorylation, and also inhibited the growth and proliferation of human A431 cells, which overexpress EGFR. These compounds can therefore be regarded as examples of a new scaffold for tyrosine kinase inhibitors.

Dibasic non-imidazole histamine H3 receptor antagonists with a rigid biphenyl scaffold.

A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a biphenyl fragment. Modulation of the distance between the two amine groups, and of their alkyl substituents, was driven by superposition of molecular models and docking into a receptor model, resulting in the identification of 1,1'-[biphenyl-4,4'-diylbis(methylene)]bis-piperidine (5) as a subtype-selective H3 antagonist with high binding affinity (pKi=9.

Synthesis, antioxidant activity and structure-activity relationships for a new series of 2-(N-acylaminoethyl)indoles with melatonin-like cytoprotective activity.

5-Methoxy-2-(N-acetylaminoethyl)indole (5d), a melatonin analogue derived from the transposition of the acetylaminoethyl side chain from C3 to C2 of the indole nucleus, had been previously characterized as a low affinity antagonist at MT1 and MT2 membrane receptors; this molecule is endowed with good in vitro antioxidant and cytoprotective potency in rat cerebellar cell cultures, comparable to or better than those of melatonin. In order to further investigate the role of structure-antioxidant activity relationships in cytoprotection, the structure of 5d was systematically modulated to design a new series of compounds. The 5-methoxy group was replaced by substituents with different electronic and lipophilic properties and it was moved to a different position on the indole ring.

Synthesis and biological evaluation of new non-imidazole H3-receptor antagonists of the 2-aminobenzimidazole series.

A novel series of non-imidazole H(3)-receptor antagonists was developed, by chemical modification of a potent lead H(3)-antagonist composed by an imidazole ring connected through an alkyl spacer to a 2-aminobenzimidazole moiety (e.g., 2-[[3-[4(5)-imidazolyl]propyl]amino]benzimidazole), previously reported by our research group.

Validation of a histamine H3 receptor model through structure-activity relationships for classical H3 antagonists.

Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H(3) antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H(3) receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H(3) antagonists.

Analysis of structure-activity relationships for MT2 selective antagonists by melatonin MT1 and MT2 receptor models.

Three-dimensional homology models of human MT(1) and MT(2) melatonin receptors were built with the aim to investigate the structure-activity relationships (SARs) of MT(2) selective antagonists. A common interaction pattern was proposed for a series of structurally different MT(2) selective antagonists, which were positioned within the binding site by docking and simulated annealing. The proposed antagonist binding mode to the MT(2) receptor is characterized by the accommodation of the out-of-plane substituents in a hydrophobic pocket, which resulted as being fundamental for the explanation of the antagonist behavior and the MT(2) receptor selectivity.

Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies.

Fatty acid amide hydrolase (FAAH) is a promising target for modulating endocannabinoid and fatty acid ethanolamide signaling, which may have important therapeutic potential. We recently described a new class of O-arylcarbamate inhibitors of FAAH, including the cyclohexylcarbamic acid biphenyl-3-yl ester URB524 (half-maximal inhibitory concentration, IC(50) = 63 nM), which have significant anxiolytic-like properties in rats. In the present study, by introducing a selected group of substituents at the meta and para positions of the distal phenyl ring of URB524, we have characterized structure-activity profiles for this series of compounds and shown that introduction of small polar groups in the meta position greatly improves inhibitory potency.

Imidazole H3-antagonists: relationship between structure and ex vivo binding to rat brain H3-receptors.

H3-antagonists possess promising pharmacological effects on awakening, learning and memory, but few data on their access to the central nervous system (CNS) have been reported so far. The purpose of this work was to investigate the relationships between structure and brain penetration of a series of H3-antagonists, using ex vivo binding experiments in rats. H3-antagonists belonging to different chemical classes but all having an imidazole ring, an alkyl spacer, a polar fragment and a lipophilic ending group, were selected among the numerous H3-antagonists recently described by us.

Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity.

This work reports the design and synthesis of novel alkylamides, characterized by a dibenzo[a,d]cycloheptene nucleus, as melatonin (MLT) receptor ligands. The tricyclic scaffold was chosen on the basis of previous quantitative structure-activity studies on MT1 and MT2 antagonists, relating selective MT2 antagonism to the presence of an aromatic substituent out of the plane of the MLT indole ring. Some dibenzo seven-membered structures were thus selected because of the noncoplanar arrangement of their benzene rings, and an alkylamide chain was introduced to fit the requirements for MLT receptor binding, namely, dibenzocycloheptenes with an acylaminoalkyl side chain at position 10 and dibenzoazepines with this side chain originating from the nitrogen atom bridging the two phenyl rings.

Antioxidant and cytoprotective activity of indole derivatives related to melatonin.

Melatonin (MLT) is known for its radical scavenger activity, which had been related to its ability to protect neuronal cells from different kinds of oxidative stress. In particular, MLT protects rat cerebellum granular cells from kainate-induced necrosis at concentrations higher than 100 microM, and is able to reduce lipoperoxidation induced by radical stress in rat brain homogenate at similar concentrations. On the other hand, MLT has nanomolar affinity for its membrane receptors (MT1 and MT2), and these are completely saturated at the high concentrations employed when the cytoprotective effect is observed.

Indole-based analogs of melatonin: in vitro antioxidant and cytoprotective activities.

The known neuroprotective actions of melatonin could be due to its antioxidant or radical scavenging activity, or they could be due to specific interactions of the indole with its receptors. A study of structure-activity relationships may provide useful information when a validated macromolecular target has not been (or is not) identified. A set of indole derivatives, with changes in the 5-methoxy and acylamino groups, the side chain position and the lipophilic/hydrophilic balance, were selected and tested for their in vitro antioxidant potency in the ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid disodium salt) and thiobarbituric acid reactive substances (TBARS) assays and for their cytoprotective activity against kainate excitotoxicity on cerebellar cell cultures.

Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H3-antagonists.

We report the design, synthesis, QSPR and QSAR of a new class of H(3)-antagonists, having a 2-aminobenzimidazole moiety connected to the 4(5) position of an imidazole ring through di- or tri-methylene chains. Eleven substituents, selected by experimental design to obtain broad and non-correlated variation in their lipophilic, electronic and steric properties, were introduced at the 5(6) position of the benzimidazole nucleus. The compounds were tested for their H(3)-receptor affinity, by displacement of [(3)H]-(R)-alpha-methylhistamine ([(3)H]-RAMHA) binding to rat brain membranes (pK(i)), for intrinsic activity, evaluating their effect on [(35)S]GTPgammaS binding to rat brain membranes, and for H(3)-antagonist potency, on electrically stimulated guinea-pig ileum (pK(B)).

Synthesis and three-dimensional quantitative structure-activity relationship analysis of H3 receptor antagonists containing a neutral heterocyclic polar group.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity.

pH-partition profiles of 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenyl and phenoxyalkanoic acids.

The 1,2-benzisothiazolin-3-one nucleus is well known in the medicinal chemistry literature for the variety of biological effects exerted by its derivatives. In the present paper, the dependence of the n-octanol/buffer distribution coefficient (D) on pH of four 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenyl and phenoxyalkanoic acids was investigated, employing the reference shake-flask method. From the analysis of the pH-partition profiles in the chosen partition system, the logP(AH), the logP(A(-)) and the pK(a) values for each compound were determined.

The role of HB-donor groups in the heterocyclic polar fragment of H3-antagonists. I. Synthesis and biological assays.

It has been recently reported that compounds composed of an imidazole connected through an alkyl spacer to a 2-aminobenzimidazole showed high affinity towards the H(3)-receptor. The guanidine fragment of the 2-aminobenzimidazole is probably involved in hydrogen bond interactions at the binding site, and is referred to as the 'polar fragment'. In the present work, starting from 2-aminobenzimidazole derivatives with a di-methylene spacer 1 (pK(i)=7.

Synthesis and structure-activity relationships of a series of pyrrole cannabinoid receptor agonists.

We designed and synthesized a series of pyrrole derivatives with the aim of investigating the structure-activity relationship (SAR) for the binding of non-classical agonists to CB(1) and CB(2) cannabinoid receptors. Superposition of two pyrrole-containing cannabinoid agonists, JWH-007 and JWH-161, allowed us to identify positions 1, 3 and 4 of the pyrrole nucleus as amenable to additional investigation. We prepared the 1-alkyl-2,5-dimethyl-3,4-substituted pyrroles 10a-e, 11a-d, 17, 21, 25 and the tetrahydroindole 15, and evaluated their ability to bind to and activate cannabinoid receptors.

Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors.

Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the deactivation of fatty acid ethanolamides such as the endogenous cannabinoid anandamide, the intestinal satiety factor oleoylethanolamide, and the peripheral analgesic and anti-inflammatory factor palmitoylethanolamide. In the present study, we report on the design, synthesis, and structure-activity relationships (SAR) of a novel class of potent, selective, and systemically active inhibitors of FAAH activity, which we have recently shown to exert potent anxiolytic-like effects in rats. These compounds are characterized by a carbamic template substituted with alkyl or aryl groups at their O- and N-termini.

Three-dimensional quantitative structure-activity relationship studies on selected MT1 and MT2 melatonin receptor ligands: requirements for subtype selectivity and intrinsic activity modulation.

The three-dimensional quantitative structure-activity relationship comparative molecular field analysis (3D-QSAR CoMFA) approach was applied to some classes of melatonin (MLT) membrane receptor ligands, with the principal aim of exploring the correlation between their steric features and MT(2)-selective antagonism. Binding data obtained from cloned MT(1) and MT(2) receptor subtypes were used to develop 3D-QSAR models for agonists and for antagonists at the two receptor subtypes, looking for the structural requirements for receptor subtype selectivity. In particular, we superposed the compounds showing antagonist activity, or very low intrinsic activity at the GTPgammaS test, following the hypothesis that the occupation of an additional pocket positioned out of the plane of MLT is one of the major determinants for MT(2) selectivity; the statistical models obtained confirmed this hypothesis.