Novel imidazobenzazepine derivatives as dual H1/5-HT2A antagonists for the treatment of sleep disorders

A novel imidazobenzazepine template (5a) with potent dual H₁/5-HT_2A antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R¹-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H₁/5-HT_2A receptor antagonist activities and good developability profiles.     

N-Substituted acetamidines and 2-methylimidazole derivatives as selective inhibitors of neuronal nitric oxide synthase

A series of N-substituted acetamidines and 2-methylimidazole derivatives structurally related to W1400 were synthesized and evaluated as Nitric Oxide Synthase (NOS) inhibitors. Analogs with sterically hindering isopropyl and phenyl substituents on the benzylic carbon connecting the aromatic core of W1400 to the acetamidine nitrogen, showed good inhibitory potency for nNOS (IC(50)=0.2 and 0.3 μM) and selectivity over eNOS (500 and 1166) and to a lesser extent over iNOS (50 and 100). A molecular modeling study allowed to shed light on the effects of the structural modifications on the selectivity of the designed inhibitors toward the different NOS isoforms.     

Discovery and structure–activity relationship of a novel spirocarbamate series of NPY Y5 antagonists

A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3 mg/kg po.     

Synthesis and structure–activity relationship of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-5-(2-pyridinyl)-1,3-thiazol-2-amines derivatives as NPY Y5 antagonists

A novel class of small molecule NPY Y5 antagonists based around an azabicyclo[3.1.0]hexane scaffold was identified through modification of a screening hit. Structure–activity relationships and efforts undertaken to achieve a favourable pharmacokinetic profile in rat are described.     

Chaotic Red Queen coevolution in three-species food chains

Coevolution between two antagonistic species follows the so-called ‘Red Queen dynamics’ when reciprocal selection results in an endless series of adaptation by one species and counteradaptation by the other. Red Queen dynamics are ‘genetically driven’ when selective sweeps involving new beneficial mutations result in perpetual oscillations of the coevolving traits on the slow evolutionary time scale. Mathematical models have shown that a prey and a predator can coevolve along a genetically driven Red Queen cycle. We found that embedding the prey–predator interaction into a three-species food chain that includes a coevolving superpredator often turns the genetically driven Red Queen cycle into chaos. A key condition is that the prey evolves fast enough. Red Queen chaos implies that the direction and strength of selection are intrinsically unpredictable beyond a short evolutionary time, with greatest evolutionary unpredictability in the superpredator. We hypothesize that genetically driven Red Queen chaos could explain why many natural populations are poised at the edge of ecological chaos. Over space, genetically driven chaos is expected to cause the evolutionary divergence of local populations, even under homogenizing environmental fluctuations, and thus to promote genetic diversity among ecological communities over long evolutionary time.     

Bovine lactoferrin interacts with cable pili of Burkholderia cenocepacia

In this study we evaluated the ability of lactoferrin, the most abundant antimicrobial protein in airway secretions, to bind the surface structures of a Burkholderia strain cystic fibrosis-isolated. Burkholderia cenocepacia is a gram-negative bacterium involved as respiratory pathogen in cystic fibrosis patient infections. This bacterium possesses filamentous structures, named cable pili that have been proposed as virulence factors because of their ability to bind to respiratory epithelia and mucin. Previously, we demonstrated that bovine lactoferrin was able to influence the efficiency of invasion of different iron-regulated morphological forms of B. cenocepacia. Bovine lactoferrin showed to efficiently inhibit invasion of alveolar epithelial cells by free-living bacteria or iron-induced aggregates or biofilm. Results of the present study demonstrate that bovine lactoferrin is also able to specifically bind to B. cenocepacia cells and show that cable pili are involved in this interaction. The attachment of bovine lactoferrin to pili led to a reduced binding of bacterial cells to mucin. Since cable pili are implicated in mediating the bacterial interactions with mucin and epithelial cells, lactoferrin binding to these structures could play an important role in neutralizing bacterial infection in cystic fibrosis patients.     

Structure–activity relationships in 1,4-benzodioxan-related compounds. 10. Novel α1-adrenoreceptor antagonists related to openphendioxan: Synthesis,biological evaluation,and α1d computational study

A series of novel openphendioxan analogues were synthesized and tested at α₁-adrenoreceptor (AR) subtypes by binding and functional assays. The α_1d-AR binding profile was also examined by means of 2D, 3D-QSAR together with docking studies. Multiple regression analysis suggested the relevance of adequate number of heteroatoms in the whole molecule and of passive membrane diffusion to enhance α_1d-AR affinity. Docking simulations against a computational structural model of the biological target further proved this evidence and furnished support for chemiometric analysis, where polar, electrostatic, hydrophobic and shape effects of the ortho substituents in the phenoxy terminal, most likely governing ligand binding, helped the depiction of pharmacophore hypothesis for the examined ligands data set.     

Synthesis and biological evaluation of diastereoisomerically pure N,O-nucleosides

Several N,O-nucleosides have been synthesized in good yields by direct 1,3-dipolar cyclization methodology, in the absence of solvent. A remarkable cis stereoselectivity (de 98%) was observed by tuning the substituents on the nitrone moiety. A good number of these N,O-nucleosides have been evaluated for cytotoxic activity against selected cellular lines. Some of the tested compounds have proven to be potential antiproliferative drugs.     

Association between MUC1 gene polymorphism and expected progeny differences in Nelore cattle (Bos primigenius indicus)

MUC1 is a heavily glycosylated mammalian transmembrane protein expressed by mucosal secretory tissues for both protection against microbial infection and lubrication. An important characteristic of MUC1 is its variable number of tandem repeats (VNTR) containing several sites for O-glycosylation. VNTR length has been associated with many human diseases and with certain economically important traits in domestic ruminants. The aim of the present study was to correlate the length of MUC1 gene VNTR with expected progeny differences (EPDs) obtained for growth, fertility and carcass traits. Five alleles were identified, with alleles containing short VNTRs being more frequent than those with long, thereby demonstrating that Brazilian Nelore cattle are characterized by high frequencies in short MUC1 VNTRs. Statistical analyses revealed there to be no significant association between VNTR length and EPDs for weight at 120 days (W(120) ), scrotal circumference at 365 (SC (365) ) and 450 (SC (450) ) days, age at first calving (AFC), and rib eye area (REA).