Benzimidazoles as new potent and selective DP antagonists for the treatment of allergic rhinitis

A series of 2-substituted N-benzyl benzimidazole containing molecules has been synthesized and its structure-activity relationship for the human DP receptor has been evaluated. Selective DP antagonists with nanomolar potency for the DP receptor were identified in this novel series of benzimidazoles.     

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis,biological evaluation,and molecular docking study

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.     

Synthesis and antibacterial activity of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives

A series of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives has been synthesized. The best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.     

Indole amide hydroxamic acids as potent inhibitors of histone deacetylases

A series of hydroxamic acid-based HDAC inhibitors with an indole amide residue at the terminus have been synthesized and evaluated. Compounds with a 2-indole amide moiety have been found as the most active inhibitors among the different regioisomers. Introduction of substituents on the indole ring further improved the potency and generated a series of very potent inhibitors with significant antiproliferative activity. A representative compound in the series, 7b, has been found to be orally active in tumor growth inhibition model.     

Orally bioavailable nonpeptide vitronectin receptor antagonists with efficacy in an osteoporosis model.

A new series of potent nonpeptide vitronectin receptor antagonists, based on a novel carbocyclic Gly-Asp mimetic, has been discovered. A representative of this series, SB 265123 (4), has 100% oral bioavailability in rats, and is orally active in vivo in the ovariectomized rat model of osteoporosis.     

Fractal dimension of birds population sizes time series

Information about fractal dimension is collected so that it can be applied to time series interpreting Hurst coefficient. The population size of a species is modelled as a dynamic system. The Hurst coefficient is calculated for these times series. A computer programme has been elaborated to compute the Hurst exponent of time series using the algorithms of range increment, second order moment increment and local second order moment increment. It has been applied to time series of birds' populations.     

Synthesis and antibacterial activity of 3-O-acyl-6-O-carbamoyl erythromycin A derivatives

A series of 3-O-acyl-6-O-carbamoyl erythromycin A derivatives has been synthesized. Several functional groups were identified as the optimal C3-substituents, and the best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.     

2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion

A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure–activity relationships of these inhibitors, which show potential as antibacterial agents.     

New dual inhibitors of EGFR and HER2 protein tyrosine kinases

A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.     

Optimising inhibitors of trypanothione reductase using solid-phase chemistry

A series of inhibitors of the enzyme trypanothione reductase has been identified using directed solid-phase chemistry. The compounds were based on a series of polyamine scaffolds and used the natural product kukoamine A as the lead structure. A compound with a Ki of 76 nM was identified, although somewhat surprisingly the compound appeared to be noncompetitive in nature.     

Synthesis and antibacterial activity of novel 6-O-substituted erythromycin A derivatives

A series of novel 6-O-substituted erythromycin A derivatives has been synthesized. Good in vitro antibacterial activity has been demonstrated for analogues incorporating a variety of structural features. The methodology disclosed is expected to find application in the design of future macrolide antibiotics that target the prevalent bacterial resistance problem.     

A quantitative structure-activity relationship study on Clostridium histolyticum collagenase inhibitors: roles of electrotopological state indices

A quantitative structure-activity relationship (QSAR) study has been made on eight different series of Clostridium histolyticum collegenase (ChC) inhibitors. These series are comprised of four different groups of sulfonylated amino acids and their corresponding hydroxamates. In each series, the inhibition potency of the compounds has been found to be significantly correlated with the electrotopological state (E-state) indices of nitrogen and sulfur atoms of the sulfonylated amino group in the molecules, showing the importance of the electronic characterstics of these atoms in controlling the inhibition potency of the compounds.     

4,4-Disubstituted cyclohexylamine based CCR5 chemokine receptor antagonists as anti-HIV-1 agents

A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure–activity relationship has been extensively explored.     

Inhibitors of prostaglandin biosynthesis. A bicyclo-[2.2.1]-heptene analogue of ‘2’ series prostaglandins and related derivatives

A series of bicycloheptene prostaglandin analogues has been prepared as potential inhibitors of prostaglandin biosynthesis. Their inhibitory effect has been examined using a ram seminal vesicle preparation.     

Synthesis, hydrolysis and anti-EBV activity of a series of 3'-modified cycloSal-BVDUMP pronucleotides

A series of cycloSal-BVDUMP phosphate triesters has been prepared. The prototype compound was 3-methyl-cycloSal-BVDUMP 2. Furthermore, a series of 3'-O-acyl-modified derivatives having carboxylic acids with different lipophilicity or a L-configurated alpha-amino acid (phenylalanine) was prepared. The hydrolysis properties in phosphate buffer PBS as well as in PBS containing pig liver esterase (PLE) will be described. Finally, the biological activity against EBV has been determined.     

Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors

A novel series of pyrrole inhibitors of MEK kinase has been developed using structure-based drug design. Optimization of the series led to the identification of potent inhibitors with good pharmaceutical properties.     

Synthesis of potent taxoids for tumor-specific delivery using monoclonal antibodies

The targeted delivery of taxoids, in the form of taxane-antibody immunoconjugates, requires the preparation of taxoids containing moieties suitable for their conjugation to monoclonal antibodies. A series of taxoids incorporating a disulfide-containing linker at various positions of the taxoid framework have been prepared to investigate the most suitable position for conjugation. A second series of taxoids modified at the C-2 position aimed at increasing the potency of these taxanes has also been prepared.     

Activity–lipophilicity relationship studies on P-gp ligands designed as simplified tariquidar bulky fragments

A series of alkyloxyquinoline derivatives has been developed to evaluate the relationship between P-gp potency and lipophilicity. The results show a satisfactory lipophilicity-activity correlation although a series of derivatives showing higher P-gp potency is needed in order to confirm this hypothesis.     

The discovery of GSK221149A: a potent and selective oxytocin antagonist

Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.     

Synthesis and Cytotoxic Activity of a Number of Functionalized 2,3-Allenoates

Russian Journal of Bioorganic Chemistry - A series of new functionalized allenoates has been synthesized, and their cytotoxic effect has been studied against the tumor cell line (HepG2 and Jurkat)...