1,721,028 research outputs found
The application of microwaves in combinatorial and high-throughput synthesis as new synthetic procedure in drug discovery.
No full textHeterocyclic compounds hold a special place among pharmaceutically important natural and synthetic materials. The remarkable ability of heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely contributed to their unique value as traditional key elements of numerous drugs. In both lead identification and optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds; so, the fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery, within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry.
In this review, it is impossible to cover all significant developments in the area of microwave-assisted organic synthesis (MAOS). Rather, outlines the basic principles behind the technology and summarizes the areas in which microwave technology has made an impact, to date. Specific attention is given to application of microwave technology in Combinatorial Organic Synthesis of several representative biologically interesting nuclei obtained both in liquid systems and in the solid state
Synthesis of 6-beta-D-glucosyl and 6-nitroxy (-)-galanthamine derivatives as acetylcholinesterase inhibitors
No full textGalanthamine is an alkaloid approved for the treatment of Alzheimer’s disease. In this paper the syntheses and the anticholinesterase activities of new glucosyl and nitroxy derivatives substituted on position 6 are reported. Compounds 2, 3 and 5 presented a percentage of inhibition of 35.22%, 47.48% and 67.89 % respectivel
Lipophilic and polar interaction forces between acidic drugs and membrane phospholipids encoded in IAM-HPLC indexes: their role in membrane partition and relationships with BBB permeation data.
No full textThe membrane phospholipid affinity data, logkwIAM , for 18 acidic and unionized drugs spanning a wide lipophilicity range were measured by HPLC on two different phospholipid stationary phases, i.e. IAM.PC.MG and IAM.PC.DD2. These data related weakly with both log PN values, the n-octanol/water partition coefficients of the neutral forms, and log D7.4 values, the n-octanol/water partition coefficients of the mixtures of neutral and ionized forms at pH 7.4. The lack of collinearity confirms that, differently from partition in n-octanol/water, partition in phospholipids encodes not only lipophilic/hydrophobic intermolecular recognition forces but also ionic bonds, due to electrostatic interactions between electrically charged species and phospholipids, according to the ???pH-piston hypothesis???. Since, differently from bases, electrostatic interactions between acids and phospholipids take place at the surface of phospholipid layers (choline moieties), and not near their lipophilic core (phosphate moieties), they were parameterized by a new procedure yielding ?????' logkwIAM??? parameters, i.e. the difference between the IAM retention factors observed for the analytes and those of neutral compounds with the same n-octanol partition values displayed by the analytes at pH 7.4. All acidic analytes, but one, and all unionized analytes, but the unionizable ones, showed positive ??'logkwIAM values, indicating that they partition stronger in phospholipids than in n-octanol. Log BB values (capability to pass BBB) weakly related with both lipophilicity and phospholipid affinity values; in contrast they inversely related with ??'logkwIAM values. The relationships between log BB and ??'logkwIAM practically overlapped the previously found log BB/??logkwIAM relationships for bases. The excess of polar interaction component between acidic drugs and phospholipids, mainly electrostatic forces, although enhancing partition in phospholipids, hinders membrane passage, analogously to the behavior previously reported for bases.
The study suggests that IAM-HPLC is an effective technique to perform simple and fast measurements of the intermolecular recognition forces related to membrane partition and permeation. This can contribute to better understand the mechanisms governing both partition of charged species in cell membranes and passage through them, also allowing the possible optimization of the pharmacokinetic properties of the drugs at the early stages of their development
Montelukast salts and pharmaceutical compositions containing the same
No full textThe present invention relates to salts of Montelukast with β2 adrenergic agonists, pharmaceutical compositions containing the same and the use thereof in the treatment of respiratory inflammatory pathologies, obstructive pathologies and allergen-induced airway dysfunctions. The invention further relates to the process for preparing said salts
Microwave Assisted Synthesis: A New Technology in Drug Discovery
No full textThe interest in the microwave assisted organic synthesis has been growing during the recent years. It results from an increasing knowledge of fundamentals of the dielectric heating theory, availability of an equipment designed especially for the laboratory use as well as the discovery of the special techniques of the microwave syntheses. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry and this aspect is of great importance in high-speed combinatorial and medicinal chemistry. In this contribution, the current state of the art is summarized providing examples of the most recent applications in the field of microwave assisted synthesis of biologically active compounds both in heterocyclic and in peptide and peptidomimetic optimization
Synthesis and pharmacological evaluation of peptide-mimetic protease-activated receptor-1 antagonists containing novel heterocyclic scaffolds
No full textProtease-activated receptor-1 (PAR-1) is a G-coupled receptor activated by a-thrombin and other proteases. In this paper
we describe the synthesis and the pharmacological evaluation of novel peptide-mimetic antagonists (compounds 1–16) characterized
by the presence of new heterocyclic nuclei such as 2-methyl-indole (5- and 6-substituted) and 1,4-benzodiazepine moiety. The new
derivatives, tested in order to evaluate their antagonist potency by using human platelet aggregation induced by PAR-1AP, resulted
in some cases (compounds 1 and 4) more potent than the reference. The compounds, tested on aortic rings, confirmed the results
obtained in the aggregation assay
Multiple in Vitro Inhibition of HIV-1 Proteins by 2,6-Dipeptidyl-anthraquinone Conjugates Targeting the PBS RNA
Full text linkWe recently reported a series of 2,6-dipeptidyl-anthraquinone conjugates (AQs) as Trans-Activation Response element (TAR) RNA-binding agents able to inhibit in vitro the HIV-1 nucleocapsid (NC) protein-mediated processes. Because NC is a highly adaptable nucleic acid chaperone assisting several crucial steps along reverse transcription, in this study we investigate the ability of AQs to interact with other virus-derived nucleic acid structures thus potentially inhibiting multiple NC functions. Focusing on the HIV-1 Primer Binding Site (PBS) RNA sequence, we demonstrate that properly substituted dipeptidyl-anthraquinone conjugates efficiently inhibit the NC-mediated primer annealing in the low micromolar range. Similarly, we extended the analysis to the HIV-1 trans-activator of transcription (Tat) peptide, which has been recently shown to mimic the annealer functions of NC upon interacting with the same nucleic acid regulatory sequences. Our results highlight how RNA-targeting agents can act as multimode inhibitors of key viral proteins affecting their chaperone activity in reverse transcription processes
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