In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C(2)-symmetrical proline- and valine-based amides and their Zn(II) complexes were designed for use as efficient and flexible chiral catalysts for enantioselective aldol reactions in water, on water, and in the presence of water. The presence of 5 mol % of the prolinamide-based catalyst affords asymmetric intermolecular aldol reactions between unmodified ketones and various aldehydes to give anti products with excellent enantioselectivities. We also demonstrate aldol reactions of more demanding substrates with high affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making the elaborated methodology interesting from a green chemistry perspectives.
Experimental drugs for NP can be a treatment option which should be tailor-made for each individual on the basis of pain features, previous therapies, associated clinical conditions, recurrence of pain, adverse effects, contraindications and patients' preferences. At present, there are only some agents which may have potential as novel treatments. Increasing knowledge about mechanisms underlying NP, mechanisms of drug action, as well as available data from preclinical and clinical studies make botulinum toxin A, minocycline, ambroxol, statins and PPAR agonists (ATx086001) promising potential future treatment options.
There is a real hope that new drugs for NP may be available soon. This hope is based on advancing methods of genomics, developing new targets and more efficient drug screening. Some forms of direct influence on voltage-gated ion channels have a place in the treatment of NP, while the development of entirely novel Ang II AT₂ receptor antagonists or NGF inhibitors may be available for many chronic pain sufferers in the foreseeable future.
Malaria continues to be a potentially fatal threat to almost half of the world's population. In the present review, efforts have been made to provide a literature concerning the study of quinoline as a privilege structure for search of new malarials. The review covers advances in that field made in few last years.
Neuropathic pain
resistance to pharmacotherapy has encouraged researchers
to develop effective therapies for its treatment. γ-Aminobutyric
acid (GABA) transporters 1 and 4 (mGAT1 and mGAT4) have been increasingly
recognized as promising drug targets for neuropathic pain (NP) associated
with imbalances in inhibitory neurotransmission. In this context,
we designed and synthesized new functionalized amino acids as inhibitors
of GABA uptake and assessed their activities toward all four mouse
GAT subtypes (mGAT1–4). According to the obtained results,
compounds 2
RS
,4
RS
-
39c
(pIC
50
(mGAT4) = 5.36),
50a
(pIC
50
(mGAT2) = 5.43), and
56a
(with moderate subtype selectivity
that favored mGAT4, pIC
50
(mGAT4) = 5.04) were of particular
interest and were therefore evaluated for their cytotoxic and hepatotoxic
effects. In a set of
in vivo
experiments, both compounds
50a
and
56a
showed antinociceptive properties
in three rodent models of NP, namely, chemotherapy-induced neuropathic
pain models (the oxaliplatin model and the paclitaxel model) and the
diabetic neuropathic pain model induced by streptozotocin; however
compound
56a
demonstrated predominant activity. Since
impaired motor coordination is also observed in neuropathic pain conditions,
we have pointed out that none of the test compounds induced motor
deficits in the rotarod test.
Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.
In the present review, we provide a comprehensive summary of recent pharmacological studies on dopamine transporter (DAT) inhibitors, which are potential treatments for neurodegenerative and psychiatric disorders. Extensive structure-activity relationship studies have identified numerous tropane-based ligands with high affinity and selectivity for the DAT or with high affinity to the DAT and other monoamine transporters (dual and triple monoamine reuptake inhibitors). The review covers advances in the field in past fifteen years. Among the described compounds, many appear to be promising drug candidates, while other may serve as valuable tools for research or as prototypes for new classes of selective DAT inhibitors. Special attention is being paid to separation of the DAT inhibition from NET and SERT inhibition.
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