| 1. |
- Lehmann, Fredrik, 1976, et al.
(author)
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Design, parallel synthesis and SAR of novel urotensin II receptor agonists
- 2007
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 42, s. 276-285
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Journal article (peer-reviewed)abstract
- A 30-membered library of amides based on the potent urotensin II (UII) receptor agonist FL104, has been synthesized from ten different carboxylic acids and three amines. A synthetic protocol producing the amides in 47-98% yield has been developed in which the purification involved only extractions and in a few cases filtration through an ion-exchange resin. It was found that 5 mg of starting material was enough to obtain reproducible results and excellent purities. Thus, the procedure is estimated to be transferable to fully automated systems. The synthesized compounds were evaluated for their UII receptor agonistic activities using a cell-based assay (R-SAT). The most active compounds were the 4-trifluoromethylcinnamic amides of 1-(4-chlorophenyl)-3-dimethylamino-propylamine and 1-(2-naphthyl)-3-dimethylamino-propylamine, both showed EC50 values of 130 nM. © 2006 Elsevier Masson SAS. All rights reserved.
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| 2. |
- Minkkilä, Anna, et al.
(author)
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The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors.
- 2009
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In: European Journal of Medicinal Chemistry. - Paris : Édifor. - 0223-5234 .- 1768-3254. ; 44:7, s. 2994-3008
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Journal article (peer-reviewed)abstract
- A series of para-substituted phenolic N-alkyl carbamates were evaluated for their FAAH and MGL inhibitory activities. The compounds were generally selective for FAAH, with IC50 values in the nM range, whereas inhibition of MGL required concentrations three orders of magnitude higher. The most potent compounds, dodecylcarbamic acid 4-(4,5-dihydrothiazol-2-yl)phenyl (12) and 4-(1,2,3-thiadiazol-4-yl)phenyl (26) esters, inhibited FAAH and MGL with IC50 values at the low-nanomolar (IC50s; 0.0063 and 0.012 μM) and the low-micromolar ranges (IC50s; 2.1 and 1.0 μM), respectively. Compound 26 also inhibited both FAAH-dependent AEA uptake and AEA hydrolysis (IC50; 0.082 μM) by intact RBL2H3 cells, and could also reduce 2-AG hydrolysis by these cells at concentrations ≥0.030 μM.
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| 3. |
- Velkov, Zhivko A., et al.
(author)
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Melatonin : Quantum-chemical and biochemical investigation of antioxidant activity
- 2009
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 44:7, s. 2834-2839
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Journal article (peer-reviewed)abstract
- Experimental and theoretical investigation of the antioxidant activity of melatonin is carried out. The theoretical approach comprises the evaluation of several appropriate descriptors of scavenging activity with the help of quantum-chemistry methods. The values obtained are compared with available data for substances with established antioxidant properties. One of the most widely used markers for in vivo free radical oxidation processes is malondialdehyde (MDA) as an end product of membrane lipid peroxidation. Experimental support of the computed scavenging parameters is provided by estimation of the effect of supplementary melatonin therapy on the plasma levels of MDA in CRF patients on maintenance HD therapy. Different reaction paths have been considered and related to the obtained data, allowing speculations about the reaction mechanism and the antioxidant potential of melatonin for practical purposes.
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| 4. |
- Paulino, M., et al.
(author)
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Studies of trypanocidal (inhibitory) power of naphthoquinones: : evaluation of quantum chemical molecular descriptors for structure-activity relationships
- 2008
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 43:10, s. 2238-2246
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Journal article (peer-reviewed)abstract
- Electronic, lipophilic and steric descriptors included in QSAR-2D and -3D are analyzed for a set of ortho- and para-naphthoquinones that have proved to be powerful oxidative agents with potent trypanocidal activities specially against Leptomonas seymouri and Trypanosoma cruzi. Electronic properties are calculated by means of semiempirical (PM3), ab initio (HF/3-21G) and density functional theory (B3LYP/6-31 + G*) methodologies. Three different electronic states, neutral quinones, hydroquinones and semiquinones, are studied to investigate if any one of them are statistically related with the biological activities. The best correlations were obtained at the B3LYP level of theory because it includes electronic correlation. The QSAR-2D indicates that the best trypanocidal growth inhibitors are molecules in the semiquinone electronic state, with the following properties: (a) high negative value of EHOMO, (b) high negative charge in the oxygen atoms of the carbonyl groups, (c) high positive charge in the carbon atom of one of carbonyl moieties and (d) high electronegativity (χ). In a complementary way, the QSAR-3D indicates that the electrostatic field correlates with trypanocidal activity and the presence of bulk moieties would increase activity. The idea of comparing the three electronic states may prove to be of most importance in the general strategy to the design of new trypanocidal drugs. In fact, the experimental results showed that semiquinone is the one really statistically relevant indicating a clear connection between biochemical and theoretical aspects. Finally, we demonstrated that to be a good anti-trypanosomatid compound, the molecule must be a good electron acceptor to reach easily the essential semiquinone state. We expect that the present results motivate new experimental as well as theoretical investigations that confirm our findings.
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