Eduarda Mendes

Acyloxymethyl as a drug protecting group: Part 4. The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acid agents.

AbstractPurpose. Novel tertiary amidomethyl esters were synthesized and evaluated as potential prodrugs of carboxylic acid agents. Methods. The hydrolyses of the title compounds in buffer solutions and in plasma were studied by UV spectroscopy and HPLC. Results. Amidomethyl esters were hydrolyzed by acid-catalyzed, base-catalyzed and pH-independent pathways. Both the acid-catalyzed,

Synthesis and pharmacological assessment of diversely substituted pyrazolo(3,4-b)quinoline, and benzo(b)pyrazolo(4,3-g)(1,8)naphthyridine derivatives

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A new direct synthesis of tertiary N-acyloxymethylamide prodrugs of carboxylic acid drugs

, and pH-independent processes, ko, were strongly affected by the electronic and steric nature of the N-substituent in the pro-moiety. For both processes, the electronic effect exerted greater influence, and electron-withdrawing substituents retarded reaction. The pH-independent hydrolysis of amidomethyl esters were dependent on the pKa of the carboxylate leaving group, giving a Brönsted βlg value of −0.91. The base-catalyzed,

Diterpenoids from Salvia candelabrum

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Targeting KRAS Oncogene in Colon Cancer Cells with 7-Carboxylate Indolo[3,2-b]quinoline Tri-Alkylamine Derivatives.

, pathway was mainly affected by the steric bulk of the nitrogen substituents in the amide moiety, the reactivity being reduced with larger N-substituents. Hydrolysis in human plasma appeared to be mediated by enzymic processes and is dependent upon the steric bulk in the carboxylic acid moiety. Plasma hydrolysis rates were inversely dependent on the lipophilicity of the ester. Conclusions. Derivatives containing the ethyl hippurate carrier are useful prodrugs for carboxylic acid-containing drugs with pKa > 3.5, such as non-steroidal anti-inflammatory agents and valproic acid.

Dopamine- and tyramine-based derivatives of triazenes: activation by tyrosinase and implications for prodrug design.

The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2-7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14-18), and quinolinodonepezils (19-21) are described. Pyridonepezils 15-18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19-21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC(50) (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15-18 and quinolinodonepezils 20-21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC(50) (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ(1-42). All compounds were effective in preventing the enhancement of AChE activity induced by Aβ(1-42). Compounds 2-7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ(1-42). Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca(2+) influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimers disease.