Browsing by Author "Lopes, F"
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- Acyloxymethyl as a drug protecting group. Part 6Publication . Lopes, F; Moreira, R; Iley, JTertiary N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides were synthesised and evaluated as novel classes of potential prodrugs of agents containing a secondary sulfonamide group. The chemical and plasma hydrolyses of the title compounds were studied by HPLC, Tertiary N-acyloxymethylsulfonamides are slowly and quantitatively hydrolysed to the parent sulfonamide ill pH 7.4 phosphate buffer, with half-lives ranging from 20 h, for 7d, to 30 days, for 7g. Quantitative formation of the parent sulfonamide also occurs in human plasma, the half-lives being within 0.2-2.0 min for some substrates. The rapid rate of hydrolysis can be ascribed to plasma cholinesterase, as indicated by the complete inhibition observed at. [eserine] = 0.10 mM. These results suggest that tertiary N-acyloxymethylsulfonamides are potentially useful prodrugs for agents containing a secondary sulfonamide group, especially with pK(a) 8, combining a high stability in aqueous media with a high rate of plasma activation. In contrast, N-[(aminocarbonyloxy)methyl]sulfonamides 7h-j do not liberate the parent sulfonamide either in aqueous buffers or in human plasma and thus appear to be unsuitable for development as sulfonamide prodrugs. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Acyloxymethyl as a drug protecting group. Part 7Publication . Iley, J; Barroso, H; Moreira, R; Lopes, F; Calheiros, TTertiary sulfonamidomethyl esters of benzylpenicillin (4) were synthesised and evaluated as a new class of potential prodrugs for beta-lactam antibiotics. Their hydrolysis in aqueous buffers was studied by HPLC and reveal a U-shaped pH-rate profile with a pH-independent process extending from ca. pH 2 to ca. pH 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion Formation and penicillinoate expulsion. Benzylpenicillin and the corresponding sulfonamide are the ultimate products detected and isolated, indicating that beta-lactam ring opening is much slower than ester hydrolysis. As expected from the high reactivity, benzylpenicillin esters (4) displayed similar in vitro antibacterial activity to benzylpenicillin itself. Compared to the benzylpenicillin derivatives, sulfonamidomethyl esters of benzoic, clofibric and valproic acids display a much higher stability, giving rise to a Bronsted beta(Ig) value of -0.96 and suggesting that tertiary sulfonamidomethyl esters may be useful prodrugs for carboxylic acid drugs with pK(a) 4. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Amidomethylation of amodiaquinePublication . Lopes, F; Capela, R; Goncaves, JO; Horton, PN; Hursthouse, MB; Iley, J; Casimiro, CM; Bom, J; Moreira, RNovel N-Mannich base-type derivatives of the antimalarial drug amodiaquine were synthesised by reaction with tertiary N-chloromethylamides. With the exception of the derivative of ethyl hippurate, all the so-formed (1-amidomethyl-1H-quinolin-4-ylidene)arylamines displayed high chemical and enzymatic stability. These compounds displayed antimalarial activity against the multi-drug resistant Plasmodium falciparum strain Dd2 (IC50 values 15-31 nM) and demonstrated no significant loss in activity compared to amodiaquine (IC50 30nM). (C) 2004 Elsevier Ltd. All rights reserved.
- Estilo de vida e obesidade em adolescentes da região de LisboaPublication . Soveral, G; Lopes, F; Ferreira, C; Cabrita, J
- Imidazolidin-4-one derivatives of primaquine as novel transmission-blocking antimalarialsPublication . Araujo, MJ; Bom, J; Capela, R; Casimiro, C; Chambel, P; Gomes, P; Iley, J; Lopes, F; Morais, J; Moreira, R; de Oliveira, E; do Rosario, V; Vale, NImidazolidin-4-one derivatives of primaquine were synthesized as potential double prodrugs of the parent drug. The title compounds inhibit the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The imidazolidin-4-ones are very stable, both in human plasma and in pH 7.4 buffer, indicating that they are active per se. Thus, imidazolidin-4-ones derived from 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships.
- Kinetics and mechanism of hydrolysis of N-amidomethylsulfonamidesPublication . Iley, J; Lopes, F; Moreira, RThe kinetics of the hydrolyses of secondary and tertiary N-amidomethylsulfonamides were studied at 50 degreesC. Both types of N-amidomethylsulfonamide hydrolyse through acid- and base-catalysed processes, as indicated by the pH-rate profiles. The order of reactivity for the acid-catalysed pathway implies a mechanism involving protonation of the amide followed by expulsion of a neutral amide and formation of a sulfonyliminium ion. In the base-catalysed region, compound 5c, which is substituted at both amide and sulfonamide nitrogen atoms, hydrolyses by nucleophilic attack of hydroxide ion at the amide carbonyl carbon atom to form benzoic acid and a sulfonamide. In contrast, compound 5b, which contains a sulfonamide NH group, hydrolyses to benzamide and sulfonamide products by an E1cb(rev) mechanism involving ionisation of the sulfonamide. Compound 5a, which contains an amide NH, also hydrolyses to sulfonamide and amide products, probably by an E2 mechanism.
- Medicinal ChemistryPublication . Moreira, R; Carreiras, MC; Lopes, F; Rocha, MJP; Mendes, E; LConstantino, Dias,; Santos, MM; Lavrado, J; Capela, R; Santana, AB; Valente, E; Rodrigues, T