Papers by Francisca Lopes
Bioorganic & Medicinal Chemistry Letters, 1995
Tertiary N-acyloxymethylsulfonamide prodrugs 3, encompassing penicillin and sulfonamide antibioti... more Tertiary N-acyloxymethylsulfonamide prodrugs 3, encompassing penicillin and sulfonamide antibiotics, have been synthesised. The pH-independent hydrolysis of these compounds ocurrs via the rate-determining formation of an N-sulfonyl iminium ion. SCF-MO calculations using the PM3 method indicate that iminium ion formation is slightly favoured, when compared with the corresponding amides, by ca. 10 kJmo1-1.
Tetrahedron Letters, 2004
The antimalarial drug amodiaquine (I) reacts with tertiary N-chloromethylamides (II) to form a no... more The antimalarial drug amodiaquine (I) reacts with tertiary N-chloromethylamides (II) to form a novel antimalarial of type (III), that contains the 1H-quinolin-4-ylideneamine core structure. -(LOPES, F.; CAPELA, R.; GONCAVES, J. O.; HORTON, P. N.; HURSTHOUSE, M. B.; ILEY*, J.; CASIMIRO, C. M.; BOM, J.; MOREIRA, R.; Tetrahedron Lett. 45 (2004) 41, 7663-7666; Dep. Chem., Open Univ., Milton Keynes MK7 6AA, UK; Eng.) -M. Paetzel 04-153
Bioorganic & Medicinal Chemistry, 2000
Tertiary sulfonamidomethyl esters of benzylpenicillin (4) were synthesised and evaluated as a new... more Tertiary 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 Brønsted beta1g value of -0.96 and suggesting that tertiary sulfonamidomethyl esters may be useful prodrugs for carboxylic acid drugs with pKa > 4.
Bioorganic & Medicinal Chemistry, 2000
Tertiary N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides were synthesised and evalu... more Tertiary 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 in 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 pKa < 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.
Archiv der Pharmazie, 2008
Sumatriptan is a potent and selective 5-HT 1B and 5-HT 1D agonist used in the symptomatic treatme... more Sumatriptan is a potent and selective 5-HT 1B and 5-HT 1D agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferentially at the indole nitrogen rather than at sulfonamide nitrogen, reflecting a difference either in product stability or in the nucleophilicities of the indole and sulfonamide anions. The hydrolysis of the corresponding N 1 -acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N 1 -Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N 1 -hydroxymethylsumatriptan at pH 1-13. Slow formation of the parent drug was observed only at high pH values. Hydrolysis of sumatriptan derivatives is slower in human plasma than in phosphate buffer and also generates N 1hydroxymethylsumatriptan rather than the parent drug. These results indicate that N 1 -acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.
Journal of Medicinal Chemistry, 2014
The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to pr... more The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.
Uploads
Papers by Francisca Lopes