Assessing impacts of future climate change on extreme fire weather and pyro-regions in Iberian Peninsula.

Weather conditions play an important role in wildfire activity. In many regions, future climate could lead to different fire weather, with impacts on the ignition, behaviour, and suppression of wildfires, which may, therefore, force new fire regimes. This study aimed to assess the evolution of fire weather indices and the Number of Extreme Days (NED) in the context of climate change. We estimated the impact of these changes on monthly Normalized Burnt Area (NBA) and in the spatial distribution of Pyro-Regions (PR), using a recently identified relationship between NED and NBA intra-annual patterns. The components of the Canadian Forest Fire Weather Index System (CFFWIS) in the Iberian Peninsula were analysed for present-day conditions and future climate scenarios, using daily data from ERA-Interim (1980-2014) and an ensemble of simulations from 11 EURO-CORDEX high spatial resolution models, for two future periods (2041-2070 and 2071-2100) and scenarios (RCP4.5 and RCP8.5). Results suggest a significant increase in future fire weather risk, especially in late spring and early autumn, and also in southern and eastern Iberian Peninsula. NED is expected to strongly increase in summer months in the four PRs, but also to decrease in March and April in the northwestern and southwestern PR. This could change the spatial distribution of PRs, with a general northwards movement: the northern PR is expected to disappear except north of the Cantabrian Mountains, being replaced by the northwestern PR; the southwestern PR is expected to grow and occupy part of the area currently in the northwestern PR; and a new PR could appear in parts of the current eastern PR. These PR changes follow the projected modifications in the major climate regions. Results suggest different fire regimes in the future, with higher fire weather risk, and a longer and harsher fire season.

Acyloxymethyl as a drug protecting group. Part 7: Tertiary sulfonamidomethyl ester prodrugs of benzylpenicillin: chemical hydrolysis and anti-bacterial activity.

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.

Phthalimidomethyl as a drug pro-moiety. Probing its reactivity.

Phthalimidomethyl derivatives 1, encompassing a wide range of leaving group abilities, are rapidly hydrolysed to the corresponding phthalamic acid via rate-determining attack at the phthalimide carbonyl group.

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

PURPOSE: 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, kH+, 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 beta(1g) value -0.91. The base-catalyzed, kOH-, 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.

Acyloxymethyl as a drug protecting group. Part 3. Tertiary O-amidomethyl esters of penicillin G: chemical hydrolysis and anti-bacterial activity.

PURPOSE: O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. METHODS: The hydrolysis in aqueous buffers containing 20 % (v/v) of acetonitrile was investigated by HPLC. RESULTS: A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that beta-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself. CONCLUSIONS: Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted Beta 1g value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pKa > 4.