Environmental and biomedical applications of natural metal stable isotope variations

10.2113/gselements.5.6.381Elements56381-38

The boron isotope systematics of Icelandic geothermal waters: 1. Meteoric water charged systems

We have measured the boron isotope composition and boron and chloride concentrations of 27 Icelandic geothermal fluids from both high- and low-temperature systems. The ?11B values range from -6.7‰ in the Krafla system, to +25.0‰ in a warm spring from the Southern Lowlands. In addition, we have also determined the ?11B values of basaltic glass from Nesjavellir (-5.3 ± 1.4‰) and travertine from Snaefellsnes (-22 ± 0.5‰). The B isotope and Cl/B systematics of the high-temperature systems are dominated by the composition of the local basalts. The lower temperature systems show evidence for mixing with B and Cl of a marine origin, together with some uptake of B into secondary mineral phases. The data from the Snaefellsnes geothermal system indicate that the fluids have undergone interaction with basalts that have undergone significant low-temperature alteration by seawater

Application of multiple isotopic and geochemical tracers for investigation of recharge, salinization, and residence time of water in the Souss–Massa aquifer, southwest of Morocco.

International audienc

Application of multiple isotopic and geochemical tracers for investigation of recharge, salinization, and residence time of water in the Souss–Massa aquifer, southwest of Morocco.

International audienc

Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity

Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.Trent D. Ashton, Anna Ngo, Paola Favuzza, Hayley E. Bullen, Maria R. Gancheva, Ornella Romeo, Molly Parkyn Schneider, Nghi Nguyen, Ryan W.J. Steel, Sandra Duffy, Kym N. Lowes, Helene Jousset Sabroux, Vicky M. Avery, Justin A. Boddey, Danny W. Wilson, Alan F. Cowman, Paul R. Gilson, Brad E. Sleeb

Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity

Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.Trent D. Ashton, Anna Ngo, Paola Favuzza, Hayley E. Bullen, Maria R. Gancheva, Ornella Romeo, Molly Parkyn Schneider, Nghi Nguyen, Ryan W.J. Steel, Sandra Duffy, Kym N. Lowes, Helene Jousset Sabroux, Vicky M. Avery, Justin A. Boddey, Danny W. Wilson, Alan F. Cowman, Paul R. Gilson, Brad E. Sleeb