1. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities
Francesc Marti, James Chadwick, Richard K. Amewu, Paul M. O’Neill*. Med. Chem. Commun., 2011, 2, 661–665
Malaria is a parasitic disease that causes over 1 million deaths every year. The emergence of resistance to most available drugs, including the semi-synthetic artemisinin derivatives artemether and artesunate, has led to efforts to create new synthetic peroxides as potential antimalarial agents. Leading examples of synthetic endoperoxides include OZ277 (arterolane), a molecule in Phase III clinical trials in combination with piperaquine, and OZ439, a second generation derivative with improved pharmacokinetics and enhanced in vivo antimalarial activity. 1,2,4,5-Tetraoxanes are another class of peroxides, which have proved to be an interesting pharmacophore that possesses excellent antimalarial activity against both chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum. Previously in our group, RKA182 (Fig. 1) was selected as a candidate for full preclinical development from a series of synthetic tetraoxane derivatives; this compound shows superior in vitro and in vivo activity to artemether and artesunate, has good oral bioavailability in rodent models and is more stable than arterolane in malaria infected human red blood cells.
2. High throughput quantitation of artesunate and its degradation products by ﬂow injection gradient ratio standard addition mass spectrometry (FI-GRSA-MS)
Dana M. Hostetler, Prabha Dwivedi, Michael D. Greenb and Facundo M. Fern andez*. Anal. Methods, 2012, 4, 3392–3398
Due to relatively large API concentration in the pharmaceutical tablet extracts along with the absence of chromatographic separation and the presence of concomitant excipient compounds, ionization suppression is often observed during electrospray ionization. To improve artesunate detection by ESI, DDA a primary amine, was used as an ESI modiﬁer to quantify artesunate in tablets by FI-GRSA-MS. The reasons for using DDA as an ESI modiﬁer for improving artesunate analysis sensitivity were several-fold, including: (1) primary amines such as DDA have been shown to preferentially form a stable protonbound non-covalent complex with artesunate and other artemisinins while inhibiting the formation of unwanted species that split the ionic signal into various channels, (2) the formation of the more stable DDA–artesunate complex inhibits collision-induced fragmentation during transport through the ion optics, resulting in a higher ESI intensity, (3) the aliphatic carbon chain in DDA increases the hydrophobicity of the complex with artesunate, increasing its overall fugacity, ion evaporation ability and ion yields, and (4) the localization of the positive charge at the DDA nitrogen atom results in an additional gain in ESI sensitivity.
3. Antimalarial peroxides: advances in drug discovery and design
Rachel D. Slack, Alexander M. Jacobine and Gary H. Posner*. Med. Chem. Commun., 2012, 3, 281–297
Despite their rapid killing of parasites, artemether (8b), arteether (8c), and artesunate (8d) have extremely short half lives (t1/2 = 1–3 h) due to their catabolism to DHA (8a). For example, in vivo artemether (8b) undergoes cytochrome P450 methyl hydroxylation and dealkylation to DHA (8a, Fig. 4). DHA (8a) is then glucuronidated and rapidly excreted. Therefore, the artemisinins 8 must be administered repeatedly over several days in monotherapeutic treatments. Unfortunately, patient non-compliance resulting in recrudescence and relapse is a problem; this increases the risk of artemisinin-resistant parasites. The World Health Organization (WHO) suggests combining artemisinin (3) or one of its ﬁrst generation derivatives 8 with slower acting but longer lived antimalarial drugs, known as artemisinin combination therapy (ACT). This ACT protocol features several improvements over monotherapy administration. The slower acting partner drug not only possesses a longer half life, but it generally operates through a different mechanism of action. Therefore, once taken, the endoperoxide rapidly kills most of the parasites before it is catabolized and excreted, and the non-peroxide drug slowly clears the rest. This combination shortens the treatment period, thereby increasing patient compliance and decreasing the risk of resistance.