Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action

An efficient synthesis of rac-6-desmethyl-5β–hydroxy-d-secoartemisinin 2, a tricyclic analog of R-(+)-artemisinin 1, was accomplished and the racemate was resolved into the (+)-2b and (−)-2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R-(−)-2a. Several new compounds 9–16, 19a, 19b, 22 and 29 were synthesized from rac-2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs had moderate activity in comparison to the natural product 1. Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22, while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.

Toward Multitasking Pharmacological COX-Targeting Agents: Non-Steroidal Anti-Inflammatory Prodrugs with Antiproliferative Effects

The antitumor activity of certain anti-inflammatory drugs is often attributed to an indirect effect based on the inhibition of COX enzymes. In the case of anti-inflammatory prodrugs, this property could be attributed to the parent molecules with mechanism other than COX inhibition, particularly through formulations capable of slowing down their metabolic conversion. In this work, a pilot docking study aimed at comparing the interaction of two prodrugs, nabumetone (NB) and its tricyclic analog 7-methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (MC), and their common active metabolite 6-methoxy-2-naphthylacetic acid (MNA) with the COX binding site, was carried out. Cytotoxicity, cytofluorimetry, and protein expression assays on prodrugs were also performed to assess their potential as antiproliferative agents that could help hypothesize an effective use as anticancer therapeutics. Encouraging results suggest that the studied compounds could act not only as precursors of the anti-inflammatory metabolite, but also as direct antiproliferative agents.

HPLC and HPLC/MS/MS Studies on Stress, Accelerated and Intermediate Degradation Tests of Antivirally Active Tricyclic Analog of Acyclovir

The degradation behavior of a tricyclic analog of acyclovir [6-(4-MeOPh)-TACV] was determined in accordance with International Conference on Harmonization guidelines for good clinical practice under different stress conditions (neutral hydrolysis, strong acid/base degradation, oxidative decomposition, photodegradation, and thermal degradation). Accelerated [40 ± 2°C/75% ± 5% relative humidity (RH)] and intermediate (30 ± 2°C/65% ± 5% RH) stability tests were also performed. For observation of the degradation of the tested compound the RP-HPLC was used, whereas for the analysis of its degradation products HPLC/MS/MS was used. Degradation of the tested substance allowed its classification as unstable in neutral environment, acidic/alkaline medium, and in the presence of oxidizing agent. The tested compound was also light sensitive and was classified as photolabile both in solution and in the solid phase. However, the observed photodegradation in the solid phase was at a much lower level than in the case of photodegradation in solution. The study showed that both air temperature and RH had no significant effect on the stability of the tested substance during storage for 1 month at 100°C (dry heat) as well as during accelerated and intermediate tests. Based on the HPLC/MS/MS analysis, it can be concluded that acyclovir was formed as a degradation product of 6-(4-MeOPh)-TACV.