The available chemical entities to treat malaria cases are still currently based on few and quite old chemical scaffolds, like the anti-folates or the 4-aminoquinoline derivatives. Although the combination of these molecules with artemisinin and other endoperoxide analogues is giving some good results, the therapeutic choices are still too limited and the prospect of resistance remains. However, few new drug targets or classes of drugs have been recently clinically validated, and, therefore, a continuous search for effective and innovative drugs, with both unique structures and new mechanisms of action to treat sensitive and drug-resistant strains of malaria, stands to reason. Nature provides a remarkable diversity of chemical starting points for new leads identification and, concurrently, it could suggest novel mechanisms of antimalarial action on which to base new antimalarial drug-discovery campaigns. Therefore the screening of biologically active natural compounds with potential antimalarial activity, isolated from both terrestrial and marine organisms, is still now of considerable interest. A number of quinones have been shown to be effective antimalarials; the observed effects are most likely related to the most prominent chemical feature of these kind of molecules, that is their ability to undergo redox cycling. Recently, the antiplasmodial activity of quinone structures of marine origin has been reported. Examples are the xestoquinone (1), its derivative orlaquinone (2), and ketoadociaquinones A and B (3 and 4) isolated from Xestospongia species, and thiaplakortones A-D (5-8) isolated from Plakortis lita. (Figure 1). These studies also evidenced that the presence of a dioxothiazine moiety fused to the quinone moiety to give the thiazinoquinone scaffold enhances the antiplasmodial activity.10 Having identified the thiazinoquinone as a possible chemotype active against Plasmodium falciparum, the synthetic derivatives 11-22 (Figure 2) have been prepared using the natural thiazinoquinones aplidinones A and B (9 and 10, respectively) as model structures. Compounds 11-22 have been tested in vitro against D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of P. falciparum. Some of the tested compounds have shown a significant antiplasmodial activity and many structural requirements, critical for their activity, have been evidenced. The redox properties of the prepared compounds have been investigated by computational studies and electrochemical assays.
Synthesis, biological evaluation, and electrochemical studies of antiplasmodial thiazinoquinones inspired by marine natural products / Filomena, D’Aniello; Imperatore, Concetta; Aiello, Anna; Luciano, Paolo; Fattorusso, Caterina; Persico, Marco; Donatella, Taramelli; Silvia, Parapini; Gerardo Cebrián, Torrejón; Antonio Doménech, Carbó; Menna, Marialuisa. - (2014). (Intervento presentato al convegno I International Symposium on Marine Biotechnology and Ocean Conservation tenutosi a Surya University, Gading Serpong, Indonesia nel 15-16 September).
Synthesis, biological evaluation, and electrochemical studies of antiplasmodial thiazinoquinones inspired by marine natural products
IMPERATORE, CONCETTA;AIELLO, ANNA;LUCIANO, PAOLO;FATTORUSSO, CATERINA;PERSICO, MARCO;MENNA, MARIALUISA
2014
Abstract
The available chemical entities to treat malaria cases are still currently based on few and quite old chemical scaffolds, like the anti-folates or the 4-aminoquinoline derivatives. Although the combination of these molecules with artemisinin and other endoperoxide analogues is giving some good results, the therapeutic choices are still too limited and the prospect of resistance remains. However, few new drug targets or classes of drugs have been recently clinically validated, and, therefore, a continuous search for effective and innovative drugs, with both unique structures and new mechanisms of action to treat sensitive and drug-resistant strains of malaria, stands to reason. Nature provides a remarkable diversity of chemical starting points for new leads identification and, concurrently, it could suggest novel mechanisms of antimalarial action on which to base new antimalarial drug-discovery campaigns. Therefore the screening of biologically active natural compounds with potential antimalarial activity, isolated from both terrestrial and marine organisms, is still now of considerable interest. A number of quinones have been shown to be effective antimalarials; the observed effects are most likely related to the most prominent chemical feature of these kind of molecules, that is their ability to undergo redox cycling. Recently, the antiplasmodial activity of quinone structures of marine origin has been reported. Examples are the xestoquinone (1), its derivative orlaquinone (2), and ketoadociaquinones A and B (3 and 4) isolated from Xestospongia species, and thiaplakortones A-D (5-8) isolated from Plakortis lita. (Figure 1). These studies also evidenced that the presence of a dioxothiazine moiety fused to the quinone moiety to give the thiazinoquinone scaffold enhances the antiplasmodial activity.10 Having identified the thiazinoquinone as a possible chemotype active against Plasmodium falciparum, the synthetic derivatives 11-22 (Figure 2) have been prepared using the natural thiazinoquinones aplidinones A and B (9 and 10, respectively) as model structures. Compounds 11-22 have been tested in vitro against D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of P. falciparum. Some of the tested compounds have shown a significant antiplasmodial activity and many structural requirements, critical for their activity, have been evidenced. The redox properties of the prepared compounds have been investigated by computational studies and electrochemical assays.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.