There is an urgent need to discover new antimalarials, due to the spread of chloroquine resistance and the limited number of available drugs. 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. Antiplasmodial activity of quinone structures of marine origin has been reported. Examples are xestoquinone and halenaquinone (Laurent et al., 2006, Bioorg. Med. Chem., 14:4477-82), their derivative orlaquinone (Longeon et al., 2010, Bioorg. Med. Chem., 18:6006-11), and ketoadociaquinones (Shmitz et al., 1988, J. Org. Chem., 53:3922-25; Cao et al., 2005, Bioorg. Med. Chem., 13:999-1003), isolated from Xestospongia sponges, and thiaplakortones (Davis et al., 2013, J. Org. Chem., 78: 9608-13), isolated from Plakortis lita. It has been also evidenced that the presence of a dioxothiazine moiety enhances the antiplasmodial activity (Figure 1). Within our search for bioactive compounds from Mediterranean ascidians, we have previously isolated a large group of thiazinoquinones (Menna et al., 2013, Eur. J. Org. Chem,, 16:3241-46; Aiello et al., 2005, Eur. J. Org. Chem., 23:5024-30; Aiello et al., 2005, J. Med. Chem., 48:3410-16; Aiello et al., 2003, Eur. J. Org. Chem., 5: 98-900). Some of these compounds have been used as lead structures for the synthesis of simplified analogues for pharmacological screening (Aiello et al., 2010, Bioorg. Med. Chem., 18: 719-27). Based on the structural analogy with the reported antimalarial quinone structures, the synthetic derivatives prepared using the natural thiazinoquinones aplidinones A and B as model structures (1-12, Figure 2) have been tested in vitro against D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of P. falciparum. The synthetic derivatives have shown a significant antiplasmodial activity and many structural requirements, critical for their activity, have been evidenced. Conformational (MD and MM) and electronic (tautomeric form, pka values, percentage of neutral/ionized forms at different pH values) analysis have been performed by computational means. The propensity for electron acceptance of the active compounds has been explored by LUMO orbital and anionic radical analysis. A correlation between electrochemistry (???direct??? and in the presence of Fe(III)-Heme) of the studied compounds and their antiplasmodial effects has been evidenced by using solid-state electrochemical assays (Dome??nech-Carbo?? et al., 2013, Anal. Chem., 85: 4014-21).

ANTIMALARIAL POTENTIAL OF SYNTHETIC QUINONE DERIVATIVES DESIGNED ON THE MODEL OF THE APLIDINONES, NATURAL MARINE THIAZINOQUINONES

IMPERATORE, CONCETTA;AIELLO, ANNA;LUCIANO, PAOLO;FATTORUSSO, CATERINA;PERSICO, MARCO;MENNA, MARIALUISA
2014

Abstract

There is an urgent need to discover new antimalarials, due to the spread of chloroquine resistance and the limited number of available drugs. 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. Antiplasmodial activity of quinone structures of marine origin has been reported. Examples are xestoquinone and halenaquinone (Laurent et al., 2006, Bioorg. Med. Chem., 14:4477-82), their derivative orlaquinone (Longeon et al., 2010, Bioorg. Med. Chem., 18:6006-11), and ketoadociaquinones (Shmitz et al., 1988, J. Org. Chem., 53:3922-25; Cao et al., 2005, Bioorg. Med. Chem., 13:999-1003), isolated from Xestospongia sponges, and thiaplakortones (Davis et al., 2013, J. Org. Chem., 78: 9608-13), isolated from Plakortis lita. It has been also evidenced that the presence of a dioxothiazine moiety enhances the antiplasmodial activity (Figure 1). Within our search for bioactive compounds from Mediterranean ascidians, we have previously isolated a large group of thiazinoquinones (Menna et al., 2013, Eur. J. Org. Chem,, 16:3241-46; Aiello et al., 2005, Eur. J. Org. Chem., 23:5024-30; Aiello et al., 2005, J. Med. Chem., 48:3410-16; Aiello et al., 2003, Eur. J. Org. Chem., 5: 98-900). Some of these compounds have been used as lead structures for the synthesis of simplified analogues for pharmacological screening (Aiello et al., 2010, Bioorg. Med. Chem., 18: 719-27). Based on the structural analogy with the reported antimalarial quinone structures, the synthetic derivatives prepared using the natural thiazinoquinones aplidinones A and B as model structures (1-12, Figure 2) have been tested in vitro against D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of P. falciparum. The synthetic derivatives have shown a significant antiplasmodial activity and many structural requirements, critical for their activity, have been evidenced. Conformational (MD and MM) and electronic (tautomeric form, pka values, percentage of neutral/ionized forms at different pH values) analysis have been performed by computational means. The propensity for electron acceptance of the active compounds has been explored by LUMO orbital and anionic radical analysis. A correlation between electrochemistry (???direct??? and in the presence of Fe(III)-Heme) of the studied compounds and their antiplasmodial effects has been evidenced by using solid-state electrochemical assays (Dome??nech-Carbo?? et al., 2013, Anal. Chem., 85: 4014-21).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/586634
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