Antimalarial versus cytotoxic properties of dual drugs derived from 4-aminoquinolines and Mannich bases: interaction with DNA.

The synthesis and biological evaluation of new organic and organometallic dual drugs designed as potential antimalarial agents are reported. A series of 4-aminoquinoline-based Mannich bases with variations in the aliphatic amino side chain were prepared via a three-steps synthesis. These compounds were also tested against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum and assayed for their ability to inhibit the formation of beta-hematin in vitro using a colorimetric beta-hematin inhibition assay. Several compounds showed a marked antimalarial activity, with IC(50) and IC(90) values in the low nM range but also a high cytotoxicity against mammalian cells, in particular a highly drug-resistant glioblastoma cell line. The newly designed compounds revealed high DNA binding properties, especially for the GC-rich domains. Altogether, these dual drugs seem to be more appropriate to be developed as antiproliferative agents against mammalian cancer cells than Plasmodium parasites.

Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum.

Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems providing a steady glutathione flux. As a future generation of dual drugs, 18 naphthoquinones and phenols (or their reduced forms) containing three different linkers between the 4-aminoquinoline core and the redox active component were synthesized. Their antimalarial effects have been characterized in parasite assays using chloroquine-sensitive and -resistant strains of Plasmodium, alone or in drug combination, and in the Plasmodium berghei rodent model. In particular, two tertiary amides 34 and 36 showed potent antimalarial activity in the low nanomolar range against CQ-resistant parasites. The ability to compete both for (Fe (III))protoporphyrin and for chloroquine transporter was determined. The data are consistent with the presence of a carrier for uptake of the short chloroquine analogue 2 but not for the potent antimalarial amide 34, suggesting a mode of action distinct from chloroquine mechanism.

Antitumoral activity of non-platinum xanthate complexes.

To establish structure-activity relationships, derivatives of bis(O-alkyldithiocarbonato)platinum(II) complexes were analyzed. Eighteen bis(O-alkyldithiocarbonato) metal complexes were synthesized, and their cytotoxic activity on two human cancer cell lines was compared with the corresponding platinum bis(O-alkyldithiocarbonato) complexes and cisplatin. Complexes were synthesized with palladium, gold, nickel, copper, rhodium, and bismuth. Palladium and bismuth complexes were found to display significant cytotoxic activity. Palladium complexes were most active with up to 10-fold lower IC50 values as compared with the corresponding platinum complexes. The other complexes were only poorly active. Palladium, bismuth, and nickel complexes were more active at pH 6.8 than at pH 7.4. This difference in activity was most pronounced with palladium complexes. A pH of 6.8 and lower has been frequently found in solid tumors. Drugs with such pH dependent activity are supposed to have an improved therapeutic index as compared to drugs that are active irrespective of pH.

Synthesis and structure-activity relationship of novel antitumoral platinum xanthate complexes.

To establish structure-activity relationships, derivatives of a recently described sulfur-containing antitumoral platinum complex, bis(O-ethyldithiocarbonato)platinum(II), named thioplatin, were analyzed. Twenty different bis(O-alkyldithiocarbonato)platinum(II) complexes were synthesized and tested for cytotoxic activity in a panel of six human tumor lines. Derivatives with up to 7-fold increased activity compared to thioplatin and up to 25-fold more activity than cisplatin were identified. Bis(O-alkyldithiocarbonato)platinum(II) complexes with short n-alkyl chains such as methyl, ethyl, propyl, and butyl were found to be superior to compounds with long n-alkyl chains such as hexyl, octyl, and decyl. Complexes derived from secondary xanthates displayed significantly higher activity than those derived from primary xanthates with the same number of C atoms. Like thioplatin, all tested platinum complexes were more active at pH 6.8 than at pH 7.4. A pH of 6.8 and lower has been frequently found in solid tumors because of the tendency of tumor cells to undergo anaerobic fermentation. Drugs with such pH-dependent antitumoral activity have an improved therapeutic index compared to drugs that are active irrespective of pH.