STRUCTURE-ACTIVITY AND MECHANISM STUDIES ON SILICON PHTHALOCYANINES WITH PLASMODIUM-FALCIPARUM IN THE DARK AND UNDER RED-LIGHT

Syntheses for the new photosensitizers HOSiPcOSi(CH3)(2)(CH2)(3)N(CH2) (1) or (3)(CH3)(2), Pc 34 and Pc 25, have been developed and the order of activity of these photosensitizers and the previously reported pho tosensitizer Pc 4, HOSiPcOSi(CH3)(2)(CH2)(3)N(CH3)(2), in the dark and with broad-band red light toward Plasmodium falciparum in red blood c ell (RBC) suspensions has been studied, The order of activity has been found to be Pc 4 > Pc 34 > Pc 25, Thus, the activity of the photosens itizers under both sets of conditions is inversely proportional to the length of their terminal amino alkyl chains, The 50% inhibition dye c oncentration (IC50) in the dark for the parasites in RBC suspension wi th Pc 4 is 24 nM and the dye concentration and light fluence that yiel d greater than or equal to 3 log(10) of parasite inactivation with Pc 4 are 2 mu M and 3 J/cm(2), respectively. The synthesis of DNA and pro teins by the parasites in culture was strongly inhibited by Pc 4 in th e dark while parasite lactate dehydrogenase (pLDH) activity was unaffe cted, With Pc 4 and light, DNA acid protein synthesis of the parasites in culture was strongly inhibited, pLDH activity of the parasites was moderately inhibited, pLDH activity of the parasites was moderately i nhibited and ribosome density df tile parasite cells was reduced, Gel electrophoresis studies showed that synthesis of all parasite proteins was inhibited to a similar extent, These results suggest that Pc 4 bo th in tile dark and with light inactivates the cells by disturbing the ir machinery for the synthesis of not just one but a whole series of p roteins, It is concluded that Pc 4 and light may be able to serve as a practical sterilization combination not only for HIV and other viruse s but also for malaria parasites in RBC concentrates, and that Pr 4 by itself may have potential as a chemotherapeutic agent toward malaria.