Decoding the Role of Melatonin Structure on Plasmodium falciparum Human Malaria Parasites Synchronization Using 2-Sulfenylindoles Derivatives.

Melatonin acts to synchronize the parasite's intraerythrocytic cycle by triggering the phospholipase C-inositol 1,4,5-trisphosphate (PLC-IP3) signaling cascade. Compounds with an indole scaffold impair in vitro proliferation of blood-stage malaria parasites, indicating that this class of compounds is potentially emerging antiplasmodial drugs. Therefore, we aimed to study the role of the alkyl and aryl thiol moieties of 14 synthetic indole compounds against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum. Four compounds (3, 26, 18, 21) inhibited the growth of P. falciparum (3D7) by 50% at concentrations below 20 µM. A set of 2-sulfenylindoles also showed activity against Dd2 parasites. Our data suggest that Dd2 parasites are more susceptible to compounds 20 and 28 than 3D7 parasites. These data show that 2-sulfenylindoles are promising antimalarials against chloroquine-resistant parasite strains. We also evaluated the effects of the 14 compounds on the parasitemia of the 3D7 strain and their ability to interfere with the effect of 100 nM melatonin on the parasitemia of the 3D7 strain. Our results showed that compounds 3, 7, 8, 10, 14, 16, 17, and 20 slightly increased the effect of melatonin by increasing parasitemia by 8-20% compared with that of melatonin-only-treated 3D7 parasites. Moreover, we found that melatonin modulates the expression of kinase-related signaling components giving additional evidence to investigate inhibitors that can block melatonin signaling.

Role of Melatonin in the Synchronization of Asexual Forms in the Parasite Plasmodium falciparum.

The indoleamine compound melatonin has been extensively studied in the regulation of the circadian rhythm in nearly all vertebrates. The effects of melatonin have also been studied in Protozoan parasites, especially in the synchronization of the human malaria parasite Plasmodium falciparum via a complex downstream signalling pathway. Melatonin activates protein kinase A (PfPKA) and requires the activation of protein kinase 7 (PfPK7), PLC-IP3, and a subset of genes from the ubiquitin-proteasome system. In other parasites, such as Trypanosoma cruzi and Toxoplasma gondii, melatonin increases inflammatory components, thus amplifying the protective response of the host's immune system and affecting parasite load. The development of melatonin-related indole compounds exhibiting antiparasitic properties clearly suggests this new and effective approach as an alternative treatment. Therefore, it is critical to understand how melatonin confers stimulatory functions in host-parasite biology.