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

Author(s)

Mallaupoma, Lenna Rosanie Cordero ; Dias, Barbara Karina de Menezes ; Singh, Maneesh Kumar ; Honorio, Rute Isabel ; Nakabashi, Myna ; Kisukuri, Camila de Menezes ; Paixao, Marcio Weber ; Garcia, Celia R. S.

• Document type: Journal article
• Source: BIOMOLECULES; v. 12, n. 5, p. 15-pg., 2022-05-01.

Abstract

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 mu M. 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. (AU)

• FAPESP's process: 18/12986-1 - Development of photochemical and electrocatalytic methodologies to the synthesis and modification of heterocyclic scaffolds
• Grantee: Camila de Menezes Kisukuri
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/08684-7 - Decoding Plasmodium signaling at molecular level as a new tool to the development of new antimalarials
• Grantee: Célia Regina da Silva Garcia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/09490-7 - Screening of novel ligands for PfSR1, a putative GPCR-like receptor and identification of potential IP3 receptor in calcium signaling in the Plasmodium falciparum
• Grantee: Maneesh Kumar Singh
• Support Opportunities: Scholarships in Brazil - Post-Doctoral