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In this research, we discovered that melatonin is unable to increase the parasitemia in the human malaria <jats:italic>Plasmodium falciparum<\/jats:italic> that lacks the kinase PfeIK1. The PfeIK1 knockout strain is a valuable tool in the screening of indol\u2010related compound that blocks the melatonin effect in wild\u2010type (WT) parasite development. The assays were performed by using flow cytometry with simultaneous labeling for mitochondria viability with MitoTracker Deep Red and nucleus staining with SYBR Green. We found that Melatotosil\u00a0leads to an increase in parasitemia in <jats:italic>P. falciparum<\/jats:italic> and blocks melatonin effect in the\u00a0WT parasite. Using microscopy imaging system, we found that Melatotosil at 500\u00a0nM\u00a0is able to induce cytosolic calcium rise in\u00a0transgenic PfGCaMP3 parasites. On the contrary, the compound Triptiofen blocks\u00a0<jats:italic>P. falciparum<\/jats:italic> cell cycle with\u00a0IC<jats:sub>50<\/jats:sub> 9.76\u00a0\u00b5M\u00a0\u00b1\u00a00.6, inhibits melatonin action, and does not lead to a cytosolic calcium rise in\u00a0PfGCaMP3 parasites. We also found that\u00a0the synthetic indol\u2010related compounds arrested parasite cycle for PfeIK1 knockout and (WT) <jats:italic>P. falciparum<\/jats:italic> (3D7) in\u00a072\u00a0hours culture assays\u00a0with the IC<jats:sub>50<\/jats:sub> values slighting lower for the WT strain. We concluded that the kinase PfeIK1 is central for melatonin downstream signaling pathways involved in parasite cell cycle progression. More importantly, the indol\u2010related compounds block its cycle as an upstream essential mechanism for parasite survival. Our data clearly show that this class of compounds emerge as an alternative for the problem of resistance with the classical antimalarials.<\/jats:p>","DOI":"10.1111\/jpi.12685","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T21:00:12Z","timestamp":1595538012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The <i>Plasmodium falciparum<\/i> eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle"],"prefix":"10.1111","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2310-3611","authenticated-orcid":false,"given":"B\u00e1rbara K.M.","family":"Dias","sequence":"first","affiliation":[{"name":"Departamento de Parasitologia Instituto de Ci\u00eancias Biom\u00e9dicas Universidade de S\u00e3o Paulo S\u00e3o Paulo SP Brazil"},{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas Universidade de S\u00e3o Paulo S\u00e3o Paulo SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myna","family":"Nakabashi","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas Universidade de S\u00e3o Paulo S\u00e3o Paulo SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Rangel Rodrigues","family":"Alves","sequence":"additional","affiliation":[{"name":"Departamento de Farm\u00e1cia Faculdade de Farm\u00e1cia Universidade Federal do Rio 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