Indole based antimalarial compounds targeting the melatonin pathway: Their design, synthesis and biological evaluation

Luthra, Tania; Nayak, Akshay Kumar; Bose, Sarpita; Chakrabarti, Saikat; Gupta, Ashish; Sen, Subhabrata

doi:10.1016/j.ejmech.2019.02.019

Cited by 37 publications

(13 citation statements)

References 38 publications

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“…In the same line, Lunga et al tested a library of indole compounds as potential antimalarials. 36,45,46 Other indole compound, indolmycin, inhibit the protein translation in P. falciparum apicoplast by inhibiting the tryptophanyl-tRNA synthetase leading to a delayed death of the parasite. 47,48 Since PfeIK1parasites were susceptible to indole derivatives, we also investigated if PfeIK1 knockout would interfere with susceptibility of parasite against classical antimalarials.…”

Section: Discussionmentioning

confidence: 99%

“…Smears of infected erythrocytes stained with Giemsa were performed at regular intervals (0, 12, 24, 36 and 48 hours after treatment). 36 Parasite images were acquired under a light microscope (Zeiss) with 100× magnification to assess the parasite's blood development stages. The parasitemia at the end of the experiment was quantified for comparison between groups.…”

Section: Microscopy Evaluation Of Blood-stage Development Of P Falmentioning

confidence: 99%

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The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

Dias

Nakabashi

Alves

et al. 2020

Journal of Pineal Research

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Melatonin and its indoles derivatives are central in the synchronization of malaria parasites. In this research, we discovered that melatonin is unable to increase the parasitemia in the human malaria Plasmodium falciparum that lacks the kinase PfeIK1. The PfeIK1 knockout strain is a valuable tool in the screening of indol‐related compound that blocks the melatonin effect in wild‐type (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 leads to an increase in parasitemia in P. falciparum and blocks melatonin effect in the WT parasite. Using microscopy imaging system, we found that Melatotosil at 500 nM is able to induce cytosolic calcium rise in transgenic PfGCaMP3 parasites. On the contrary, the compound Triptiofen blocks P. falciparum cell cycle with IC50 9.76 µM ± 0.6, inhibits melatonin action, and does not lead to a cytosolic calcium rise in PfGCaMP3 parasites. We also found that the synthetic indol‐related compounds arrested parasite cycle for PfeIK1 knockout and (WT) P. falciparum (3D7) in 72 hours culture assays with the IC50 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‐related 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.

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Section: Discussionmentioning

confidence: 99%

Section: Microscopy Evaluation Of Blood-stage Development Of P Falmentioning

confidence: 99%

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

Dias

Nakabashi

Alves

et al. 2020

Journal of Pineal Research

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“…As a novel approach to tackle malaria, harmonized administration of high dose of melatonin and its antagonist is considered. 58,59 Further ensuring their future in antimalarial pipeline, indole alkaloids showed synergistic/additive interactions with conventional antimalarial agents. Mice treated with 16a (15mg kg −1 ) and suboptimal dose of 2 (1.5mg kg −1 ), for instance, had a drastic reduction in the number of intraerythrocytic parasites.…”

Section: Melatonin Receptors Modulationmentioning

confidence: 99%

<p>Indole: The After Next Scaffold of Antiplasmodial Agents?</p>

Surur¹,

Huluka²,

Mitku³

et al. 2020

DDDT

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Malaria remains a global public health problem due to the uphill fight against the causative Plasmodium parasites that are relentless in developing resistance. Indole-based antiplasmodial compounds are endowed with multiple modes of action, of which inhibition of hemozoin formation is the major mechanism of action reported for compounds such as cryptolepine, flinderoles, and isosungucine. Indole-based compounds exert their potent activity against chloroquine-resistant Plasmodium strains by inhibiting hemozoin formation in a mode of action different from that of chloroquine or through a novel mechanism of action. For example, dysregulating the sodium and osmotic homeostasis of Plasmodium through inhibition of PfATP4 is the novel mechanism of cipargamin. The potential of developing multi-targeted compounds through molecular hybridization ensures the existence of indole-based compounds in the antimalarial pipeline.

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“…Five compounds (2g, 2i, 2j, 2k and 2p) presented antimalarial activity against P. falciparum in vitro and presented IC 50 values of 4.28 µM, 0.89 µM, 0.74 µM, 2.73 µM and 0.73 µM, respectively. In addition, these compounds also showed efficacy against the chloroquine-resistant strain RKL9 [ 110 ]. To elucidate whether these compounds act in the pathway triggered by melatonin in P. falciparum , they were tested against an asynchronous culture of parasites, and compound 2j was able to impede the effect of the hormone and bind strongly to the mammalian melatonin receptor MT1 [ 110 ].…”

Section: Indole-derivative Compounds As Antimalarialsmentioning

confidence: 99%

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

2020

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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.

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Indole based antimalarial compounds targeting the melatonin pathway: Their design, synthesis and biological evaluation

Cited by 37 publications

References 38 publications

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

<p>Indole: The After Next Scaffold of Antiplasmodial Agents?</p>

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

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