Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium falciparum

Schuck, Desirée Cigaran; Jordão, Alessandro K.; Nakabashi, Myna; Cunha, Anna C.; Ferreira, Vı́tor F.; Garcia, Célia Regina da Silva

doi:10.1016/j.ejmech.2014.03.055

Cited by 49 publications

(24 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, Elmahallawy et al and Schuck et al reported that melatonin exhibited anti-parasite activity [27,28]. Tekbas reported that melatonin exerted a potent antimicrobial activity on multidrug-resistant, gram-positive and gram-negative bacteria [29].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Receptor Agonists as the “Perioceutics” Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response

Wei¹,

Zhang²,

Zhu³

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

Aim“Perioceutics” including antimicrobial therapy and host modulatory therapy has emerged as a vital adjunctive treatment of periodontal disease. Melatonin level was significantly reduced in patients with periodontal diseases suggesting melatonin could be applied as a potential “perioceutics” treatment of periodontal diseases. This study aims to investigate the effects of melatonin receptor agonists (melatonin and ramelteon) on Porphyromonas gingivalis virulence and Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS)-induced inflammation.MethodsEffects of melatonin receptor agonists on Porphyromonas gingivalis planktonic cultures were determined by microplate dilution assays. Formation, reduction, and viability of Porphyromonas gingivalis biofilms were detected by crystal violet staining and MTT assays, respectively. Meanwhile, biofilms formation was also observed by confocal laser scanning microscopy (CLSM). The effects on gingipains and hemolytic activities of Porphyromonas gingivalis were evaluated using chromogenic peptides and sheep erythrocytes. The mRNA expression of virulence and iron/heme utilization was assessed using RT-PCR. In addition, cell viability of melatonin receptor agonists on human gingival fibroblasts (HGFs) was evaluated by MTT assays. After pretreatment of melatonin receptor agonists, HGFs were stimulated with Pg-LPS and then release of cytokines (IL-6 and lL-8) was measured by enzyme-linked immunosorbent assay (ELISA).ResultsMelatonin and ramelteon did exhibit antimicrobial effects against planktonic culture. Importantly, they inhibited biofilm formation, reduced the established biofilms, and decreased biofilm viability of Porphyromonas gingivalis. Furthermore, they at sub-minimum inhibitory concentration (sub-MIC) concentrations markedly inhibited the proteinase activities of gingipains and hemolysis in a dose-dependent manner. They at sub-MIC concentrations significantly inhibited the mRNA expression of virulence factors (kgp, rgpA, rgpB, hagA, and ragA), while increasing the mRNA expression of ferritin (ftn) or hemolysin (hem). They did not show obvious cytotoxicity toward HGFs. They inhibited Pg-LPS-induced IL-6 and IL-8 secretion, which was reversed by luzindole, the melatonin receptor antagonist.ConclusionMelatonin receptor agonists can inhibit planktonic and biofilm growth of Porphyromonas gingivalis by affecting the virulent properties, as well as Pg-LPS-induced inflammatory response. Our study provides new evidence that melatonin receptor agonists might be useful as novel “perioceutics” agents to prevent and treat Porphyromonas gingivalis-associated periodontal diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Melatonin Receptor Agonists as the “Perioceutics” Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response

Wei¹,

Zhang²,

Zhu³

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Site selective acylation led to the melatonin-like tryptamine 23 in modest yield. 49 Studies are underway to functionalize each PNZ-tryptamine in Table 1 to generate a library of molecules for biological activity screening.…”

Section: Resultsmentioning

confidence: 99%

“…49 Purification by silica gel chromatography (2:1 ethyl acetate/hexanes) afforded a white solid in 44% yield (0.0191 g). 1 H NMR (400 MHz, Chloroform- d ) δ 8.25 (br s, 1H), 7.67 (d, J =7.9 Hz, 1H), 7.40 (d, J =8.1 Hz, 1H), 7.22 (t, J =7.5, 1H), 7.14 (t, J =7.5, 1H), 7.05 (d, J =2.4 Hz, 1H), 5.46 (br s, 1H), 3.73–3.64 (m, 1H), 3.45 (ddd, J =13.2, 8.2, 5.1 Hz, 1H), 3.35–3.24 (m, 1H), 1.89 (s, 3H), 1.38 (d, J =7.0 Hz, 3H).…”

Section: Methodsmentioning

confidence: 99%

Synthesis of β-substituted tryptamines by regioselective ring opening of aziridines

2016

View full text Add to dashboard Cite

Functionalized tryptamines are targets of interest for development as small molecule therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine synthesis if site selectivity can be controlled. 4-Nitrobenzyl carbamate (PNZ)-protected aziridines undergo regioselective ring opening to produce β-substituted tryptamines for a series of indoles. The PNZ-protected tryptamines can be further manipulated by PNZ removal under mild conditions.

show abstract

“…[24] Furthermore, melatonin features aC 5-methoxylated indole, which has been implicated asacritical factor in malaria biology and exploited as an endogenous ligand for antimalarial drug design. [25][26][27] Consequently,w eo pted to synthesise analogues featuring aC 5-methyl-or methoxyindole. In addition to this strategics tructural modification, aC 2-methylindole was incorporated to explore potential effects of this substitution.…”

Section: Sar Strategymentioning

confidence: 99%

Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

et al. 2018

View full text Add to dashboard Cite

Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non-haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long-term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.

show abstract

Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium falciparum

Cited by 49 publications

References 42 publications

Melatonin Receptor Agonists as the “Perioceutics” Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response

Melatonin Receptor Agonists as the “Perioceutics” Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response

Synthesis of β-substituted tryptamines by regioselective ring opening of aziridines

Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

Contact Info

Product

Resources

About