Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent

Moreira, Diogo Rodrigo Magalhães; Sá, Matheus Santos de; Macedo, Taís Soares; Menezes, Melody; Reys, José Rui M.; Santana, Antônio Euzébio Goulart; Silva, Thaissa L.; Maia, Gabriela L. A.; Barbosa-Filho, José Maria; Câmara, Celso A.; Silva, Tania M. S. da; Silva, Katia N. da; Guimarães, Elisalva Teixeira; Santos, Ricardo Ribeiro dos; Goulart, Marília Oliveira Fonseca; Soares, Milena Botelho Pereira

doi:10.3109/14756366.2014.958083

Cited by 21 publications

(8 citation statements)

References 26 publications

(18 reference statements)

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“…In addition to MMV085203, GNF-Pf-3600, and atovaquone, the pfmfr3 Q487E single point mutant also showed 3-fold resistance against another compound with a naphthoquinone group, GNF-Pf-3703 (data not shown). If this is indeed the case, MFR3 activity could be a significant correlate of resistance against a multitude of candidate antimalarials given that naphthoquinone derivatives have immense potential as antiplasmodial leader molecules and have been widely used for the development of many compound series. ,− Importantly, polymorphisms in pfmfr3 have been found to naturally exist in parasite populations in the field with over 50% occurring in transmembrane domains . Although none of the genetic alterations that were identified in this study have been documented in clinical isolates, one cannot rule out the possibility of these natural mutations leading to modifications in transporter activity and specificity and eventually contributing to clinical drug resistance.…”

Section: Discussionmentioning

confidence: 99%

PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

et al. 2021

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In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone phenotypic screening hits that kill both blood- and sexual-stage P. falciparum parasites in the low nanomolar to low micromolar range. In order to understand their mechanism of action, parasites from two different genetic backgrounds were exposed to sublethal concentrations of MMV085203 and GNF-Pf-3600 until resistance emerged. Whole genome sequencing revealed all 17 resistant clones acquired nonsynonymous mutations in the gene encoding the orphan apicomplexan transporter PF3D7_0312500 ( pfmfr3 ) predicted to encode a member of the major facilitator superfamily (MFS). Disruption of pfmfr3 and testing against a panel of antimalarial compounds showed decreased sensitivity to MMV085203 and GNF-Pf-3600 as well as other compounds that have a mitochondrial mechanism of action. In contrast, mutations in pfmfr3 provided no protection against compounds that act in the food vacuole or the cytosol. A dihydroorotate dehydrogenase rescue assay using transgenic parasite lines, however, indicated a different mechanism of action for both MMV085203 and GNF-Pf-3600 than the direct inhibition of cytochrome bc1. Green fluorescent protein (GFP) tagging of PfMFR3 revealed that it localizes to the parasite mitochondrion. Our data are consistent with PfMFR3 playing roles in mitochondrial transport as well as drug resistance for clinically relevant antimalarials that target the mitochondria. Furthermore, given that pfmfr3 is naturally polymorphic, naturally occurring mutations may lead to differential sensitivity to clinically relevant compounds such as atovaquone.

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Section: Discussionmentioning

confidence: 99%

PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

et al. 2021

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“…The RuCl 3 .nH 2 O, bis (diphenylphosphine)methane (dppm), 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), and KPF 6 were purchased from Sigma-Aldrich MERCK (St. Louis, MO, USA) and used as received. Lapachol (Lap) was extracted from the bark of Tabebuia aurea (Manso) S. Moore as reported in the literature ( 27 ).…”

Section: Methodsmentioning

confidence: 99%

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

et al. 2021

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Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF6 (1) and [Ru(Lap)(dppm)(phen)]PF6 (2) [Lap = lapachol, dppm = 1,1′-bis(diphosphino)methane, bipy = 2,2′-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex (2) suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex (2) stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex (2), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy.

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“…In this review, the current discoveries and studies of inhibitors, particularly nonquinoline inhibitors, are introduced to the heme detoxiﬁcation pathway and Hz formation. Naphthoquinone‐derivated 99 , related to the naturally occurring lapachol ( 98 ) and lapachone, was investigated for its inhibition of Hz crystal formation comparable with 88 , without affecting the mitochondrial structure or causing DNA fragmentation in parasite‐treated cells . On the basis of the effects of 7‐chloroquinoline‐based antimalarial drugs in Hz formation in the food vacuoles of the Plasmodium parasite, Blackie and Jacobs developed two serial novel ferroquine (FQ) and phenylequine derivatives.…”

Section: Pigments Of Representative Colored Pathogens and Their Inhibmentioning

confidence: 99%

“…Naphthoquinone-derivated 99, related to the naturally occurring lapachol (98) and lapachone, was investigated for its inhibition of Hz crystal formation comparable with 88, without affecting the mitochondrial structure or causing DNA fragmentation in parasite-treated cells. 211 On the basis of the effects of 7-chloroquinoline-based antimalarial drugs in Hz formation in the food vacuoles of the Plasmodium parasite, Blackie and Jacobs developed two serial novel ferroquine (FQ) and phenylequine derivatives. Both derivatives displayed good efficiency in vitro toward the chloroquine-sensitive (CQS) NF54 (IC 50 = 4.2 nM) and CQR Dd2 (IC 50 = 33.7 nM) strains of P. falciparum along with good inhibitory activity against β-hematin formation in an NP-40 detergent assay (IC 50 = 10.4-19.2 μM).…”

Section: The Discovery Of Quinoline Art and Xanthone-derived Antimentioning

confidence: 99%

Targeting virulence factors as an antimicrobial approach: Pigment inhibitors

et al. 2019

Medicinal Research Reviews

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The fascinating and dangerous colored pathogens contain unique chemically pigmented molecules, which give varied and efficient assistance as virulence factors to the crucial reproduction and growth of microbes. Therefore, multiple novel strategies and inhibitors have been developed in recent years that target virulence factor pigments. However, despite the importance and significance of this topic, it has not yet been comprehensively reviewed. Moreover, research groups around the world have made successful progress against antibacterial infections by targeting pigment production, including our serial works on the discovery of CrtN inhibitors against staphyloxanthin production in Staphylococcus aureus. On the basis of the previous achievements and recent progress of our group in this field, this article will be the first comprehensive review of pigment inhibitors against colored pathogens, especially S. aureus infections, and this article includes design strategies, representative case studies, advantages, limitations, and perspectives to guide future research.

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Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent

Cited by 21 publications

References 26 publications

PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

Targeting virulence factors as an antimicrobial approach: Pigment inhibitors

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