Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives

Onambele, Liliane A.; Riepl, Herbert; Fischer, Rainer; Pradel, Gabriele; Prokop, Aram; Aminake, Makoah N.

doi:10.1016/j.ijpddr.2015.03.002

Cited by 23 publications

(23 citation statements)

References 31 publications

(37 reference statements)

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“…We transferred 100 μl of the supernatant to another new microtiter plate. The absorbance of free hemoglobin was measured at 550 nm (Onambele et al, ). The hemolytic rate was calculated using the 0.1% Triton X‐100 positive control for hemolysis of human RBCs, which was considered 100%.…”

Section: Methodsmentioning

confidence: 99%

Apigenin inhibits growth of the Plasmodium berghei and disrupts some metabolic pathways in mice

Amiri

Nourian

Khoshkam

et al. 2018

Phytotherapy Research

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Due to the challenges in the control, prevention, and eradication of parasitic diseases like malaria, there is an urgent need to discover new therapeutic agents. Plant-derived medicines may open new ways in the field of antiplasmodial therapy. This study is aimed to investigate the toxicity and in vivo antiplasmodial activity of apigenin, a dietary flavonoid. Apigenin cytotoxicity was investigated on Huh7 cell line, brine shrimp (Artemia salina) larva, and human red blood cells. In vivo toxicity of apigenin was assessed by metabolomics approaches. Apigenin exhibited significant suppression of parasitemia in a dose-dependent manner; it suppressed Plasmodium berghei growth by 69.74%, 50.3%, and 49.23% at concentrations of 70, 35, and 15 mg/kg/day, respectively. The IC value for apigenin after 24 hr exposure to Huh7 cells was 225 μg/ml. Apigenin did not show noticeable toxicity on A. salina and also on the membrane integrity of red blood cells. After 24 hr exposure of mice to apigenin, alterations were seen in the metabolism of glucocorticoids and mineralocorticoids, bile acid metabolism (alternative pathway), sulfur metabolism, bile acid metabolism, metabolism of estrogens and androgens, cholesterol catabolism, and biosynthesis of cholesterol. These findings indicate that apigenin has potential in vivo antiplasmodial activity against P. berghei infected mice with high selectivity against malaria, but it can disrupt some metabolic pathways in mice.

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Section: Methodsmentioning

confidence: 99%

Apigenin inhibits growth of the Plasmodium berghei and disrupts some metabolic pathways in mice

Amiri

Nourian

Khoshkam

et al. 2018

Phytotherapy Research

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“…Structural modification of natural compounds can increase compound potency and selectivity, enhance their pharmacological properties, and significantly diminish their detrimental effects ( Guo, 2017 ). Several TRYP derivatives with various tetracyclic scaffold modifications have been developed, including compounds with anti-plasmodium and anti-toxoplasma properties ( Krivogorsky et al., 2008 ; Onambele et al., 2015 ), indoleamine 2,3-dioxygenase inhibitors ( Yang et al., 2013 ), and DNA triplex stabilizing agents ( Chen et al., 2007 ). Recently, we found that tryptanthrin-6-oxime (TRYP-Ox) had high affinity for JNK1-3 and also blocked activation of NF-κB/AP-1 and the production of IL-6 by lipopolysaccharide-treated monocytic cells ( Schepetkin et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

et al. 2020

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Rheumatoid arthritis (RA) is a chronic autoimmune disease involving joint and bone damage that is mediated in part by proteases and cytokines produced by synovial macrophages and fibroblast-like synoviocytes (FLS). Although current biological therapeutic strategies for RA have been effective in many cases, new classes of therapeutics are needed. We investigated anti-inflammatory properties of the natural alkaloid tryptanthrin (TRYP) and its synthetic derivative tryptanthrin-6-oxime (TRYP-Ox). Both TRYP and TRYP-Ox inhibited matrix metalloproteinase (MMP)-3 gene expression in interleukin (IL)-1b-stimulated primary human FLS, as well as IL-1b-induced secretion of MMP-1/3 by FLS and synovial SW982 cells and IL-6 by FLS, SW982 cells, human umbilical vein endothelial cells (HUVECs), and monocytic THP-1 cells, although TRYP-Ox was generally more effective and had no cytotoxicity in vitro. Evaluation of the therapeutic potential of TRYP and TRYP-Ox in vivo in murine arthritis models showed that both compounds significantly attenuated the development of collagen-induced arthritis (CIA) and collagen-antibody-induced arthritis (CAIA), with comparable efficacy. Collagen II (CII)specific antibody levels were similarly reduced in TRYP-and TRYP-Ox-treated CIA mice. TRYP and TRYP-Ox also suppressed proinflammatory cytokine production by lymph node cells from CIA mice, with TRYP-Ox being more effective in inhibiting IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor activator of nuclear factor-kB ligand (RANKL). Thus, even though TRYP-Ox generally had a better in vitro profile, possibly due to its ability to inhibit c-Jun N-terminal kinase (JNK), both TRYP and TRYP-Ox were equally effective in inhibiting the clinical symptoms and damage associated with RA. Overall, TRYP and/or TRYP-Ox may represent potential new directions for the pursuit of novel treatments for RA.

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“…The quinazoline alkaloid, tryptanthrin and its synthetic derivatives designated NT1 and T8, have significant gametocytocidal activity in vitro (Figure 3, Table 2, Table S1) [95]. However, of the three agents only NT1 strongly inhibited exflagellation of micro-gametes (Table S1) [95]. Cryptolepine and a root extract of its parent plant, Cryptolepis sanguinolenta (Lindl.)…”

Section: Alkaloids Steroids and Miscellaneousmentioning

confidence: 99%

“…Other alkaloids including dihydronitidine and heitziquinone, isolated from the plant species Zanthoxylum heitzii (Rutaceae), also showed activity against ookinete development in vitro [ 94 ]. The quinazoline alkaloid, tryptanthrin and its synthetic derivatives designated NT1 and T8, have significant gametocytocidal activity in vitro ( Figure 3 , Table 2 , Table S1 ) [ 95 ]. However, of the three agents only NT1 strongly inhibited exflagellation of micro-gametes ( Table S1 ) [ 95 ].…”

Section: Effectiveness Of Natural Products Against Transmission-blmentioning

confidence: 99%

Natural Products: A Potential Source of Malaria Transmission Blocking Drugs?

et al. 2020

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The ability to block human-to-mosquito and mosquito-to-human transmission of Plasmodium parasites is fundamental to accomplish the ambitious goal of malaria elimination. The WHO currently recommends only primaquine as a transmission-blocking drug but its use is severely restricted by toxicity in some populations. New, safe and clinically effective transmission-blocking drugs therefore need to be discovered. While natural products have been extensively investigated for the development of chemotherapeutic antimalarial agents, their potential use as transmission-blocking drugs is comparatively poorly explored. Here, we provide a comprehensive summary of the activities of natural products (and their derivatives) of plant and microbial origins against sexual stages of Plasmodium parasites and the Anopheles mosquito vector. We identify the prevailing challenges and opportunities and suggest how these can be mitigated and/or exploited in an endeavor to expedite transmission-blocking drug discovery efforts from natural products.

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Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives

Cited by 23 publications

References 31 publications

Apigenin inhibits growth of the Plasmodium berghei and disrupts some metabolic pathways in mice

Apigenin inhibits growth of the Plasmodium berghei and disrupts some metabolic pathways in mice

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

Natural Products: A Potential Source of Malaria Transmission Blocking Drugs?

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