Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-<i>Toxoplasma gondii</i> agents

Luan, Tian; Jin, Chi; Gong, Guo-Hua; Quan, Zhe‐Shan

doi:10.1080/14756366.2019.1584622

Cited by 23 publications

(15 citation statements)

References 24 publications

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“…Ursolic acid-triazole derivatives not only possess anti-inflammatory activity 112 , but also they exhibit anti -Toxoplasma gondii activity 146 . Ursolic acid derivatives displayed some anti- Toxoplasma gondii activity and exhibited less cytotoxicity than ursolic acid in vitro 146 . The compounds with 1,2,4-phenyltriazole showed considerably higher anti- Toxoplasma gondii activity.…”

Section: Biological Activitiesmentioning

confidence: 99%

Application of triazoles in the structural modification of natural products

Guo

Zheng-ai

Shen

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Nature products have been extensively used in the discovery and development of new drugs, as the most important source of drugs. The triazole ring is one of main pharmacophore of the nitrogen-containing heterocycles. Thus, a new class of triazole-containing natural product conjugates has been synthesised. These compounds reportedly exert anticancer, anti-inflammatory, antimicrobial, antiparasitic, antiviral, antioxidant, anti-Alzheimer, and enzyme inhibitory effects. This review summarises the research progress of triazole-containing natural product derivatives involved in medicinal chemistry in the past six years. This review provides insights and perspectives that will help scientists in the fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.

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Section: Biological Activitiesmentioning

confidence: 99%

Application of triazoles in the structural modification of natural products

Guo

Zheng-ai

Shen

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The majority of the lead compounds were identified through phenotypic screening of small molecule libraries. More recently, analogs of various natural products such as thiolactomycin ( Martins-Duarte et al, 2009 ), trypanthrin ( Krivogorsky et al, 2013 ), arctigenin ( Zhang et al, 2018 ), (+)-usnic and ursolic acids ( Guo et al, 2019 ; Luan et al, 2019 ), and dihydroartemisinin ( Deng et al, 2020 ) have been reported to be effective against T. gondii . More interestingly, some compounds were initially discovered as antiplasmodial agents and subsequently were shown to be also active against T. gondii .…”

Section: Introductionmentioning

confidence: 99%

Novel acyl carbamates and acyl / diacyl ureas show in vitro efficacy against Toxoplasma gondii and Cryptosporidium parvum

Grooms

Khan

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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Toxoplasma gondii and Cryptosporidium parvum are protozoan parasites that are highly prevalent and opportunistically infect humans worldwide, but for which completely effective and safe medications are lacking. Herein, we synthesized a series of novel small molecules bearing the diacyl urea scaffold and related structures, and screened them for in vitro cytotoxicity and antiparasitic activity against T. gondii and C. parvum . We identified one compound (GMG-1-09), and four compounds (JS-1-09, JS-2-20, JS-2-35 and JS-2-49) with efficacy against C. parvum and T. gondii , respectively, at low micromolar concentrations and showed appreciable selectivity in human host cells. Among the four compounds with efficacy against T. gondii , JS-1-09 representing the diacyl urea scaffold was the most effective, with an anti- Toxoplasma IC 50 concentration (1.21 μM) that was nearly 53-fold lower than its cytotoxicity IC 50 concentration, indicating that this compound has a good selectivity index. The other three compounds (JS-2-20, JS-2-35 and JS-2-49) were structurally more divergent from JS-1-09 as they represent the acyl urea and acyl carbamate scaffold. This appeared to correlate with their anti- Toxoplasma activity, suggesting that these compounds’ potency can likely be enhanced by selective structural modifications. One compound, GMG-1-09 representing acyl carbamate scaffold, depicted in vitro efficacy against C. parvum with an IC 50 concentration (32.24 μM) that was 14-fold lower than its cytotoxicity IC 50 concentration in a human intestinal cell line. Together, our studies unveil a series of novel synthetic acyl/diacyl urea and acyl carbamate scaffold-based small molecule compounds with micromolar activity against T. gondii and C. parvum that can be explored further for the development of the much-needed novel anti-protozoal drugs.

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“…Oldenlandia diffusa and Rosmarinus officinalis ). It has been reported that ursolic acid possessed diverse biological and pharmacological properties including anticancer, anti-microbial, anti-inflammatory, anti-angiogenic and antioxidant activities ( 43 ). In terms of antitumor mechanisms, accumulating studies have reported that ursolic acid could inhibit cancer proliferation, invasion, angiogenesis, metastasis ( 34 ) as well as inducing cell cycle arrest, apoptosis ( 44 ) and autophagy-dependent death of cancer cells ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Ursolic Acid Inhibits Breast Cancer Metastasis by Suppressing Glycolytic Metabolism via Activating SP1/Caveolin-1 Signaling

Wang

Zhang

et al. 2021

Front. Oncol.

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Breast cancer remains the most common malignancy and the leading causality of cancer-associated mortality among women worldwide. With proven efficacy, Oldenlandia diffusa has been extensively applied in breast cancer treatment in Traditional Chinese Medicine (TCM) for thousands of years. However, the bioactive compounds of Oldenlandia diffusa accounting for its anti-breast cancer activity and the underlying biological mechanisms remain to be uncovered. Herein, bioactivity-guided fractionation suggested ursolic acid as the strongest anti-breast cancer compound in Oldenlandia diffusa. Ursolic acid treatment dramatically suppressed the proliferation and promoted mitochondrial-mediated apoptosis in breast cancer cells while brought little cytotoxicities in nonmalignant mammary epithelial cells in vitro. Meanwhile, ursolic acid dramatically impaired both the glycolytic metabolism and mitochondrial respiration function of breast cancer cells. Further investigations demonstrated that ursolic acid may impair the glycolytic metabolism of breast cancer cells by activating Caveolin-1 (Cav-1) signaling, as Cav-1 knockdown could partially abrogate the suppressive effect of ursolic acid on that. Mechanistically, ursolic acid could activate SP1-mediated CAV1 transcription by promoting SP1 expression as well as its binding with CAV1 promoter region. More meaningfully, ursolic acid administration could dramatically suppress the growth and metastasis of breast cancer in both the zebrafish and mouse xenotransplantation models of breast cancer in vivo without any detectable hepatotoxicity, nephrotoxicity or hematotoxicity. This study not only provides preclinical evidence supporting the application of ursolic acid as a promising candidate drug for breast cancer treatment but also sheds novel light on Cav-1 as a druggable target for glycolytic modulation of breast cancer.

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Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents

Cited by 23 publications

References 24 publications

Application of triazoles in the structural modification of natural products

Application of triazoles in the structural modification of natural products

Novel acyl carbamates and acyl / diacyl ureas show in vitro efficacy against Toxoplasma gondii and Cryptosporidium parvum

Ursolic Acid Inhibits Breast Cancer Metastasis by Suppressing Glycolytic Metabolism via Activating SP1/Caveolin-1 Signaling

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