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Planta Med 2023; 89(04): 377-384
DOI: 10.1055/a-1908-0935
Biological and Pharmacological Activity
Original Papers

Urease and Carbonic Anhydrase Inhibitory Effect of Xanthones from Aspergillus nidulans, an Endophytic Fungus of Nyctanthes arbor-tristis

Talea Sana
1   H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
,
Majid Khan
1   H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
,
Almas Jabeen
2   Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
,
Sidrah Shams
2   Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
,
Taibi Ben Hadda
3   Laboratoire de Chimie des Matériaux, Faculté des Sciences, Université Mohammed Premier, Oujda, Morocco
,
Sabira Begum
1   H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
,
Bina Shaheen Siddiqui
1   H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
› Author AffiliationsSupported by: Pakistan Academy of Sciences 5-9/PAS/52
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Abstract

Urease plays a major role in the pathogenesis of peptic and gastric ulcer and also causes acute pyelonephritis and development of infection-induced reactive arthritis. Carbonic anhydrases (CA) cause pathological disorders such as epilepsy (CA I), glaucoma, gastritis, renal, pancreatic carcinomas, and malignant brain tumors (CA II). Although various synthetic urease and carbonic anhydrase inhibitors are known, these have many side effects. Hence, present studies were undertaken on ethyl acetate extract of Aspergillus nidulans, an endophytic fungus separated from the leaves of Nyctanthes arbor-tristis Linn. and led to the isolation of five furanoxanthones, sterigmatin (1), sterigmatocystin (3), dihydrosterigmatocystin (4), oxisterigmatocystin C (5), acyl-hemiacetal sterigmatocystin (6), and a pyranoxanthone (2). Acetylation of 3 gave compound O-acetyl sterigmatocystin (7). Their chemical structures were elucidated by 1H and 13C NMR and MS. The inhibitory effect of isolated compounds was evaluated on urease and carbonic anhydrase (bCA II) enzymes in vitro. Compounds 3 and 6 showed significant urease inhibition (IC50 19 and 21 µM), while other compounds exhibited varying degrees of urease inhibition (IC50 33 – 51 µM). Compounds 4, 6 and 7 exhibited significant inhibition of bCA II (IC50 values 21, 25 and 18 µM respectively), compounds 1–3 displayed moderate inhibition (IC50 61, 76 and 31 µM respectively) while 5 showed no inhibition. A mechanistic study of the most active urease inhibitors was also performed using enzyme kinetics and molecular docking. All compounds were found non-toxic on the NIH-3T3 cell line.

Key words

Nyctanthes arbor-tristis - Oleaceae - Aspergillus nidulans - urease - carbonic anhydrase - inhibitory effect

Supporting Information

    1H- and 13C-NMR data of compounds 1–7, and 1H-NMR spectra of compounds 1–7 are provided as Supporting Information.

  • Supporting Information


Publication History

Received: 01 April 2022

Accepted after revision: 12 July 2022

Article published online:
10 January 2023

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Wilson D. Endophyte: The evaluation of a term and clarification of its use and definition. Oikos 1995; 73: 274-276
    CrossrefPubMedGoogle Scholar
  • 2 Adeleke BS, Babalola OO. Pharmacological potential of fungal endophytes associated with medicinal plants: A review. J Fungi 2021; 7: 147
    CrossrefPubMedGoogle Scholar
  • 3 Chopra RN, Nayar SL, Chopra IC. Glossary of Indian medicinal Plants. New Delhi: Council of Scientific & Industrial Research; 1956: 177
    Google Scholar
  • 4 Ganesan N, Rajendran R, Ilanchezhiyan S. Nyctanthes arbor-tristis Linn. associated fungal endophyte Aspergillus niger derived isolation of camptothecin for its antimicrobial and cytotoxic activity. Scigen J Sci Tech 2015; 1: 2-9
    PubMedGoogle Scholar
  • 5 Gond SK, Mishra A, Sharma VK, Verma SK, Kumar J, Kharwar RN, Kumar A. Diversity and antimicrobial activity of endophytic fungi isolated from Nyctanthes arbor-tristis, a well-known medicinal plant of India. Mycoscience 2012; 53: 113-121
    CrossrefPubMedGoogle Scholar
  • 6 Sana T, Siddiqui BS, Shahzad S, Farooq AD, Siddiqui F, Sattar S, Begum S. Antiproliferative activity and characterization of metabolites of Aspergillus nidulans: An endophytic fungus from Nyctanthes arbor-tristis Linn. against three human cell lines. Med Chem 2019; 15: 352-359
    CrossrefPubMedGoogle Scholar
  • 7 Sana T, Siddiqui BS, Khan M, Shahzad S, Sattar S, Begum S. Bioactive natural products from endophytic fungus Aspergillus nidulans associated with Nyctanthes arbor-tristis Linn. Rec Nat Prod 2021; 15: 608-612
    CrossrefPubMedGoogle Scholar
  • 8 Kalra P, Sharma S, Suman. Kumar S. Antiulcer effect of the methanolic extract of Tamarindus indica seeds in different experimental models. J Pharm Bioallied Sci 2011; 3: 236-241
    CrossrefPubMedGoogle Scholar
  • 9 Mobley HL, Island MD, Hausinger RP. Molecular biology of microbial ureases. Microbiol Rev 1995; 59: 451-480
    CrossrefPubMedGoogle Scholar
  • 10 Amtul Z, Rasheed M, Choudhary MI, Rosanna S, Khan KM. Atta-Ur-Rahman. Kinetics of novel competitive inhibitors of urease enzymes by a focused library of oxadiazoles/thiadiazoles and triazoles. Biochem Biophys Res Commun 2004; 319: 1053-1063
    CrossrefPubMedGoogle Scholar
  • 11 Krajewska B. Ureases I. Functional, kinetic and catalytic properties: A review. J Mol Catal B Enzym 2009; 59: 9-21
    CrossrefPubMedGoogle Scholar
  • 12 Abid OU, Babar TM, Ali FI, Ahmed S, Wadood A, Rama NH, Uddin R, Zaheer-Ul-Haq. Khan A, Choudhary MI. Identification of novel urease inhibitors by high-throughput virtual and in vitro screening. ACS Med Chem Lett 2010; 1: 145-149
    CrossrefPubMedGoogle Scholar
  • 13 Akhtar T, Hameed S, Khan KM, Khan A, Choudhary MI. Design, synthesis, and urease inhibition studies of some 1,3,4-oxadiazoles and 1,2,4-triazoles derived from mandelic acid. J Enzym Inhib Med Chem 2010; 25: 572-576
    CrossrefPubMedGoogle Scholar
  • 14 Rauf A, Ahmed F, Qureshi AM, Aziz-Ur-Rehman. Khan A, Qadir MI, Choudhary MI, Chohan ZH, Youssoufid MH, Hadda TB. Synthesis and urease inhibition studies of barbituric and thiobarbituric acid derived sulphonamides. J Chin Chem Soc 2011; 58: 528-537
    CrossrefPubMedGoogle Scholar
  • 15 Nar M, Çetinkaya Y, Gülçin İ, Menzek A. (3,4-Dihydroxyphenyl) (2,3,4-trihydroxyphenyl) methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors. J Enzyme Inhib Med Chem 2013; 28: 402-406
    CrossrefPubMedGoogle Scholar
  • 16 Turkan F, Cetin A, Taslimi P, Karaman HS, Gulçin İ. Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorg Chem 2019; 86: 420-427
    CrossrefPubMedGoogle Scholar
  • 17 Özbey F, Taslimi P, Gülçin İ, Maraş A, Göksu S, Supuran CT. Synthesis of diaryl ethers with acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase inhibitory actions. J Enzyme Inhib Med Chem 2016; 31: 79-85
    CrossrefPubMedGoogle Scholar
  • 18 Khan A, Khan M, Halim SA, Khan ZA, Shafiq Z, Al-Harrasi A. Quinazolinones as competitive inhibitors of carbonic anhydrase-II (human and bovine): Synthesis, in-vitro, in-silico, selectivity, and kinetics studies. Front Chem 2020; 8: 598095
    CrossrefPubMedGoogle Scholar
  • 19 Karioti A, Carta F, Supuran CT. Phenols and polyphenols as carbonic anhydrase inhibitors. Molecules 2016; 21: 1649
    CrossrefPubMedGoogle Scholar
  • 20 Hamasaki T, Matsui K, Isono K, Hatsuda Y. A new metabolite from Aspergillus versicolor . Agr Biol Chem 1973; 37: 1769-1770
    CrossrefPubMedGoogle Scholar
  • 21 Kamel RA, Abdel-Razek AS, Hamed A, Ibrahim RR, Stammler HG, Frese M, Sewald N, Shaaban M. Isoshamixanthone: a new pyranoxanthone from endophytic Aspergillus sp. ASCLA and absolute configuration of epiisoshamixanthone. Nat Prod Res 2020; 34: 1080-1090
    CrossrefPubMedGoogle Scholar
  • 22 Essigmann JM, Barker LJ, Fowler KW, Francisco MA, Reinhold VN, Wogan GN. Sterigmatocystin-DNA interactions: Identification of a major adduct formed after metabolic activation in vitro . Proc Natl Acad Sci USA 1979; 76: 179-183
    CrossrefPubMedGoogle Scholar
  • 23 Cox RH, Cole RJ. Carbon-13 nuclear magnetic resonance studies of fungal metabolites, aflatoxins, and sterigmatocystin. J Org Chem 1977; 42: 112-114
    CrossrefPubMedGoogle Scholar
  • 24 Cai S, Zhu T, Du L, Zhao B, Li D, Gu Q. Sterigmatocystins from the deep-sea-derived fungus Aspergillus versicolor . J Antibiot 2011; 64: 193-196
    CrossrefPubMedGoogle Scholar
  • 25 Song F, Ren B, Chen C, Yu K, Liu X, Zhang Y, Yang N, He H, Liu X, Dai H, Zhang L. Three new sterigmatocystin analogues from marine-derived fungus Aspergillus versicolor MF359. Appl Microbiol Biotechnol 2014; 98: 3753-3758
    CrossrefPubMedGoogle Scholar
  • 26 Gengan RM, Chuturgoon AA, Mulholland DA, Dutton MF. Synthesis of sterigmatocystin derivatives and their biotransformation to aflatoxins by a blocked mutant of Aspergillus parasiticus . Mycopathologia 1999; 144: 115-122
    CrossrefPubMedGoogle Scholar
  • 27 Kucuk M, Gulcin İ. Purification and characterization of the carbonic anhydrase enzyme from Black Sea trout (Salmo trutta Labrax Coruhensis) kidney and inhibition effects of some metal ions on enzyme activity. Environ Toxicol Pharmacol 2016; 44: 134-139
    CrossrefPubMedGoogle Scholar
  • 28 Özgeriş B, Göksu S, Polat Köse L, Gülçin İ, Salmas RE, Durdagi S, Tümer F, Supuran CT. Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds. Bioorg Med Chem 2016; 24: 2318-2329
    CrossrefPubMedGoogle Scholar
  • 29 Taslimi P, Gülçin İ, Öztaşkın N, Çetinkaya Y, Göksu S, Alwasel SH, Supuran CT. The effects of some bromophenols on human carbonic anhydrase isoenzymes. J Enzyme Inhib Med Chem 2016; 31: 603-607
    CrossrefPubMedGoogle Scholar
  • 30 Akhtar T, Hameed S, Khan KM, Choudhary MI. Syntheses, urease inhibition, and antimicrobial studies of some chiral 3-substituted-4-amino-5-thioxo-1H,4H-1,2,4-triazoles. Med Chem 2008; 4: 539-543
    CrossrefPubMedGoogle Scholar
  • 31 Khan KM, Iqbal S, Lodhi MA, Maharvi GM, Ullah Z, Choudhary MI, Rahman AU, Perveen S. Biscoumarin: New class of urease inhibitors, economical synthesis and activity. Bioorg Med Chem 2004; 12: 1963-1968
    CrossrefPubMedGoogle Scholar
  • 32 Molecular Operating Environment, 2014. Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite 910, Montreal, QC, Canada.
    PubMedGoogle Scholar
  • 33 Pocker Y, Meany JE. The catalytic versatility of erythrocyte carbonic anhydrase. II. Kinetic studies of the enzyme-catalyzed hydration of pyridine aldehydes. Biochemistry 1967; 6: 239-246
    CrossrefPubMedGoogle Scholar
  • 34 Taha M, Ismail NH, Imran S, Mohamad MH, Wadood A, Rahim F, Saad SM, Rehman AU, Khan KM. Synthesis, α-glucosidase inhibitory, cytotoxicity and docking studies of 2-aryl-7-methylbenzimidazoles. Bioorg Chem 2016; 65: 100-109
    CrossrefPubMedGoogle Scholar
  • 35 Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
    CrossrefPubMedGoogle Scholar