New semisynthetic α-glucosidase inhibitor from a doubly-chemically engineered extract

doi:10.1007/s13659-024-00488-2

Natural Products and Bioprospecting

2025, Vol. 15

Issue (1) : 4-4 DOI: 10.1007/s13659-024-00488-2

ORIGINAL ARTICLES

New semisynthetic α-glucosidase inhibitor from a doubly-chemically engineered extract

María I. Osella¹, Mario O. Salazar^1,2, Carlos M. Solís², Ricardo L. E. Furlan^1,2

1. Consejo Nacional de Investigaciones Científicas y Técnicas, Suipacha 531, S2002LRK, Rosario, Argentina;
2. Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina

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Abstract Chemically engineered extracts represent a promising source of new bioactive semi-synthetic molecules. Prepared through direct derivatization of natural extracts, they can include constituents enriched with elements and sub-structures that are less common in natural products compared to drugs. Fourteen such extracts were prepared through sequential reactions with hydrazine and a fluorinating reagent, and their α-glucosidase inhibition properties were compared. For the most bioactive mixture, a chemically modified propolis extract, enzyme inhibition increased 22 times due to the reaction sequence. Bio-guided fractionation led to the isolation of a new fluorinated pyrazole produced within the extract by chemical transformation of the flavonoid chrysin. The inhibitor results from the action of the two reagents used on four common functional groups present in natural products (carbonyl, phenol, aromatic carbon, and a double bond). The reactions led to the opening of a 6-member oxygenated heterocycle to produce a 5-member nitrogenated one, as well as the dehydroxylation and fluorination in two different positions of one of the aromatic rings of the natural starting material, all within a complex mixture of natural products. Overall, these transformations led to an approximately 20-fold increase in the α-glucosidase inhibition by the isolated inhibitor compared to its natural precursor.

Keywords Natural products Chemically engineered extracts Glucosidase inhibitor Pyrazole Fluorine

Fund:Ricardo L. E. Furlan and Mario O. Salazar would like to acknowledge for provided financial support by Universidad Nacional de Rosario (80020180300114UR and 80020180100128UR), CONICET (PIP No 11220200102423) and FONCYT (PICT2019-02232 and PICT2021-1034) for the development of this work.

Corresponding Authors: Ricardo L. E. FURLAN,E-mail:rfurlan@fbioyf.unr.edu.ar E-mail: rfurlan@fbioyf.unr.edu.ar

Issue Date: 15 February 2025

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María I. Osella,Mario O. Salazar,Carlos M. Solís, et al. New semisynthetic α-glucosidase inhibitor from a doubly-chemically engineered extract[J]. Natural Products and Bioprospecting, 2025, 15(1): 4-4.

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http://npb.kib.ac.cn/EN/10.1007/s13659-024-00488-2 OR http://npb.kib.ac.cn/EN/Y2025/V15/I1/4

[1] Beato A, Haudecoeur R, Boucherle B, Peuchmaur M. Expanding chemical frontiers: approaches for generating diverse and bioactive natural product-like compounds libraries from extracts. Chem Eur J. 2022;28: e202304166. https://doi.org/10.1002/chem.202304166.
[2] Ramallo IA, Salazar MO, García P, Furlan RLE. Chemical diversification of natural product extracts. In: Rahman A, editor. Studies in natural products chemistry, vol. 60. Amsterdam: Elsevier; 2018. p. 371–98.
[3] Li G, Lou H-X. Strategies to diversify natural products for drug discovery. Med Res Rev. 2018;38:1255–94. https://doi.org/10.1002/med.21474.
[4] Ramallo IA, Salazar MO, Mendez L, Furlan RLE. Chemically engineered extracts: source of bioactive compounds. Acc Chem Res. 2011;44:241–50. https://doi.org/10.1021/ar100106n.
[5] Lopez SN, Ramallo IA, Gonzalez Sierra M, Zacchino SA, Furlan RLE. Chemically engineered extracts as an alternative source of bioactive natural product-like compounds. Proc Natl Acad Sci USA. 2007;104:441–4. https://doi.org/10.1073/pnas.0608438104.
[6] Righi D, Marcourt L, Koval A, Ducret V, Pellissier L, Mainetti A, Katanaev VL, Perron K, Wolfender J-L, Ferreira QE. Chemo-diversification of plant extracts using a generic bromination reaction and monitoring by metabolite profiling. ACS Comb Sci. 2019;21:171–82. https://doi.org/10.1021/acscombsci.8b00132.
[7] García P, Salazar MO, Ramallo IA, Furlan RLE. A new fluorinated tyrosinase inhibitor from a chemically engineered essential oil. ACS Comb Sci. 2016;18:283–6. https://doi.org/10.1021/acscombsci.6b00004.
[8] García P, Ramallo IA, Salazar MO, Furlan RLE. Chemical diversification of essential oils, evaluation of complex mixtures and identification of a xanthine oxidase inhibitor. RSC Adv. 2016;6:57245–52. https://doi.org/10.1039/C6RA05373D.
[9] Mendez L, Salazar MO, Ramallo IA, Furlan RLE. Brominated extracts as source of bioactive compounds. ACS Comb Sci. 2011;13:200–4. https://doi.org/10.1021/co100073k.
[10] Ramallo IA, Alonso VL, Rua F, Serra E, Furlan RLE. A bioactive trypanosoma cruzi bromodomain inhibitor from chemically engineered extracts. ACS Comb Sci. 2018;20:220–8. https://doi.org/10.1021/acscombsci.7b00172.
[11] Solís CM, Salazar MO, Ramallo IA, García P, Furlan RLE. A tyrosinase inhibitor from a nitrogen-enriched chemically engineered extract. ACS Comb Sci. 2019;21:622–7. https://doi.org/10.1021/acscombsci.9b00064.
[12] Salazar MO, Ramallo IA, Micheloni O, Gonzalez Sierra M, Furlan RLE. Chemically engineered extracts: bioactivity alteration through sulfonylation. Bioorg Med Chem Lett. 2009;19:5067–70. https://doi.org/10.1016/j.bmcl.2009.07.038.
[13] Salazar MO, Micheloni O, Escalante AM, Furlan RLE. Discovery of a β-glucosidase inhibitor from a chemically engineered extract prepared through sulfonylation. Mol Divers. 2011;15:713–9. https://doi.org/10.1007/s11030-010-9301-2.
[14] Salazar MO, Osella MI, Ramallo IA, Furlan RLE. N^α-arylsulfonyl histamines as selective β-glucosidase inhibitors. RSC Adv. 2018;8:36209–18. https://doi.org/10.1039/C8RA06625F.
[15] Salazar MO, Osella MI, Arcusin DEJ, Lescano LE, Furlán RLE. New α-glucosidase inhibitors from a chemically engineered essential oil of Origanum vulgare L. Ind Crops Prod. 2020;156: 112855. https://doi.org/10.1016/j.indcrop.2020.112855.
[16] Tomohara K, Ohashi N, Uchida T, Nose T. Synthesis of natural product hybrids by the Ugi reaction in complex media containing plant extracts. Sci Rep. 2022;12:15568. https://doi.org/10.1038/s41598-022-19579-6.
[17] Tomohara K, Maneenet J, Ohashi N, Nose T, Fujii R, Kim MJ, Sun S, Awale S. Ugi adducts as novel anti-austerity agents against PANC-1 human pancreatic cancer cell line: a rapid synthetic approach. Biol Pharm Bull. 2023;46:1412–20. https://doi.org/10.1248/bpb.b23-00224.
[18] Tomohara K, Ito T, Hasegawa N, Kato A, Adachi I. Direct chemical derivatization of natural plant extract: straightforward synthesis of natural plant-like hydantoin. Tetrahedron Lett. 2016;57:924–7. https://doi.org/10.1016/j.tetlet.2016.01.054.
[19] Wu T, Jiang C, Wang L, Morris-Natschke SL, Miao H, Gu L, Xu J, Lee KH, Gu Q. 3,5-Diarylpyrazole derivatives obtained by ammonolysis of the total flavonoids from chrysanthemum indicum extract show potential for the treatment of Alzheimer’s disease. J Nat Prod. 2015;78:1593–9. https://doi.org/10.1021/acs.jnatprod.5b00156.
[20] Zhang J-L, Xu W, Zhou Z-R, Li J, Jiang L-L, Zhang X-X, Jiang R-W. Antineoplastic constituents from the chemical diversified extract of radix puerariae. Chem Biodiversity. 2019;16: e1800408. https://doi.org/10.1002/cbdv.201800408.
[21] Kikuchi H, Sakurai K, Oshima Y. Development of diversity-enhanced extracts of curcuma zedoaria and their new sesquiterpene-like compounds. Org Lett. 2014;16:1916–9. https://doi.org/10.1021/ol5004324.
[22] Suzuki Y, Ichinohe K, Sugawara A, Kida S, Zhang J, Yamada O, Hattori T, Oshima Y, Murase S, Kikuchi H. Development of indole alkaloid-type dual immune checkpoint inhibitors against CTLA-4 and PD-L1 based on diversity-enhanced extracts. Front Chem. 2021;9: 766107. https://doi.org/10.3389/fchem.2021.766107.
[23] Kikuchi H, Kawai K, Nakashiro Y, Yonezawa T, Kawaji K, Kodama EN, Oshima Y. Construction of a meroterpenoid-like compounds library based on diversity-enhanced extracts. Chem Eur J. 2019;25:1106–12. https://doi.org/10.1002/chem.201805417.
[24] Du Y, Sun J, Gong Q, Wang Y, Fu P, Zhu W. New α-pyridones with quorum-sensing inhibitory activity from diversity-enhanced extracts of a Streptomyces sp. derived from marine algae. J Agric Food Chem. 2018;66:1807–12. https://doi.org/10.1021/acs.jafc.7b05330.
[25] Giri GF, Viarengo G, Furlan RLE, Suárez AG, Garcia Véscovi E, Spanevello RA. Soybean hulls, an alternative source of bioactive compounds: combining pyrolysis with bioguided fractionation. Ind Crops Prod. 2017;105:113–23. https://doi.org/10.1016/j.indcrop.2017.05.005.
[26] Adessi TG, Ana Y, Stempin CC, García MC, Bisogno FR, Nicotra VE, García ME. Psilostachyins as trypanocidal compounds: bioguided fractionation of Ambrosia tenuifolia chemically modified extract. Phytochem. 2022;194: 113014. https://doi.org/10.1016/j.phytochem.2021.113014.
[27] Tan Y, Sun X, Dong F, Tian H, Jiang R. Enhancing the structural diversity and bioactivity of natural products by combinatorial modification exemplified by total tanshinones. Chin J Chem. 2015;33:1084–8. https://doi.org/10.1002/cjoc.201500276.
[28] Kamauchi H, Noji M, Kinoshita K, Takanami T, Koyama K. Coumarins with an unprecedented tetracyclic skeleton and coumarin dimers from chemically engineered extracts of a marine-derived fungus. Tetrahedron. 2018;74:2846–56. https://doi.org/10.1016/j.tet.2018.04.033.
[29] Papoutsis K, Zhang J, Bowyer MC, Brunton N, Gibney ER, Lyng J. Fruit, vegetables, and mushrooms for the preparation of extracts with α-amylase and α-glucosidase inhibition properties: a review. Food Chem. 2021;338: 128119. https://doi.org/10.1016/j.foodchem.2020.128119.
[30] Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism. 2011;60:1–23. https://doi.org/10.1016/j.metabol.2010.09.010.
[31] Hu C, Jia W. Therapeutic medications against diabetes: what we have and what we expect. Adv Drug Deliv Rev. 2019;139:3–15. https://doi.org/10.1016/j.addr.2018.11.008.
[32] Dai T, Chen J, McClements DJ, Li T, Liu T. Investigation the interaction between procyanidin dimer and α-glucosidase: spectroscopic analyses and molecular docking simulation. Int J Biol Macromol. 2019;130:315–22. https://doi.org/10.1016/j.ijbiomac.2019.02.105.
[33] Narender T, Madhur G, Jaiswal N, Agrawal M, Maurya CK, Rahuja N, Srivastava AK, Tamrakar AK. Synthesis of novel triterpene and N-allylated/N-alkylated niacin hybrids as α-glucosidase inhibitors. Eur J Med Chem. 2013;63:162–9. https://doi.org/10.1016/j.ejmech.2013.01.053.
[34] Nguyen DV, Shaw LC, Grant MB. Inflammation in the pathogenesis of microvascular complications in diabetes. Front Endocrinol. 2012;3:170. https://doi.org/10.3389/fendo.2012.00170.
[35] Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782–7. https://doi.org/10.1038/414782a.
[36] Raut JS, Karuppayil SM. A status review on the medicinal properties of essential oils. Ind Crops Prod. 2014;62:250–64. https://doi.org/10.1016/J.INDCROP.2014.05.055.
[37] Maffei ME, Gertsch J, Appendino G. Plant volatiles: production, function and pharmacology. Nat Prod Rep. 2011;28:1359–80. https://doi.org/10.1039/C1NP00021G.
[38] Lescano LE, Salazar MO, Furlan RLE. Chemically engineered essential oils prepared through thiocyanation under solvent-free conditions: chemical and bioactivity alteration. Nat Prod Bioprospect. 2024;14:35. https://doi.org/10.1007/s13659-024-00456-w.
[39] Lazović M, Ivković Đ, Jankov M, Dimkić I, Janakiev T, Trifković J, Milojković-Opsenica D, Ristivojević P. Enhancement of propolis food preservation and functional ingredient characteristics by natural eutectic solvents extraction of phytochemicals. Food Biosci. 2024;57: 103467. https://doi.org/10.1016/j.fbio.2023.103467.
[40] Tran TD, Ogbourne SM, Brooks PR, Sánchez-Cruz N, Medina-Franco JL, Quinn RJ. Lessons from exploring chemical space and chemical diversity of propolis components. Int J Mol Sci. 2020;21:4988. https://doi.org/10.3390/ijms21144988.
[41] Santos LM, Fonseca MS, Sokolonski AR, Deegan KR, Araújo RP, Umsza-Guez MA, Barbosa JD, Portela RD, Machado BA. Propolis: types, composition, biological activities, and veterinary product patent prospecting. J Sci Food Agric. 2020;100:1369–82. https://doi.org/10.1002/jsfa.10024.
[42] Huang S, Zhang CP, Wang K, Li GQ, Hu FL. Recent advances in the chemical composition of propolis. Molecules. 2014;19:19610–32. https://doi.org/10.3390/molecules191219610.
[43] Tsuda T, Kumazawa S. Propolis: chemical constituents, plant origin, and possible role in the prevention and treatment of obesity and diabetes. J Agr Food Chem. 2021;69:15484–94. https://doi.org/10.1021/acs.jafc.1c06194.
[44] Bohmdorfer S. Effect-directed detection: chemical and enzyme-based assays. In: Poole CF, editor. Instrumental thin-layer chromatography. 2nd ed. Amsterdam: Elsevier; 2023. p. 297–324.
[45] Cabezudo I, Salazar MO, Ramallo IA, Furlán RLE. Effect-directed analysis in food by thin-layer chromatography assays. Food Chem. 2022;390: 132937. https://doi.org/10.1016/j.foodchem.2022.132937.
[46] Legerská B, Chmelová D, Ondrejovič M, Miertuš S. The TLC-bioautography as a tool for rapid enzyme inhibitors detection—a review. Crit Rev Anal Chem. 2022;52:275–93. https://doi.org/10.1080/10408347.2020.1797467.
[47] Capozza GP, Salazar MO, Ramallo IA, Furlan RLE. Development of a thin-layer chromatography gel-overlay α-glucosidase inhibition assay. JPC J Planar Chromat. 2023;36:483–91. https://doi.org/10.1007/s00764-023-00279-4.
[48] Solis CM, Salazar MO, Ramallo IA, García P, Furlan RLE. Cyclocondensation versus cyclocondensation plus dehydroxylation during the reaction of flavones and hydrazine. Eur J Org Chem. 2022;25: e202200455. https://doi.org/10.1002/ejoc.202200455.
[49] Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. https://doi.org/10.1038/srep42717.
[50] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3–26. https://doi.org/10.1016/s0169-409x(00)00129-0.
[51] Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem. 1999;1:55–68. https://doi.org/10.1021/cc9800071.
[52] Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45:2615–23. https://doi.org/10.1021/jm020017n.
[53] Egan WJ, Merz KM Jr, Baldwin JJ. Prediction of drug absorption using multivariate statistics. J Med Chem. 2000;43:3867–77. https://doi.org/10.1021/jm000292e.
[54] Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J Med Chem. 2001;44:1841–6. https://doi.org/10.1021/jm015507e.
[55] Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010;53:2719–40. https://doi.org/10.1021/jm901137j.
[56] Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, Wyatt PG. Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem. 2008;3:435–44. https://doi.org/10.1002/cmdc.200700139.
[57] Arnaldos TL, Serrano ML, Calderón AA, Muñoz R. A rapid and continuous spectrophotometric method to measure β-glucosidase activity based on p-nitrophenyl β-O-D-glucopyranoside hydrolysis. Phytochem Anal. 1999;10:171–4. https://doi.org/10.1002/(SICI)1099-1565(199907/08)10:4%3c171::AID-PCA452%3e3.0.CO;2-4.

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