Targeted synthesis of compounds with the potential antiviral and antimicrobial activities based on natural coumarins and their synthetic analogues

AP19579011

Objective: Synthesis of compounds with the heterocyclic and other pharmacophore fragments to further study their biological activity.

Relevance

Coumarins and their synthetic analogues with various chemical structures are very promising to synthesize the heterocyclic compounds with different structures. They have a wide range of the practically important pharmacological properties. More 2500 coumarin derivatives have been identified. They are isolated from the secondary metabolites found in green plants, fungi and bacteria. In the past decade, the pharmaceutical chemistry has been developing, and thus the creation of the new highly active hybrid derivatives based on the plant metabolites is of considerable interest. As a result, some new substances with the advanced biological activity compared to the original compounds have been synthesized. Referring to the literature, coumarins and their derivatives have the antitumor, anti-inflammatory, antiviral, anti-HIV, bronchodilator, antiulcer and anti-allergic activities.

Therefore, the search for the new heterocyclic and other pharmacophore bioactive agents among the synthesized coumarin-based derivatives is a relevant direction. Thus, it represents a great prospect to develop the new effective drugs.

Expected results:

The effective technologies to isolate the pharmacological substances based on the available plant coumarins: umbelliferone, esculetin and others will be developed and proposed. During this project implementation, the reactions of the above mentioned coumarins and their synthetic analogues will be studied. The first synthesized compounds based on the studied coumarins will be tested for various types of the pharmacological activity (antimicrobial, antioxidant, cytotoxic and antiviral).

As a result of this project implementation, among the synthesized coumarin derivatives, the most bioactive compounds to develop drugs with the desired pharmacological properties will be determined. Based on the modern methods, the pharmacological activity of the obtained compounds will be evaluated with further protection of the intellectual property.

The obtained project results will be published in two articles and (or) reviews in the peer-reviewed foreign journals in the scientific project direction, indexed in Science Citation Index Expanded and included in 1 (first), 2 (second) or 3 (third) quartile by impact factor in the Web of Science database. And also 1 (one) article or review will be published in the peer-reviewed foreign or domestic publishing house recommended by the Committee for Quality Assurance in Science and Higher Education.

Research group:
  1. Kishkentayeva Anarkul Serikovna - PhD, NJSC «KMU», associate professor-researcher at the School of pharmacy, project supervisor. Hirsch index: 3. Scopus ID: 55799125700, ORCID: 0000-0002-9169-3492.
    List of publications:
    1. Adekenov S.M., Kishkentayeva A.S., Khasenova A.B., Gatilov Y.V., Bagryanskaya I.Y. New arylhalo-derivatives of grosshemin //Chemistry of Natural Compounds.- 2021.-57(4).-P. 685–690 (Impact factor 0.708, percentile by CiteScore 1.3, Q3), https://doi.org/10.1007/s10600-021-03450-7.
    2. Adekenov S.M., Kishkentayeva A.S., ShaimerdenovaZh.R., Atazhanova G.A. Bimolecular compounds based on natural metabolites //Chemistryofnaturalcompounds.- 2018.-№3-Р.394-399 (Impact factor 0.708, percentile by CiteScore 1.3, Q3),https://doi.org/10.1007/s10600-018-2380-5
    3. Schepetkin I.A., Kirpotina L.N., Mitchell P.T., Kishkentaeva А.S., Shaimerdenova Zh.R., Atazhanova G.A., Adekenov S.M., Quinn M.T. The natural sesquiterpene lactones arglabin, grosheimin, agracin, parthenolide, and estafiatin inhibit T cell receptor (TCR) activation// Phytochemistry. - 2018.-V. 146.-P. 36-46 (Impact factor 4,004, percentile by CiteScore 6.2),https://doi.org/10.1016/j.phytochem.2017.11.010
    4. Khlebnikov A.I., Schepetkin I.A., Kishkentaeva A.S.,ShaimerdenovaZh.R., Atazhanova G.A., Adekenov S.M., Kirpotina L.N., Quinn M.T. Inhibition of T cell receptor activation by semi-synthetic sesquiterpene lactone derivatives and molecular modeling of their interaction with glutathione and tyrosine kinase ZAP-70 // Molecules. – 2019. – 24(2). – Р. 350-367 (Impact factor 4.927, percentile by CiteScore – 5.9, Q1), https://doi.org/10.3390/molecules24020350
    5. Kishkentayeva A.S., Adekenov S.M., Drašar P.B. Production technologies of pharmacologically active sesquiterpene lactones //Eurasian chemico-technological journal.-2018.-№4.-P.289-297 (Импакт-фактор 0.157, процентиль по CiteScore–1.3,https://doi.org/10.18321/ectj766 .
  2. Shulgau Zarina Toktamyssovna - candidate of medical sciences, National center of biotechnology LLP, Head of toxicology and pharmacology laboratory. Hirsch index: 8. Scopus ID: 25651954000, Researcher ID: L-1400-2015, ORCID 0000-0001-8148-0816.
    List of publications:
    1. Stalinskaya A.L., Shulgau Z.T., Sergazy Sh.D., Gulyaev A.E., Turdybekov D.M., Turdybekov K.M., Kulakov I.V. Synthesis, structure, and biological activity of N-p-(dimethylamino)-N′-(p-dimethylaminobenzylidene)-N,N′′-diphenylbenzohydrazonohydrazide // Russian Journal of General Chemistry. – 2022. –V. 92, No2. – P. 147–153 (Импактфактор0.868, процентиль по CiteScore 1.3, Q4),https://doi.org/10.1134/S107036322202002 5.
    2. Sergazy Sh., Gulyayev A., Amangeldiyeva A., Nurgozhina A., Nurgaziyev M., Shulgau Z., Chulenbayeva L., KhassenbekovaZh., Kushugulova A., Aljofan M. Antiradical and cytoprotective properties of Allium nutans L. Honey Against CCL4-Induced Liver Damage in Rats // Front. Pharmacol. - 2021.-V.12 (Импакт-фактор5.33, процентильпоCiteScore – 6,2Q1), https://doi.org/10.3389/fphar.2021.687763
    3. Sergazy S., Shulgau Z., Fedotovskikh G., Chulenbayeva L., Nurgozhina A., Nurgaziyev M., Krivyh E., Kamyshanskiy Ye., Kushugulova A., Gulyayev A., Aljofan M. Cardioprotective effect of grape polyphenol extract against doxorubicin inducedcardiotoxicity // Scientific Reports. - 2020. – V.10, No 1. – P. 1-12 (Импакт-фактор 4,576, процентиль по 7.1, Q1), https://doi.org/10.1038/s41598-020-71827-9
    4. Kayukova L.A., Uzakova А.B., Baitursunova G.P., Dusembaeva G.Т., Shulgau Z.Т., Gulyayev A.Ye., Sergazy Sh.D. Inhibition of α-amylase and α-glucosidase by new -aminopropionamidoxime derivatives // Pharmaceutical Chemistry Journal. – 2019. - Vol. 53, No. 2. – P. 129-133 (Импакт-фактор 0.837, процентиль по CiteScore – 6.9, Q4),https://doi.org/10.1007/s11094-019-01966-5
    5. Shulgau Z., Sergazy Sh., Krivoruchko T., Kenzhebayeva N., Sagindykova B., Gulyayev A. Osteoprotective properties of RNA-containing drug osteochondrin S on the model of insufficiency of sex hormones in rats // Int. J. Morphol. – 2017. – Vol. 35 (4). – P. 1233-1238 (Импакт-фактор 0.499, процентиль по CiteScore – 0.7, Q3), https://doi.org/10.4067/s0717-95022017000401233
    6. Sergazy Sh., Shulgau Z., Zhulikeyeva A., Ramankulov Y., Palamarchuk I.V., Kulakov I.V. Cytoprotective activity of newly synthesized 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones derivatives// Molecules. – 2022. – V.27(17). - 5362 (Импакт-фактор4.927, процентиль по CiteScore – 5.9, Q1),https://doi.org/10.3390/molecules27175362
    7. Keyer V., Syzdykova L., Zauatbayeva G., Zhulikeyeva A., Ramanculov Y., Shustov A.V., Shulgau Z. Tilorone and cridanimod protect mice and show antiviral activity in rats despite absence of the interferon-inducing effect in rats//Pharmaceuticals. – 2022. – V.15, No5. – P. 617 (Импакт-фактор 5.215, процентиль по CiteScore – 4.0, Q2),https://doi.org/10.3390/ph15050617
  3. Shakarimova Kuanysh Kazbekovna - NJSC «KMU» subdean at the School of pharmacy. Master of chemistry, graduated the PhD study in specialty “Technology of pharmaceutical production”. ORCID: 0000-0003-0336-7142.
  4. Telmenbetova Ainur Bekenovna - Laboratorian at NJSC «KMU».
  5. Kairatova Zhanargul - candidate for a master’s degree at NJSC «KMU»
  6. Sabitova Aruzhan -- candidate for a master’s degree at NJSC «KMU»

Based on the coumarin-3-carboxylic acid, 5 new 1,2,3-triazole-containing derivatives were first synthesized. The structure of the synthesized compounds was determined using еру modern spectral methods (IR, 1H- and 13C-NMR).

The study of the antiradical activity: The antiradical action of the above samples for the DPPH radical was evaluated. The tested compounds showed no antiradical activity under the conditions of this test-system. The study of the haemorheological activity: The synthesized samples based on the coumarin-3-carboxylic acid were researched and studied on the haemorheological activity using the model of blood hyperviscosity in vitro. Compound 1 had the haemorheological activity in the studied test-system of blood hyperviscosity in vitro, i.e. it reduced the blood viscosity at all spindle speeds. The other tested samples did not show the haemorheological activity in the studied test-system of blood hyperviscosity in vitro. The comparison drug pentoxifylline exhibited the standard haemorheological activity in an in vitro model of blood hyperviscosity.

The study of the antimicrobial activity of the samples: The antimicrobial study established that the tested samples all exhibited the antimicrobial activity for gram-positive test strains of Staphylococcus aureus, Bacillus subtilis and gram-negative strain of Escherichia coli. Their minimum inhibitory concentrations are between 12.5 and 50 µg/ml. Among all above samples, a compound Experience No. 16 showed the simultaneously moderately expressed antibacterial activity for gram-positive test strain of Staphylococcus aureus ATCC 6538 and gram-negative test strain of Essequibia coli. Its minimum inhibitory concentration was 12.5 µg/ml for these test strains. This compound Experience No. 16 showed the moderate antifungal effect for the yeast fungus of Candida albicans (MIC=25µg/ml). Samples of Experience No. 6, Experience No. 7, Experience No. 12, Experience No. 16 showed the moderately expressed antibacterial activity for the gram-positive test strain of Staphylococcus aureus ATCC 6538. Their MICs were 12.5µg/ml and 25µg/ml. The minimum inhibitory concentration of some test compounds of Experience No. 6, Experience No. 7, Experience No. 12, Experience No.16 ranges from 12.5-50 µg/ml for test strains of Bacillus subtilis ATCC 6633 and Escherichia coli ATCC 25922. The samples of Experience No.12 and Experience No.16 showed the antibacterial activity for the gram-negative test strain of Escherichia coli higher than the other samples (MIC=12.5 µg/ml). The low antifungal action was detected in compounds of Experience No. 10, Experience No. 17 for yeast-like fungus of Candida albicans ATCC 10231 and the concentrations were 50 µg/ml.

The study of the cytotoxic activity of the samples: Experience No. 6, Experience No. 7, Experience No. 10, Experience No. 12, Experience No.16 for larvae of marine crustaceans of Artemia salina (Leach) under in vitro cultivation conditions. Conclusion: the conducted experiment established that sample of Experiment No. 7 at concentrations of 1 µg/ml, 10 µg/ml and 100 µg/ml exhibited the low cytotoxic activity. The mortality of larvae at application of Experiment No.7 was 22.2%, 33.3% and 33.3%, respectively. Sample of Experiment No.10 show cytotoxicity at concentration of 10 µg/ml and 100 µg/ml was 22.2% and 44.4%, 22.2% respectively. The substances of Experiment No.6, Experiment No.12 and Experiment No.16 showed the moderate toxicity at concentrations of 100 µg/ml. Thus, samples of Experience No. 7, Experience No. 10 show the low cytotoxicity for larvae of marine crustaceans of Artemia salina (Leach). Samples of Experience No. 6, Experience No. 12 and Experience No. 16 at a concentration of 100 µg/ml showed the moderate cytotoxicity for the larvae of the marine crustaceans of Artemia salina (Leach). The appearance of toxicity of the above samples had the dose-dependent. Thus, these samples at concentrations of 1 µg/ml and 10 µg/ml show the low toxicity than at concentration of 100 µg/ml for larvae of marine crustaceans of Artemia salina.

The developed methods of synthesis based on coumarins will be used in the N.N. Vorozhtsov Novosibirsk institute of organic chemistry of SB RAS (Novosibirsk, Russia), JSC IRPH “Phytochemistry” and other research institutes for modification of the natural compounds. N.N. Vorozhtsov Novosibirsk institute of organic chemistry of SB RAS (Novosibirsk, Russian Federation), JSC IRPH “Phytochemistry” and other research institutes for modification of the natural compounds.