Hybrid materials functionalized with carboxyl groups based on plant metabolites with activity against human and agricultural pathogens

Programme

Research project within the State Program financed by the National Agency for Research and Development of the Republic of Moldova

Strategic priority

V. Economic competitiveness and innovative technologies

Strategic direction

3. Materials, innovative technologies and products

Code
ANCD/20.80009.5007.17
Duration
2020-2023
Institutions
  1. Institute of Chemistry, Centre of Applied Organic Chemistry, Laboratory of Organic Synthesis
  2. State Agrarian University of Moldova,  Catedra de Zootehnie
  3. State University of Medicine and și Farmacy ”Nicolae Testemitanu”, Laboratory Technology of Industrial drugs, Department of Drug Technology
Project manager

Corresponding member, dr. habilitate, prof. Fliur MACAEV

Team:
The team of the Institute of Chemistry  
Dr. POGREBNOI Serghei Dr. BILAN Dmitri
Dr. STINGACI Eugenia Dr. ZVEAGHINTEVA Marina
Dr. LUPASCU Lucian CIOBANU Natalia
Dr. SUCMAN Natalia TERTEAC Dumitru
Dr. GORINCIOI Elena ARMASU Svetlana
Dr. POGREBNOI Vsevolod  COJOCARI Sergiu
Abstract

Nowadays, chemistry and technology of plant metabolites with molecular mas lower than one kilodalton occupies one of the main places in the contemporary chemistry. The main objective of the project is development of alternative high efficient methods for the construction of the organic cyclic molecules and materials with nitrogen and oxygen heteroatoms based on plant metabolites for the obtaining of the hybrid materials functionalized with carboxyl groups with biological activity against phytopathogenic viruses, human viruses, phytopathogenic fungi and bacteria, as well as immunostimulating properties with the use in medicine and agriculture, including beekeeping and viticulture.
The basis for the project strategy represents the concept of bioisomerism according to which the functional groups with similar physicochemical parameters can be interchangeable, the fact that can totally be attributed to the plant metabolites functionalized with carboxyl groups. Based on the proposed concept, the following activities will be performed: design and synthesis of a series of functionalized hybrid materials and molecules, analysis of the interaction between the obtained molecules and the targeted receptors with application of the molecular docking, as well as modelling and simultaneous determination of the obtained materials’ cytotoxicity and acute toxicity. As a result, a multilateral analysis of all aspects of the physiological activity of the obtained materials on the studied biological models will be performed.
The important steps are: - determination of the length of the linker between the natural fragment and the pharmacophore group; - obtaining of the symmetric and asymmetric molecules with two fragments of the natural origin (dihydroabietenic acid with bactericidal and fungicidal properties, and dihydroabietilamine for which a high level of cytotoxicity has been determined for a range of the cancer cells) connected between them with linker groups of different length and nature; - construction of quaternary ammonium salts based on dihydroabietilamine to determine the influence of the positively charge nitrogen atom on the targeted properties, including solubility; - selective transformation of the diterpenoid glycosides Stevioside and Rebaudioside А, known for their antibacterial, anti-hyperglycaemic, anti-inflammatory and immunomodulatory properties, into the derivatives functoionalized with carboxyl groups with maintaining of the native carcases - 19-О-glycosidic and carbon structures (ent-cauranoide) or the Wagner-Meerwein rearrangement product from the ent-caurenic into the ent-beiranic carcase of the isosteviol diterpenoid and its derivatives; - construction of the molecular hybrids bound by hydrogen bonds with biologically active acids, such as citric acid and pectin with low esterification grade, which will allow us access new opportunities by matching suitable cations and anions and as a result modification of the polarity or solvation capacity of the formed system; - application of the alternative conditions of one-pot building of the poly functionalized oxindole derivatives based on proline and hydroxyproline, isatin and their hybrid derivatives with dihydroabietinic acid; - based on the research performed new model-formulations will be selected and developed with the most efficient properties, necessary for the development of the optimal formula, production technology and quality control of certain industrial pharmaceutical forms created.

Results, activities

Based on easily accessible from local sources plant raw material, the design of organic molecules with carboxyl groups grafted into the carbon skeleton was achieved, including the synthesis and determination of the structure-activity relationship for a series of hybrid materials active against phytopathogenic and human viruses, phytopathogenic fungi and with immunostimulatory properties.

The compound obtained on the basis of Rebaudioside A, trans-4-hydroxy-L-proline and glycine affected the replication of the HIV virus in concentrations about 4-6 times lower than the antiretroviral remedy didanosine, used in anti-HIV therapy, which belongs to the group of reverse transcriptase inhibitors.

The fungicidal activity of the analyzed compounds against the Alternaria alternata, Fusarium aquaeductuum and Fusarium oxysporum fungi, which causes root rot and is one of the most frequent and severe diseases of wheat plants, was higher than the activity of the reference preparations ketoconazole and bifonazole.

The obtained results demonstrate that the proposed by us compounds are promising for combating one of the main diseases of the grapevine - anthracnose, a fungal disease that affects the leaves, fruits, inflorescences and shoots, causing great damage, the fight against it being of extreme actuality. Some effective new model formulations endowed with antifungal properties were selected to develop the optimal formulation for further testing under small-plot production conditions.

The results regarding the study of biological properties of some components from the propolis extracts, collected in the central area of ​​Moldova, have proven that they exhibit enhanced biological effects due to pinocembrin, in particular, strong inhibition of the SARS-CoV-2 virus.

The preparations developed by us show remarkable antibacterial properties against strains of phytopathogenic and non-pathogenic bacteria, that are comparable to the reference antibiotics ampicillin and chloramphenicol.

It has been established that the stimulating feeding of bees with the use of bioregulators that were obtained on the basis of plant metabolites containing carboxyl groups ensures the improvement of the growth of the hatched brood and the prolificacy of the queens in different stages of honey collection from the white acacia.

The research results were presented at international conferences in the Netherlands-Belgium, Poland, the Czech Republic, Lithuania, Turkey, Azerbaijan, Romania, Russia, and Moldova in the form of 39 scientific communications, 2 monographs, 1 chapter in the monograph, 3 textbooks, 1 chapter in the textbook, 52 articles, 22 invention patents and other intellectual property objects, 49 materials at the invention salons, 4 defended doctoral theses, 4 defended bachelor's theses, 9 defended master's theses, 8 test and implementation papers.

Publications

Monographs

  1. ЕРЕМИЯ, Н., MACAEV, F., ZNAGOVAN, A., COȘELEVA, O.  Tehnologia de întreținere și exploatare a familiilor de albine. Recomandări. Studiul monografic. Chișinău. „Print-Caro”, 2023. 104 p. ISBN 978-9975-175-14-2.
  2. КРАСОЧКО, П., ЕРЕМИЯ, Н. Продукты пчеловодства: свойства, получение, применение. Монография. 2-ое изд. перераб. и доп.  Кишинэу-Витебск. „Print-Caro”, 2022. 723 с. ISBN 978-9975-164-76-4.


Chapter in nternational monograph

  1. SUCMAN, N., MACAEV, F. Photosensitive Nanopesticides for Environmentally Friendly and Sustainable Agriculture. In: Environmental and Technological Aspects of Redox Processes. (Eds) Gh. Duca, A. Vaseashta. IGI Global, May 2023, p.410. DOI:10.4018/979-8-3693-0512-6. ISBN: 9798369305126. EISBN: 9798369305140


Articles in international journals

  1. STINGACI, E.; ZVEAGHINTEVA, M.; POGREBNOI, S.; LUPASCU, L.; VALICA, V.; UNCU, L.; SMETANSCAIA, A.; DRUMEA, M.; PETROU, A.; CIRIC, A.; GLAMOCLIJA, J.; SOKOVIC, M.; KRAVTSOV, V.; GERONIKAKI, A.; MACAEV, F. New vinyl-1,2,4-triazole derivatives as antimicrobial agents: Synthesis, biological evaluation and molecular docking studies. Bioorganic & Medicinal Chemistry Letters. 2020, 30 (17), 127368. ISSN: 0960-894X. (IF: 2.572). DOI: https://doi.org/10.1016/j.bmcl.2020.127368
  2. ZVEAGHINTSEVA, M., STINGACI, E., POGREBNOI, S., SMETANSCAIA, A., VALICA, V., UNCU, L., KRAVTSOV, V., MELNIC, E., PETROU, A., GLAMOČLIJA, J., SOKOVIĆ, M., CARAZO, A., MLADĚNKA, P., POROIKOV, V., GERONIKAKI, A., MACAEV, F.Z. Chromenols derivatives as novel antifungal agents. Synthesis, In Silico and In Vitro Evaluation biological evaluation and molecular docking. În: Molecules, 2021, 26(14), 4304. (IF: 4.411). ISSN 1420-3049 (Online) DOI: 10.3390/molecules26144304 
  3. BILAN, D.Y., SUCMAN, N.S., RADUL, O.M., DRAGALIN, I.P., BARBA, A.N., MACAEV, F.  Synthesis of (–)-convolutamydine a derivatives and analogs, În: Chem. Natur. Comps.  2021, vol. 57, pp. 516-520. (IF: 0.653). DOI: https://doi.org/10.1007/s10600-021-03400-3
  4. CURLAT, S.N., MACAEV, F. Synthesis of 1,2,3-Triazole-Substituted 3,7,7-Trimethylbicyclo[4.1.0]Heptanols Based on (+)-3-Carene. În: Chem. Natur. Comps.  2021, vol. 57, pp. 733-740. (IF: 0.653). https://doi.org/10.1007/s10600-021-03461-4
  5. POGREBNOI, S., RADUL, O., STINGACI, E., LUPASCU, L., VALICA, V., UNCU, L., SMETANSCAIA, A., PETROU, A., CIRIC, A., GLAMOCLIJA, J., SOKOVIC, M., GERONIKAKI, A. MACAEV, F. Z.Triazolium salts as antifungal agents. Synthesis, biological and in silico evaluation. În: Anthibiotics 2022, 11(5), 588. (IF: 4.639). ISSN 2079-6382. https://doi.org/10.3390/antibiotics11050588
  6. CIOCARLAN, A., DRAGALIN, I., ARICU, A., LUPASCU, L., CIOCARLAN, N., VERGEL, K., DULIU, O.G., HRISTOZOVA, G., ZINICOVSCAIA, I. Chemical Profile, Elemental Composition, and Antimicrobial Activity of Plants of the Teucrium (Lamiaceae) Genus Growing in Moldova. În: Agronomy. 2022, 12, 772. (IF: 3.417). ISSN 2073-4395  https://doi.org/10.3390/agronomy12040772
  7. POGREBNOI,  V. S., POGREBNOI,  S. I., STINGACI,  E. P., SUCMAN, N. S., MACAEV F. Z. Amides of Dehydroabietic Acid Based on 5-Aminooxoindoles and Their Transformation Products. In:Chem. Nat. Compds, 2022, 58, 874–881. (IF 0.830) https://doi.org/10.1007/s10600-022-03820-9
  8. EREMIA, N., COȘELEVA, O., SUCMAN, N., BALAN, G., LUPAȘCU, L., MARDARI, T., MODVALA, S., MACAEV, F. Relationship between physicochemical parameters and antimicrobial activity of Moldavian honey. În: Gorteria, 2023, 9(4) (IF-0,333) https://doi.org/10.59879/zT0YO.
  9. КОЖОКАРЬ, С.В., КУРЛАТ, С.Н., МАКАЕВ. Ф.З. Синтез 1R-цис-дибромвинил-2,2-диметилциклопропанов изоксазольного и пиразольного ряда на основе (+)-3-карена. În: Химия природ. cоед., 2024, №1, 114-116. (IF 1.02).
  10. ZVEAGHINTSEVA, M., STINGACI, E., POGREBNOI, S., LUPASCU, L., BARBA, A., DUCA, G., VALICA, V., UNCU, L., KRAVTSOV, V., TERTEAC, D., BRINZAN, A., MACAEV, F. Resin acids as raw material for the preparation of cyclodextrin complexes loaded with dehydroabietitoic acid and chromenol hybrid. Chemistry Journal of Moldova. General, Industrial and Ecological Chemistry ISSN (p) 1857-1727 ISSN (e) 2345-1688. 2022. http://dx.doi.org/10.19261/cjm.2022.942
  11. POGREBNOI, S., EREMIA, N., BILAN, D., LUPASCU, L., BOLOCAN, N., DUCA, Gh., ARMASU, S., TERTEAC, D., CEBANU, V., TINCU, S., ZNAGOVAN, A., NEICOVCENA, I., COSELEVA, O., SLANINA, V., MACAEV F. Characterization of propolis from Moldova's central region: chemical composition, antioxidant and antimicrobial properties. In: Chemistry Journal of Moldova. General, Industrial and EcologicalChemistry. 2023, 18(1), ISSN (p) 1857-1727 ISSN (e) 2345-1688 http://doi.org/10.19261/cjm.2023.924
  12. LUPASCU, G., STINGACI, E., GAVZER, S., LUPASCU, L., CRISTEA, N., ZVEAGHINTSEVA, M., MACAEV, F. Protective activity of vinyl-triazolic derivatives against some causative agents of wheat root rot. În: Rom. J. Biol. Plant Biol. Bucharest, 2021, 66 (1–2) p. 65-76. ISSN: 1843-3782 https://www.ibiol.ro/plant/Volume%2066/Articolul%207.pdf
  13. ЧОБАНУ, Н.Г., МАКАЕВ, Ф.З. Эвтектические растворы на основе 3-(карбоксиметил)-1-винил-1H-имидазол-3-иум хлорида и тиомочевины для получения Монастрола. În: Вестник Башкирского Университета. 2021, vol. 26 (2), стр. 384-387. ISBN: 1998-4812 DOI: 10.33184/bulletin-bsu-2021.2.19
  14. ЗВЯГИНЦЕВА, М.М. Новый синтез (Z)-3-(1-амино-2-оксо-2-фенилэтилиден)индолин-2-она. În: Вестник Башкирского Университета. 2021, vol. 26 (2), стр. 398-402. ISBN: 1998-4812 DOI: 10.33184/bulletin-bsu-2021.2.22


Articles in national journals

  1. PODGORNII, A.; VALICA, V.; POGREBNOI, S.; LUPASCU, L.; UNCU, A.; MACAEV, F. Antimycotic activity of phenoxythiazolchloralum. Moldovan Medical Journal. 2020, 63(4), 61-64. ISSN 2537-6381 (Online) DOI: 10.5281/zenodo.4016818
  2. EREMIA, N., CATARAGA, I., COȘELEVA, O., POGREBNOI, S., MACAEV, F. Hrănirea stimulatoare a albinelor cu chitosan natural polidispers. În: Academos. 2021, vol. 4(63), pp. 82-86. ISSN 1857-0461.  E-ISSN 2587-3687. DOI: https:// DOI: https://doi.org/10.52673/18570461.21.4-63.10
  3. ARMAȘU S.,TERTEAC D., CEBANU V., DEGTEARI V., MIDARI A., SUCMAN N., POGREBNOI V., MACAEV F. Evaluarea acțiunii antifungice a unor noi derivați 1,2,4-1H-triazolici contra antracnozei viței-de-vie în condiții in vitro. Akademos 2023, 2, 75-80, DOI: https://doi.org/10.52673/18570461.23.2-69.08
  4. ЕРЕМИЯ, Н., CAISÎN, L., CATARAGA, I., COȘELEVA, О. Utilizarea imunomodulatorului şi aditivului nutrițional în hrana stimulatoare a albinelor în perioada de primăvară. Știința agricolă. Chișinău, 2021,  nr. 1, p. 112-116. ISSN 1857-0003.
  5. DRUMEA, M., STINGACI, E., UNCU, L., CRUDU, V., VALICA, V., MACAEV, F. Evaluarea activității antifungice și antibacteriene a unui nou derivat nesaturat de 1,2,4-triazol (nitrotriazon). În: Moldovan Medical Journal. 2021, vol. 1(69), pp. 93-98. ISSN 2537-6381 (Online) DOI: https://doi.org/10.52692/1857-0011.2021.1-69.19
  6. DRUMEA, M., VALICA, V., UNCU, L., MACAEV, F. Nitrotriazon – a new unsaturated derivative of 1,2,4-triazole with antifungal action. Structure-activity relationship. În: Revista Farmaceutică a Moldovei. 2021, 45 (1), pp. 8-11. ISSN 1812-5077. https://ibn.idsi.md/ro/vizualizare_articol/138684
  7. SUCMAN, N., UNCU, L., CRUDU, V., CIOBANU, N., CODREANU, A., VALICA, V., MACAEV, F. Study of antituberculosis activity of the cyclodextrins particles loaded with juglone. În: Revista Farmaceutică a Moldovei. 2021, 45 (1), pp. 12-15. ISSN 1812-5077. https://ibn.idsi.md/ro/vizualizare_articol/138685
  8. TINCU, S., MACAEV, F., DEZMIREAN, D. S., EREMIA, N., ZNAGOVAN, A., BOTNARU, A. Influence of external factors on the composition and therapeutic efficiency of propolis. În: Revista Farmaceutică a Moldovei. 2021, 45 (1), pp. 27-29. ISSN 1812-5077. https://ibn.idsi.md/ro/vizualizare_articol/138694
  9. EREMIA, N., MACAEV, F. Studiul indicilor fizico-chimici a propolisului. Conferința științifico-practică “Perspective în cercetarea produselor farmaceutice de origine sintetică și natural”. In: Revista Farmaceutică a Moldovei. 2021, vol. 45, nr. 2, pp. 39. ISSN 1812-5077.https://drive.google.com/file/d/1_xK1g7piGYsiyALh3FEdK9sgkd5H2g66/view?usp=sharing
  10. Terteac D., Armaşu S., Degteari V., Midari A., Cebanu V., Stîngaci E., Pogrebnoi S., Sucman N., Macaev F. Cercetarea unor noi produse biologice contra principalelor boli micotice ale viţei de vie: mana, făinarea şi putregaiul cenuşiu.Pomicultura, Viticultura şi Vinifciaţia 2022, 2, 31-39, ISSN 1857-3142. https://doi.org/10.53082/1857-3142.22.88.05


Patents

  1. MACAEV F., ZVEAGHINTEVA M., STANGACI E., POGREABNOI S., LUPASCU L. Utilizare a (Z)-4,4-dimetil-1-(4-nitrofenil)-2-(1H-1,2,4-triazol-1-il)pent-1-en-3-onei în  calitate de remediu contra bacteriilor fitopatogene. Institutul de Chimie. Сerere de brevet: a2020 0056 din 13.06.2020
  2. MACAEV, F.; BILAN, D.; RADUL,  O.;  BOLDESCU, V. Procedeu de sinteză diastereo- și enantioselectivă a (S)-3-hidroxi-3-[(R)-2-oxociclohexil]indolin-2-onei. Institutul de Chimie. Brevet de invenție MD4689 B1 acordat din 30.04.2020.
  3. MACAEV, F.; STINGACI, E., POGREBNOI, S., BOLDESCU, V. (Z)-5-metil-1-(4-nitrofenil)-2-(1H-1,2,4-triazol-1-il)hex-1-en-3-onă, procedeu de sinteză şi utilizarea ei în calitate de remediu antifungic. Brevet de invenţie MD4703 B1  acordat din 31.07.2020.
  4. MACAEV, F.; ZVEAGHINȚEVA, M.; STÂNGACI,  E.;  POGREBNOI, S.; BOLDESCU, V. Compusul 2-tert-butil-3-(1H-1,2,4-triazol-1-il)-2H-cromen-2-olului și procedeu de obținere a acestuia. Institutul de Chimie. Brevet de invenţie MD 4665 С1 eliberat din 31.07.2020
  5. MACAEV, F., STÂNGACI, E., POGREBNOI, S., BOLDESCU, V. (Z) -5-metil-1- (4-nitrofenil)-2-(1H-1,2,4-triazol-1-il)hex-1-en-3-onă, procedeuşi sinteză ei în calitate de remediu antifungic. Brevet de invenție MD № 4703C1, eliberat din 2020.07.31.
  6. MACAEV, F., ZVEAGHINȚEVA, M., STÂNGACI, E., POGREBNOI, S., LUPAŞCU, L. Utilizare a (Z)-4,4-dimetil-1-(4-nitrofenil)-2-(1H-1,2,4-triazol-1-il)pent-1-en-3-onei în  calitate de ingredient activ contra bacteriilor fitopatogene. Brevet de invenție MD № 4740B1 acordat din 2021.02.28. BOPI nr.2/2021
  7. MACAEV, F., BILAN, D., RADUL, O., BOLDESCU, V. Procedeu de sinteza diastereo- și enantioselectivă a (S)-3-hidroxi-3-((R)-2-oxociclohexil) indolin-2-onei. Brevet de invenție MD № 4689C1, acordat din 2021.02.28. BOPI nr.2/2021
  8. MACAEV, F., STÂNGACI, E., POGREBNOI, S., BOLDESCU, V. Metodă pentru sinteza 3,3-dialilindolin-2-onei. Brevet de invenție MD №4739B1, acordat din 2021.01.31.
  9. EREMIA, N., MACAEV, F., POGREBNOI, S., ZNAGOVAN, A., MODVALA, S., MARDARI T.,  EREMIA, I., SARÎ, A. Procedeu de hrănire a albinelor. Brevet de invenție de scurtă durată. MD 1598 Z acordat din 2022.09.30. BIOPI nr. 2/2022, p. 67. https://agepi.gov.md/sites/default/files/bopi/BOPI_02_2022.pdf#page=7
  10. EREMIA N., MACAEV, F., POGREBNOI, S., ZNAGOVAN, A., NEICOVCENA, I., COŞELEVA, O., SARÎ, N., JEREGHI, V. Procedeu de hrănire a albinelor. Brevet de invenție de scurtă durată. MD 1607 Z acordat din 2022.10.31. BIOPI nr. 3/2022, p. 57. https://agepi.gov.md/sites/default/files/bopi/BOPI_03_2022.pdf#page=7
  11. EREMIA, N., MACAEV, F., KRASOCIKO, P., POGREBNOI, S., ZNAGOVAN, A., NEICOVCENA, I., COŞELEVA, O., EREMIA, I., SARÎ, A. Procedeu de hrănire a albinelor. Brevet de invenție de scurtă durată. MD 1611 Z acordat din 2022.11.30. BIOPI nr. 4/2022, p. 50. https://agepi.gov.md/sites/default/files/bopi/BOPI_04_2022.pdf#page=7
  12. EREMIA N., MACAEV, F., KRASOCIKO, P., POGREBNOI, S., ZNAGOVAN, A., NEICOVCENA, I., COŞELEVA, O., SARÎ, N., EREMIA, M. Procedeu de hrănire a albinelor. Brevet de invenție de scurtă durată. MD 1612 Z  acordat din 2022.11.30. BIOPI nr. 4/2022, p. 50. https://agepi.gov.md/sites/default/files/bopi/BOPI_04_2022.pdf#page=7
  13. LUPAȘCU, G., MACAEV, F., GAVZER, S., CRISTEA, N., LUPAȘCU, L., STÂNGACI,  E., ZVEAGHINȚEVA, M., POGREBNOI, S. Procedeu de tratare a boabelor de grâu comun de toamnă. Brevet de invenţie de scurtă durată MD №1591 B1 acordat din 2022.01.31. BOPI nr. 1/2022
  14. LUPAȘCU, G., MACAEV, F., GAVZER, S., CRISTEA, N., LUPAȘCU, L., STÂNGACI,  E.,  ZVEAGHINȚEVA M.,  POGREBNOI S. Procedeu de tratare a boabelor de grâu comun de toamnă. Brevet de invenţie de scurtă durată MD № 1603 B1 acordat din 2022.03.31. BOPI nr. 3/2022
  15. LUPAȘCU, G., MACAEV, F., GAVZER, S., CRISTEA, N., LUPAȘCU, L., STÂNGACI,  E.,  POGREBNOI, V., POGREBNOI, S. Procedeu de tratare a boabelor de grâu comun de toamnă. Brevet de invenţie de scurtă durată MD №1604 B1 acordat din 2022.03.31. BOPI nr.3/2022
  16. MACAEV F., STÂNGACI  E., ZVEAGHINȚEVA M., POGREBNOI S., LUPAȘCU L., LUPAȘCU G., GAVZER S. Aplicare a (Z)-4,4-dimetil-1-(2,4-dichlorfenil)-2-(1H-1,2,4-triazol-1-il)pent-1-en-3-ona  în  calitate de remediu fungicid contra Alternaria alternata și Fusarium aquaeductuum. Brevet de invenție MD 1636, Hotărâre de acordare cu nr. 10079 din 2022.06.16
  17. MACAEV, F., STÂNGACI, E., POGREBNOI, V., POGREBNOI, S., LUPAȘCU, L., LUPAȘCU, G., GAVZER, S. Utilizarea (Z)-1-(2,4-dichlorofenil)-5-metil-2-(1H-1,2,4-triazol-1-yl)hex-1-en-3-one în  calitate de ingredient activ contra fungilor Alternaria alternata și Fusarium aquaeductuum. Brevet de inventie acordat MD 4823 B1 2022.09.30
  18. MACAEV, F., EREMIA, N., SUCMAN, N., POGREBNOI, S., ZNAGOVAN, A., COȘELEVA O., JEREGHI V. Procedeu de hrănire a albinelor. Brevet de invenție de scurtă durată. Chișinău, MD 1716 Y. Data depozit: 2022.10.17. In: BIOPI nr. 9/2023, p. 41. https://agepi.gov.md/sites/default/files/bopi/BOPI_09_2023.pdf#page=9
  19. ARMAŞU, S., MACAEV, F., STÂNGACI, E., TERTEAC, D., POGREBNOI, V., CEBANU, V. Aplicare a (Z)-1-(2,4-diclorfenil)-5-metil-2-(1H-1,2,4-triazol-1-il)hex-1-en-3-onei în calitate de compus activ contra ciupercii Gloeosporium ampelophagum Sacc. Brevet de invenție de scurtă durată. 2023. Hotărârea nr. 10843 din 2023.08.29 de acordarea brevetului de invenție de scurtă durată.
  20. MACAEV, F.,   LUPAȘCU, G., STÂNGACI,  E., POGREBNOI, S., SUCMAN, N., LUPAȘCU, L., GAVZER, S., CRISTEA, N. Bromură de 4-(2-(2,4-diclorfenil)-2-oxoetil)-1-((2-(2,4-diclorfenil)-4-propil-1,3-dioxolan-2-il)metil)-1H-1,2,4-triazol-4-iu cu proprietăți antifungice către Fusarium avenaceum şi Fusarium oxysporum. Cerere de brevet de invenție cu nr. de depozit: a 2023 0012 din 2023.05.19
  21. MACAEV, F.,   LUPAȘCU, G., STÂNGACI,  E., POGREBNOI, S., SUCMAN, N., LUPAȘCU, L., GAVZER, S., CRISTEA, N. Bromură de 4-(2-(bifenil-4-il)-2-oxoetil)-1-((2-(2,4-diclorfenil)-4-propil-1,3-dioxolan-2-il)metil)-1H-1,2,4-triazol-4-iu cu proprietăți antifungice către fungii Fusarium avenaceum şi Fusarium oxysporum. Cerere de brevet de invenție cu nr. de depozit: a2023 0030 din 2023.09.28.

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