New products with preventive and therapeutic potential basing on natural products of vegetal origin and modern methods of organic synthesis

Programme

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

Strategic priority

I. Health

Strategic direction

3. Pharmaceuticals and nutraceuticals

Code
ANCD/20.80009.8007.03
Duration
2020-2023
Abstract

Healthcare represents one of the global problems faced by humanity. Intensive industrialization, radical change in living habits and exponential population growth imposed to the society survival solutions which frequently are in disagreement with the sustainability philosophy, especially as regarding healthcare problems. In this context, elaboration of remedies with preventive and therapeutic potential on the basis of accessible vegetal sources represents a reasonable compromise which can contribute to human healthcare with minimal risks for adverse effects and reduced environmental impact. The fundamental scope of the current project represents valorization of vegetal sources available in the Republic of Moldova for the elaboration of novel pharmaceutical remedies and nutraceuticals.
The specific aspect of the project stems on several basic pillars. First of all, the priority will be given to agricultural plant sources. After their basic use substantial wastes are generated, which often contain secondary metabolites with complex structure and relevant biological activity. Currently, the scheme for efficient valorization of such materials are lacking. The spontaneous flora is also interesting from this point of view, but its collection or introduction into agriculture represents an impediment for tangible results within the limited project timeframe. Second, due to the fact that secondary metabolites with relevant activities are as a rule chemically unstable and their content in the host organisms is usually very low, we intend to develop an ample program of chemical modification of natural compounds that are available in preparative amounts from local natural sources with the aim of expanding structural diversity and study the properties of the obtained new compounds. Terpenic compounds will be investigated predominantly due to their wide availability from local raw materials. The study strategy will not be random, but based on a clear principle of biomimetic pharmacophoric groups. Their combination with the terpenic skeleton will contribute to a better biocompatibility of the synthesized compounds. Third, in order to demonstrate the viability of local raw material use for the elaboration and production of pharmaceutical products and nutraceuticals, several most promising vegetal objects will be selected and profoundly studied for the demonstration of their inofensivity and utility of intact natural components, isolated according to elaborated separation schemes in the form of individual fractions. Several pathologies will be targeted, which require remedies possessing antimicrobial, antifungal or antioxidative action. In particular, these are cutaneous lesions following burns and surgical interventions, as well as diabetes complications. In the nearest perspective maladies of central nervous system like Alzheimer and Parkinson will be addressed. The final products will be elaborated taking into consideration the ease of following promotion in different forms, including as nutraceuticals or personal hygiene means.
Project activities represent a profound interdisciplinary character, which imposed creation of a consortium of two partners: Institute of Chemistry and Medical University. Such collaborative projects have been poorly promoted previously within the former Academy of Sciences and under current circumstances represent an efficient tool to furnish viable solutions on the interface of adjacent disciplines.

Results, activities

 2020

As a result of performed investigations a series of 12 extracts have been obtained from 5 local vegatal sources which represent wastes of industrial production. The applied extraction methods have been chosen in order to ensure a maximum extraction yield with a minimum environmental impact. Optimization of extraction conditions allowed a selective enrichment of the extract composition towards either polyphenolic or terpenic compounds. The use of deep euthectic mixtures allowed selective extraction of extrapure natural lignin. The application potential has been demonstrated by identification in the obtained extracts of compounds with known biological activities (terpenoids, polyphenols, flavonoids), including 3 individual compounds that have been isolated in pure form.
A series of 12 new compounds with a hybrid terpenic-heterocyclic structure have been obtained by chemical synthesis, basing on individual terpenic compounds available from local industrial sources. Due to their natural origin, these compounds can possess sellective biological activities and diverse therapeutic applications perspectives. The newly obtained synthetic compounds have been forwarded to advanced assays of biological activity in order to evaluate their practical application potential.
The toxicity of 9 samples including extractive and synthetic compounds has been preliminary evaluated on using rapid in vitro methods, that allowed the selection of candidates for the use as nutraceuticals (low toxicity) or for the further investigation of cytotoxicity on tumoral cell cultures (high toxicity).

2021

Scientific seminar,
June 4,  2021
, 
in virtual format. 

 

The scientific seminar with international participation NEW FRONTIERS IN NATURAL PRODUCT CHEMISTRY is at its VIth edition and this year is dedicated to the memory of the distinguished chemist Pavel VLAD, who would have celebrated the 85th anniversary on June 6, 2021.
The seminar was attended by about 60 researchers from 8 countries (Italy, Germany, Romania, Poland, France, Switzerland, Belgium and the Republic of Moldova).
13 oral scientific reports and 16 poster presentations were presented, which were published in the Book of abstracts, edited in electronic format.

Program

Publications

Articles in international journals

  1. CIOCARLAN, A., LUPASCU, L., ARICU, A., DRAGALIN, I., POPESCU, V., GEANA, E.I., IONETE, R.E., VORNICU, N., DULIU, O.G., HRISTOZOVA, G. AND ZINICOVSCAIA, I. Chemical composition and assessment of antimicrobial activity of lavender essential oil and some by-products. In: Plants, 2021, 10(9), 1829. DOI: https://doi.org/10,3390/plants1091829 (FI: 3.935).
  2. PRUTEANU, E., GÎRBU, V., UNGUR, N., PERSOONS, L., DAELEMANS, D., RENAUD, P., KULCIȚKI, V. Preparation of antiproliferative terpene-alkaloid hybrids by free radical-mediated modification of ent-kauranic derivatives. In: Molecules, 26(15), 4549. DOI: https://doi.org/10.3390/molecules26154549 (FI: 4.411).
  3. GEANĂ, E.-I., CIUCURE, C.T., IONETE, R.E., CIOCARLAN, A., ARICU, A., FICAI, A., ANDRONESCU, E. Profiling of phenolic compounds and triterpene acids in different apple (Malus domestica Borkh.) cultivars. In: Foods, 2021, 10(2), 267-282.  DOI: https://doi.org/10.3390/foods10020267 (FI: 4.350).
  4. MORARESCU, O., GRINCO, M., KULCIŢKI, V., SHOVA, S., UNGUR, N. An Alternative Approach towards C-12 Functionalized Scalaranic Sesterterpenoids. Synthesis of 17-Oxo-20-norscalaran-12α,19-O-lactone. In: Marine Drugs, 2021, 19(11), 636. DOI: https://doi.org/10.3390/md19110636 (FI: 5.118).
  5. PRUTEANU, E., TAPPIN, N.D., GÎRBU, V., MORARESCU, O., DÉNÈS, F., KULCIŢKI, V., RENAUD, P. Forskolin Editing via Radical Iodo-and Hydroalkylation. In: Synthesis, 2021,  53(07), 1247-1261. DOI: https://doi.org/10.1055/s-0040-1706003 (FI: 3.157).
  6. BLAJA, S.P., LUNGU, L.V., KUCHKOVA, K.I., CIOCARLAN, A.G., BARBA, A.N., VORNICU, N., ARICU, A.N. Norlabdane Compounds Containing Thiosemicarbazone or 1,3-Thiazole Fragments: Synthesis and Antimicrobial Activity. In: Chemistry of Natural Compounds, 2021, 57(1), 101-110. DOI: https://doi.org/10.1007/s10600-021-03292-3 (FI: 0.809). 
  7. CIOCARLAN, A., LUNGU, L., BLAJA, S., DRAGALIN, I., ARICU, A. The use of some non-conventional methods in chemistry of bicyclohomofarnesenic methyl esters. In: Chemistry Journal of Moldova, 2020, 15(2), 69-77. DOI: https://doi.org/10.19261/cjm.2020.791.
  8. ARÎCU, A. The natural product chemistry of terpenoids - a tribute to the remarkable legacy of academician Pavel Vlad. In: Chemistry Journal of Moldova. 2021, 16, (1), 8-29 DOI: https://doi.org/10.19261/cjm.2021.856.
  9. CIOCARLAN, A. (+)-Larixol and larixyl acetate: syntheses, phytochemical studies and biological activity assessments. In: Chemistry Journal of Moldova. 2021, 16, (1), pp. 30-45. DOI: https://doi.org/10.19261/cjm.2021.836
  10. ANTOCI, V., CUCU, D., ZBANCIOC, Gh., MOLDOVEANU, C., MANGALAGIU, V., AMARIUCAI-MANTU, D., ARICU, A, MANGALAGIU I. I. Bis-(imidazole/benzimidazole)-pyridine derivatives: synthesis, structure and antimycobacterial activity. In: Future Medicinal Chemistry, Part XII, 2020, 12(3), 207-222. DOI: 10.4155/fmc-2019-0063 (FI 3.841).
  11. MORARESCU, O., GRINCO, M., KULCIŢKI, V., BARBA, A., GARBUZ, O., GUDUMAC, V., GULEA, A., UNGUR, N. A straightforward synthesis of natural oxygenated ent-kaurenoic acid derivatives. In: Synthetic communications, 2021, 51(1), pp. 123-133. DOI: 10.1080/00397911.2020.1821225 (FI 1.796).
  12. ZINICOVSCAIA, I., GUNDORINA, S., VERGEL, C., GROZDOV, D., CIOCARLAN, A., ARICU, A., DRAGALIN, I., CIOCARLAN, N. Elemental analysis of Lamiaceae medicinal and aromatic plants growing in the Republic of Moldova using neutron activation analysis. In: Phytochemistry Letters. 2020, nr.35, 119–127. DOI: 10.1016/j.phytol.2019.10.009 (FI 1.338).
  13. LUNGU, L., CIOCARLAN, A., SMIGON, C., OZER, I., SHOVA, S., GUTU, I., VORNICU, N., MANGALAGIU, I., D'AMBROSIO, M., ARICU, A. Synthesis and evaluation of biological activity of homodrimane sesquiterpenoids bearing 1,3,4-oxadiazole or 1,3,4-thiadiazole units. In: Chemistry of Heterocyclic Compounds, 2020, 56(5), 578-585. DOI: 10.1007/s10593-020-02703-7 (FI 1.492).
  14. ARICU, A., KUCHKOVA, K., SECARA-CUSHNIR, E., BARBA, A., UNGUR, N., VORNICU, N. Synthesis and antimicrobial activity of new drimane and homodrinane sesquiterpenoids with oxadiazole and thiadiazole fragments. In: Chemistry of Natural Compounds, 2020, 56(4), 656-662. DOI: 10.1007/s10600-020-03115-x (FI 1.029).


Articles in national journals

  1. ARÎCU, A. The natural product chemistry of terpenoids - a tribute to the remarkable legacy of academician Pavel Vlad. Chem.J.Mold., 2021, 16 (1), pp. 8-29.  DOI: http://dx.doi.org/10.19261/cjm.2021.856.
  2. ORGAN, A., GÎRBU, V., COJOCARU-TOMA, M., KULCIŢKI, V., COTELEA T., UNGUR, N. Therapeutic potential and preventive effects of major triterpenic secondary metabolites from Lavandula angustifolia. In: Revista Farmaceutică a Moldovei, 2021, 45(1), 79-81. IBN: https://ibn.idsi.md/ro/vizualizare_articol/138710
  3. MORARESCU, O., TRAISTARI, M., BARBA, A., DUCA, G., UNGUR, N. and KULCIȚKI, V. One-step selective synthesis of 13-epi-manoyl oxide. Chem.J.Mold., 2021, 16 (1), pp. 99-104. DOI: http://dx.doi.org/10.19261/cjm.2021.820.
  4. CIOCARLAN, A. (+)-Larixol and larixyl acetate: syntheses, phytochemical studies and biological activity assessments. Chem.J.Mold., 2021, 16 (1), pp. 30-45.  DOI: 10.19261/cjm.2021.836.
  5. DRAGALIN, I., MELNIC, V., PELEAH, E. Polichimismul intraspecific mentha spicata. In: Studia Universitatis Moldaviae. Seria Ştiinţe reale şi ale naturii. 2020, 6 (136), 60-63. DOI: https://doi.org/10.5281/zenodo.4431568.
  6. KULCIŢKI, V., GIRBU, V., PRUTEANU, E., RENAUD, PH., DAELEMANS, D., MOLLO, E., DEFRANOUX, F., UNGUR, N. Metil ent-17-amino-kauran-19-oat cu activitate citotoxică selectivă. In: BOPI, 10/2020, p. 47-48. AGEPI: http://agepi.gov.md/ro/bopi/10-2020
  7. CIOCARLAN, A.; LUNGU, L.; BLAJA, S.; DRAGALIN, I. and ARICU, A. The use of some non-conventional methods in chemistry of bicyclohomofarnesenic methyl esters. In: Chemistry Journal of Moldova, 2020, 15(2), pp.69-77. DOI: 10.19261/cjm.2020.791.
  8. PELEAH, E.; MELNIC, V.; DRAGALIN, I. Polichimismul intraspecific Mentha spicata. Studia Universitatis Moldaviae, 2020, 6(136), pp. 60-63. DOI: http://dx.doi.org/10.5281/zenodo.4431568.


Patents

  1. ARÎCU, A., CIOCÂRLAN, A., LUNGU, L., BLAJA, S., VORNICU, N. 5-(Homodrim-6,8-dien-11-il)-1,3,4-tiadiazol-2(3H)-imină cu proprietăţi antifungice. Patent MD 4765.
  2. ARÎCU, A., CIOCÂRLAN, A., LUNGU, L., BLAJA, S., VORNICU, N. (Z/E)-2-(1-((1R,2R,8aS)-2-hidroxi-2,5,5,8a-tetrametildecahidronaftalen-1-il)propan-2-iliden)hidrazincarbotioamidă pentru utilizare în calitate de remediu antifungic. Patent MD 4780.
  3. KULCIŢKI, V., GIRBU, V., PRUTEANU, E., RENAUD, PH., DAELEMANS, D., MOLLO, E., DEFRANOUX, F., UNGUR, N. Metil ent-17-amino-kauran-19-oat cu activitate citotoxică selectivă. Patent MD 4718 B1. In: BOPI, 10/2020, p. 47-48. http://agepi.gov.md/ro/bopi/10-2020.
  4. KULCIŢKI, V.; GÎRBU, V.; PRUTEANU, E.; RENAUD, P.; DAELEMAS, D.; MOLLO, E.; DEFRANOUX, F.; UNGUR, N. Metil ent-17-amino-kauran-19-oat cu activitate citotoxică selectivă. Patent MD 4718 (13) B1, BOPI, 2020, (10), pp. 47-48.
  5. KULCIŢKI, V.; GÎRBU, V.; PRUTEANU, E.; RENAUD, P.; DAELEMAS, D.; MOLLO, E.; DEFRANOUX, F.; UNGUR, N. Metil ent-17-amino-kauran-19-oat cu activitate citotoxică selectivă. Patent MD 4718 (13) B1, BOPI, 2020, (10), pp. 47-48.