Chemical study of secondary metabolites from local natural sources and valorization of their application potential basing on broadening molecular diversity with multiple functionality (MetNatVal))

Strategic priority

V. Innovative technologies, sustainable energy, digitization

Strategic direction

Fundamental research in physics, chemistry, mathematics

Code
010601
Duration
2024-2027
Institutions

Institute of Chemistry of MSU

Laboratories/Centers
  1. Laboratory of Chemistry of Natural and Biologically Active Compounds
  2. Laboratory of Organic Synthesis
Project manager

Dr. habilitate, assoc. prof. Veaceslav Kulcitki

Team:
Corr. memb., dr. habilitate UNGUR Nicon Corr. memb., dr. habilitate, prof. Fliur MACAEV
Dr. habilitate ARICU Aculina Corr. memb., dr. habilitate, prof Ion GERU
Dr. DRAGALIN Ion Dr. POGREBNOI Serghei
Dr. CIOCARLAN Alexandru Dr. STINGACI Eugenia
Dr. GRINCO Marina Dr. LUPASCU Lucian
Dr. BARBA Alic Dr. SUCMAN Natalia
Dr. LUNGU Lidia  Dr. GORINCIOI Elena
Dr. GIRBU Vladilena Dr. POGREBNOI Vsevolod 
Dr. BLAJA Svetlana Dr. ZVEAGHINTEVA Marina
Dr. SECARA-KUSNIR Elena COJOCARI Sergiu
BIRCA  Natalia  
Abstract

Secondary metabolites produced by living organisms provide important adaptive and survival functions in terrestrial and aquatic ecosystems. Throughout evolution, plants and animals have developed protection mechanisms against invasive species by means of secondary metabolites which are, as a rule, chemical compounds with low or medium molecular weight that exhibit relevant biological activity. Thus, the study of natural secondary metabolites offers an excellent perspective to identify new substances with interesting properties, which can be exploited in different application fields.

The main aim of the current research project proposed to be carried out in the period 2024-2027 is focused on the identification of secondary metabolites from local plant sources, available both from agriculture and spontaneous flora, and the development based on them of new substances and technological solutions with a wide impact in the most important strategic fields of scientific and economic development of the Republic of Moldova, including health protection, agriculture and plant protection, food industry, as well as in specific branches related to products with high added value such as perfumery and cosmetics. The project concept assumes a holistic approach that covers all relevant aspects for the efficient exploration of plant material from available sources, including: analytical study by modern physico-chemical methods, preparative isolation, structural modification via organic synthesis, advanced study of properties related to biological activity and evaluating the potential for commercial exploitation. The realization of the project will involve two scientific laboratories with complementary skills in the field of chemistry of natural compounds and organic synthesis and an impressive human potential, including 4 habilitate and 14 doctors in chemistry. More than 40% of the project's research team is represented by researchers under the age of 40, and two participants in the project are members of AȘM. The planned activities will include research topics for bachelor's, master's and doctoral theses, which will be carried out by students of the Faculty of Chemistry and Chemical Technology.

Results, activities

Summary of the activity and results obtained in 2024

The fractional isolation of the constituents from industrial wastes resulting from the production of sclareol and volatile oil of Clary Sage (Salvia sclarea L.) was carried out. As a result, the content of (-)-sclareol remaining in the industrial waste was identified and established. The integral extract of oregano was obtained by extraction in an ultrasonic bath with 70% EtOH, after which its fractional extraction with different solvents was carried out, obtaining an extract enriched in rosmarinic acid. The quantitative determination by the qNMR (HSQC) method of 4 organic acids was carried out simultaneously in several samples of extracts from 8 plants of the Lamiaceae family. The synthesis of drimanic and homodrimanic bromides was carried out, based on which the synthesis of a compound with a phenothiazine fragment was achieved. A series of radical carboazidation reactions were investigated under classical and photochemical conditions. The cellular mechanism of action of diterpene derivatives with ent-kauranic structure was studied. Four carboxylic acids with cyclogeranic, homodrimanic and labdanic structures were prepared. Two steps of the 4-step synthesis of 8-hydroxydrimanoic acid were performed, as well as the synthesis of 8-acetoxy-homodrimanal. The oxidation reaction of hydroxy-naphtholines under catalytic conditions was investigated. An alternative method for the synthesis of juglone by the addition reaction of molecular oxygen, using the urea-hydrogen peroxide catalytic system, was developed. Methods for the regioselective functionalization of dihydroxylated arenes and naphthoquinones under the conditions of the condensation reaction with amines were selected. In the regioselective functionalization reaction of juglone under the conditions of the condensation reaction with butylamine, diethylamine and brevicarin, 5 new derivatives of juglone with an amine structure were obtained. The optimal conditions for the selective synthesis of polycyclic derivatives of juglone were identified, 3 new polycyclic derivatives were obtained, including one with the natural alkaloid brevicarin, isolated from local plant sources. The transformation of 2-hydroxyjuglone in reductive alkylation reactions, conjugate addition of aliphatic aldehydes, including acyclic sesquiterpenoids, was studied. 8 new derivatives of 2-hydroxyjuglone were obtained. Hard-to-access di-, tri- and tetracyclic derivatives of 2-hydroxyjuglone were prepared, including 3 new compounds with a hybrid terpene-juglone skeleton. The cytotoxicity of synthesized juglone derivatives was evaluated on eight tumor cell lines. Derivatives with enhanced cytotoxicity at sub-micromolar level of IC50 values ​​were identified. New compounds with fungistatic action against grapevine diseases were identified. The fungistatic and fungicidal action of new indigenous preparations was studied, identifying original remedies against fungal diseases in cereal crops.

Publications

Articles in Web of Science and SCOPUS journals

  1. CIOCARLAN A., SHVETSOVA M., ZINICOVSCAIA I., CHALIGAVA O., GROZDOV D., ARICU A., CIOCARLAN N. Mineral composition of fifteen species of Asteraceae family growing in the Republic of Moldova using neutron activation analysis. In: Agronomy, 2024, V. 14, nr. 10, 2387-2402. (IF 3.7, Q1) https://10.3390/agronomy14102387  https://www.scimagojr.com/journalsearch.php?q=21100447811&tip=sid#google_vignette.
  2. CIOCARLAN, A., LUNGU, L. , BLAJA, S., SHOVA, S., ARICU, A. Synthesis of cycle B functionalized derivatives of (+)-larixol. In: Chemistry Journal of Moldova, 2024, vol. 19(1), pp. 86-91. https://doi.org/10.19261/cjm.2024.1056
    https://www.scimagojr.com/journalsearch.php?q=21100773812&tip=sid&clean=0. (Q4)
  3. CIOCARLAN, A., LUNGU, L., SHOVA, S., VORNICU, N., BOLOCAN, N., KULCITKI, V., ARICU, A. Synthesis of Antimicrobial Norlabdane Compounds with Rearranged Cycle B and Molecular Docking Studies. In: Molecules, 2024, 29(23), 5714. (IF 4.6, Q2) https://doi.org/10.3390/molecules29235714 https://www.scimagojr.com/journalsearch.php?q=26370&tip=sid. Domeniul articolului: Organic Chemistry.
  4. EREMIA, N. COȘELEVA, O., JEREGHI, V., SUCMAN, N., MARDARI, T., CATARAGA, I. MACAEV, F. Migration of micro-, macroelements and heavy metals in the trophic chain of bees. Chemicke Listy, 2024, 12, p.668-675.  ISSN 1213-7103 (on-line), 0009-2770 (printed), (IF 0.6, Q4)  https://doi.org/10.54779/chl20240668  https://www.scimagojr.com/journalsearch.php?q=23372&tip=sid&clean=0.          
  5. SUCMAN, N., STINGACI, E.(ICh al USM), LUPASCU, L., SMETANSCAIA, A., VALICA, V., UNCU, L., SHOVA, S., PETROU, A., GLAMOČLIJA, F., SOKOVIĆ,M., GERONIKAKI, A., MACAEV, F. New 1H-1,2,4-Triazolyl Derivatives as Antimicrobial Agents. In: Chem. Biodiversity, 2024, e202400316. (IF 2.9, Q2) https://doi.org/10.1002/cbdv.202400316 https://www.scimagojr.com/journalsearch.php?q=130069&tip=sid&clean=0
     

Articles in international journals

  1. ЕРЕМИЯ, Н.Г., КОШЕЛЕВА, О., МАКАЕВ, Ф.З. Состояние пчеловодства и физико-химические показатели некоторых сортов меда Республики Молдова. Ветеринария и кормление, 2024, № 2, с. 26-30. ISSN:1814-9588. https://doi.org/10.30917/ATT-VK-1814-9588-2024-2-6
     

Articles in national journals

  1. LUPAȘCU, G., GAVZER, S., CRISTEA, B., LUPAȘCU, L., STÎNGACI, E.,  ZVEAGHINȚEVA, Z., POGREBNOI, S., MACAEV, F. Activitatea antimicrobiană a unor derivați vinil-triazolici. In: Studia Universitatis Moldaviae, 2024, nr.1 (171), p. 3-12. ISSN 1814-3267, doi.org/10.59295/sum1(171)2024_01, https://ojs.studiamsu.md/index.php/stiinte_reale_naturii/article/view/6156
  2. 2. ȘTEFANEŢ, T., VALICA, V., STÎNGACI, E., MACAEV, F. Elaborarea și validarea metodei spectrofotometrice în ultraviolet și vizibil de dozare a dioxoindolinone. In: Revista Farmaceutică a Moldovei. 2024, 53, p. 58-64. https://ibn.idsi.md/sites/default/files/imag_file/58-64_36.pdf          


Patents

  1. 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 MD 1721 din 2024.05.31. https://www.db.agepi.md/Inventions/details/s%202022%200097/LinkTitluElib
  2. CIOCARLAN A., POPESCU V., LUPAȘCU L., DRAGALIN I., LUNGU L., BLAJA S., ARICU A. Forma oxidată a uleiului volatil de coriandru cu proprietăți antifungice și antibacteriene. Brvet de invenție MD 4904 B1 din 2024.10.31. https://www.db.agepi.md/Inventions/details/a%202023%200004/LinkTitluAcc
  3. KULCITKI, V., UNGUR, N., GRINCO, M., BUOMMINO, E., LEMBO, F. Utilizarea ent-gomeroilguanidinei și ent-13-epigomeroilguanidinei în calitate de compuși cu proprietăți antimicrobiene și efect sinergistic în terapia combinată. Brvet de invenție MD 4893 B1 din 2024.05.31. https://www.db.agepi.md/Inventions/details/a%202022%200050/LinkTitluAcc
  4. LUNGU L., CIOCARLAN A., CUCICOVA C., BLAJA S., ARICU A., VORNICU N. N-(2-Aminofenil)-8a-acetoxi-homodrimacetamidă cu proprietăţi antifungice şi antibacteriene. Brvet de invenție MD 4891 C1 din 2024.11.30. https://www.db.agepi.md/Inventions/details/a%202022%200060/LinkTitluElib
  5. LUNGU L., CIOCARLAN A., CUCICOVA C., BLAJA S., ARICU A., VORNICU N. 2-Amino-1-∆8,9-biciclohomofarnesenoil)-benzimidazol pentru utilizare în tratamentul afecțiunilor provocate de fungi și bacterii. Brvet de invenție MD 4878 C1 din 2024.07.31. https://www.db.agepi.md/Inventions/details/a%202022%200029/LinkTitluElib
  6. 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 MD 1716 din 2024.04.30. https://www.db.agepi.md/Inventions/details/s%202022%200079/LinkTitluElib
  7. MACAEV, F., KHRIPACH ,Vladimir, STÂNGACI, Eugenia, ZHABINSKII, Vladimir, SUCMAN, Natalia, HRABAVETS, Iryna, BILAN, Dmitrii, TSYBRUK, Tatsiana, COJOCARI, Sergiu. Clorură de 3-(2-((3S,10R,13S)-3-hidroxi-10,13-dimetil-2,3,4,7,8,9,10,11,12,13,14,15-dodecahidro-1H-ciclopenta[a]fenantren-17-il)-2-oxoetil)-1-vinil-1H-imidazol-3-iu cu activitate antitumorală împotriva cancerului de prostate. Brvet de invenție MD 4894 B1 din 2024.05.31. https://www.db.agepi.md/Inventions/details/a%202023%200010/LinkTitluAcc