2023 Report

2023. Stage III. Synthesis, structural analysis and biological evaluation of newly hybrid compounds with acetophenone skeleton, having in the same molecule a six member ring azaheterocycles (azine) and five member ring diazole, triazole, oxazole.

In this stage there was brought contributions to objectives O5-O12.

A.III.1. Synthesis of the necessary intermediary.

In this activity it continued the synthesis of the necessary intermediary as we described in Stage I, activity A.I.1.

A.III.2. Synthesis of newly azaheterocycles derivatives (Q13) having in the same molecule a acetophenone unit, two azine and two triazole heterocycles.

Using intermediary 8 (with 2 pyridine units), the hybrid classes of compounds type acetophenone-bispyridine-linker-bistriazole Q13 was obtained. In the Q13 hybrid classes, the acetophenone unit will assure the rigidity while the pyridine-methylene-triazole units will assure mobility.

A.III.3. Synthesis of newly azaheterocycles derivatives (Q14, Q15) having in the same molecule an acetophenone unit, two azine and two imidazole and/or oxazol heterocycles.

Synthesis was performed according to the scheme bellow. In the obtained hybrid class of compounds type acetophenone-bispyridine-linker- imidazole Q14 and – oxazole Q15, the acetophenone unit will assure the rigidity, the pyridine-methylene-imidazole (or oxazole) units will assure mobility.

A.III.4. Synthesis of supramolecular host-guest assembly based of β-cyclodextrins and azaheterocycles, as drug delivery systems.

The host-guest inclusion complexes were studied using two model compounds which prove a very good anticancer activity, the hybrid benzimidazole-spacer-quinoline I and the corresponding salt, hybrid 4-phenil-acetophenone- benzimidazole-spacer-quinoline II.

The inclusion process with β-cyclodextrine (β-CD) was studied. The formation of the inclusion complex was investigated by FT-IR, NMR and ESI-MS experiments. The studies reveal that the hybrid benzimidazole-spacer-quinoline type I realize host-guest inclusion complexes with β-CD in a molar ratio 1:1. In the hybrid I (n=1) -β-CD complex, the benzimidazole moiety is embedded in the hydrophobic cavity of β-CD through its larger rim.

A.III.5. Evaluation of the antimicrobial activity.

In case of hybrid benzimidazole salt-spacer-quinoline type II the situation is more complicated. The studies reveal that the hybrid benzimidazole salt-spacer-quinoline type II realize host-guest inclusion complexes with β-CD in a molar ratio 1:1. In the hybrid II (n=1) -β-CD complex, the 4-phenylbenzoyl unit is embedded in the lipophilic cavity of β-CD through its wide rim. Also, having in view the spectral data obtained some other structures could be taken into considerations. However, the obtained data confirm that these supramolecular host-guest assemblies could be used as drug delivery systems as well as for retard administration.

The in vitro antimicrobial activity of our newly compounds was determined by the Kirby-Bauer disk diffusion method using nutrient agar medium (Mueller Hinton agar for antibacterial tests and Sabouraud agar for antifungal tests). The antimicrobial activity was evaluated against Gram-positive and Gram-negative bacteria strains as well as on fungus. The obtained results are expressed as diameters of inhibition zones (mm). The compounds which exhibited significant antimicrobial activity were later tested using the standardized broth microdilution assay procedure to determine the minimum inhibitory concentration (MIC) of the compounds under investigation against the reference microorganisms.

The antibacterial assay reveals that some of our hybrid azaheterocycle derivatives have a very good antibacterial activity against gram positive germ Staphylococcus aureus and against gram negative germ Escherichia coli, the results for compounds type acetophenone-bispyridine-linker-bistriazole Q13 and compounds type acetophenone-bispyridine-linker- imidazole Q14 being very promising. The antifungal assay reveals that only compounds type acetophenone-bispyridine-linker-bistriazole Q13 have a significant activity against fungus Candida albicans. Analysis of the biological data reveals some interesting SAR correlations between structure and antimicrobial activity.

A.III.6. Elemental and structural analysis of the obtained structures. Final stage report.

The structure of the newly compounds was proven through elemental and structural analysis: FT-IR, NMR, UV-Vis and fluorescence, ESI-MS, X-ray.

A final stage report was accomplished and was present on the web page of the project.     

Part of the results was published in journals or presented to conferences, as follow:

  • 4 ISI papers was published ( 1 paper in Q1 journals, 3 papers in Q2 journals);
  • 6 papers were published in proceedings;
  • 11 papers were presented to Scientific Meetings.

Achievements

Results Disseminations

ISI papers published in the year 2023: 4

  1. Oniciuc, L.; Amăriucăi-Mantu, D.; Diaconu, D.; Mangalagiu, V.; Danac, R.; Antoci, V.; Mangalagiu, I.I.* Benzoquinoline Derivatives: An Attractive Approach to Newly Small Molecules with Anticancer Activity, International Journal of Molecular Sciences ( Int. J. Mol. Sci.) 2023, 24, 8124. Publisher: Molecular Diversity Preservation International, ISSN: 1422-0067; https://doi.org/10.3390/ijms24098124 FI= 5,6 (cvartila Q1)
  2. Amarandi, R.-M.; Al-Matarneh, M.-C.; Popovici, L.; Ciobanu, C.I.; Neamțu, A.; Mangalagiu, I.I.; Danac, R. Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach. Pharmaceuticals 2023, 16, 865. MDPI, ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND ISSN: eISSN: 1424-8247. https://doi.org/10.3390/ph16060865FI= 4,6 (cvartila Q2)
  3. Lungu, C.N.; Mangalagiu,V.; Mangalagiu, I.I.*; Mehedinti, M.C. Benzoquinoline Chemical Space: A Helpful Approach in Antibacterial and Anticancer Drug Design. Molecules 2023, 28, 1069. Publisher: Molecular Diversity Preservation International, CODEN: MOLEFW  ISSN: 1420-3049 https://doi.org/10.3390/molecules28031069FI= 4,6 (cvartila Q2)
  4. Mangalagiu,V.; Danac, R.; Diaconu, D.; Zbancioc, G.; Mangalagiu, I.I.* Hybrids diazine: Recent Advancements in Modern Antimicrobial Therapy, Current Medicinal Chemistry (Curr. Med. Chem.) 2023, 000, -. Bentham Science Publishers,  ISSN (Print): 0929-8673; ISSN (Online): 1875-533X . DOI:10.2174/0929867330666230418104409 FI= 4,1 (cvartila Q2)

Papers published in proceedings in the year 2023: 6

  1. Violeta Mangalagiu, Dumitrela Diaconu, Costel Moldoveanu, Gheorghiţă Zbancioc, Ramona Dănac, Dorina Amăriucăi-Mantu, Vasilichia Antoci, Mangalagiu, I.I.*Hybrid and chimeric nitrogen heterocycles with biological activity. In: New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. (Plenary conference). Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki. ISBN 978-9975-62-579-1 (PDF), page 8. Publisher: Moldova State University, Institute of Chemistry, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova DOI: https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf
  2. Roxana Ciorteanu, Monica Sardaru, Dumitrela Diaconu, Mangalagiu, I.I.; Ramona Danac.Synthesis and anticancer properties of new indolizinic derivatives. In: New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. (Poster, pag. 32). Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki. ISBN 978-9975-62-579-1 (PDF), page 32. ublisher: Moldova State University, Institute of Chemistry, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova DOI: https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf
  3. Violeta Mangalagiu, Dumitrela Diaconu, Mangalagiu, I.I.; QUINOLINE – SULFONAMIDE – COMPLEXES WITH ANTIMICROBIAL ACTIVITY. In: New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki. ISBN 978-9975-62-579-1 (PDF), page 33 Publisher: Moldova State University, Institute of Chemistry, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova DOI: https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf
  4. Dumitrela Diaconu, Violeta Mangalagiu, Dorina Amăriucăi-Mantu, Vasilichia Antoci, Ramona Dănac, Mangalagiu, I.I.1,3-DIPOLAR CYCLOADDITION REACTIONS OF BENZIMIDAZOLIUM-YLIDES TO AN ACTIVATED SYMMETRIC ALKYN. In: New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki. ISBN 978-9975-62-579-1 (PDF), page 34. DOI: https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf Publisher: Moldova State University, Institute of Chemistry, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova
  5. Mangalagiu, I.I.; Oniciuc, L.; Antoci, V.; Mangalagiu, V. Benzo[f]quinoline Derivatives: a NMR Study Concerning Structure Determination, Adriatic NMR 2023, Mali Ston, Croatia, June 1-4, 2023. Book of Abstracts / editors: Nikola Bregović, Danijel Namjesnik, Predrag Novak, Jelena Parlov Vuković. ISSN 2806-6227, page 56. Publisher: Croatian Chemical Society, Zagreb, Croatia 1-Adriatic_NMR_2023_Book_of_Abstracts.pdf
  6. Mangalagiu, V.; Amariucai-Mantu, D.; Mangalagiu, I.I. A NMR Study Concerning Conformational Equilibria of Some Pyridazinones Derivatives, Adriatic NMR 2023, Mali Ston, Croatia, June 1-4, 2023. Book of Abstracts / editors: Nikola Bregović, Danijel Namjesnik, Predrag Novak, Jelena Parlov Vuković. ISSN 2806-6227, page 55. Publisher: Croatian Chemical Society, Zagreb, Croatia 1-Adriatic_NMR_2023_Book_of_Abstracts.pdf

Papers presented to Scientific Meetings in the year 2023: 11

  1. Violeta Mangalagiu, Dumitrela Diaconu, Costel Moldoveanu, Gheorghiţă Zbancioc, Ramona Dănac, Dorina Amăriucăi-Mantu, Vasilichia Antoci, Mangalagiu, I.I.*Hybrid and chimeric nitrogen heterocycles with biological activity. New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. (Plenary conference, pag. 8). https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf https://conferinte.stiu.md/sites/default/files/evenimente/NFNPC_2023_Abstracts%20Book.pdf https://ichem.md/seminar-stiintific-noi-frontiere-in-chimia-compusilor-naturali
  2. Roxana Ciorteanu, Monica Sardaru, Dumitrela Diaconu, Mangalagiu, I.I.; Ramona Danac.Synthesis and anticancer properties of new indolizinic derivatives. New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. (Poster, pag. 32). https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf https://conferinte.stiu.md/sites/default/files/evenimente/NFNPC_2023_Abstracts%20Book.pdf https://ichem.md/seminar-stiintific-noi-frontiere-in-chimia-compusilor-naturali
  3. Violeta Mangalagiu, Dumitrela Diaconu, Mangalagiu, I.I.; QUINOLINE – SULFONAMIDE – COMPLEXES WITH ANTIMICROBIAL ACTIVITY. New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. (Poster, pag. 33). https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf https://conferinte.stiu.md/sites/default/files/evenimente/NFNPC_2023_Abstracts%20Book.pdf https://ichem.md/seminar-stiintific-noi-frontiere-in-chimia-compusilor-naturali
  4. Dumitrela Diaconu, Violeta Mangalagiu, Dorina Amăriucăi-Mantu, Vasilichia Antoci, Ramona Dănac, Mangalagiu, I.I.1,3-DIPOLAR CYCLOADDITION REACTIONS OF BENZIMIDAZOLIUM-YLIDES TO AN ACTIVATED SYMMETRIC ALKYN. New frontiers in natural product chemistry – Ed. 7, 12-13 octombrie 2023, Chișinău, Republica Moldova. (Poster, pag. 34). https://ibn.idsi.md/sites/default/files/imag_file/NFNPC_2023_Book_Abstracts_DOI_2.pdf https://conferinte.stiu.md/sites/default/files/evenimente/NFNPC_2023_Abstracts%20Book.pdf https://ichem.md/seminar-stiintific-noi-frontiere-in-chimia-compusilor-naturali
  5. Mangalagiu, I.I.; Mangalagiu, V.; Diaconu, D.; Danac,R. Antimicrobial and anticancer activity of hybrid nitrogen heterocycles, IUPAC 2023 World Forum, Haga, Netherlands, August 20-25, 2023 (O11 PARALLEL SESSION 11: Antibiotics and Antivirals; O11-0026; pag. 143). https://iupac2023.org/ ;  https://iupac2023.org/wp-content/uploads/2023/08/IUPAC-Abstractbook_11aug.pdf
  6. Danac,R.; Sardaru, M.; Ciorteanu, R.; Amarandi, R.; Ciobanu, C.I.; Diaconu, D.; Mangalagiu, I.I. New Indolizinic Tubulin Inhibitors with Anticancer Properties, IUPAC 2023 World Forum, Haga, Netherlands, August 20-25, 2023 (Poster presentation, P1-A0052, pag. 443).https://iupac2023.org/ ;  https://iupac2023.org/wp-content/uploads/2023/08/IUPAC-Abstractbook_11aug.pdf
  7. Diaconu, D.; Amariucai-Mantu, D.; Mangalagiu, V.; Antoci, V.; Mangalagiu, I.I. Sulfonamide hybrids with antimicrobial activity, IUPAC 2023 World Forum, Haga, Netherlands, August 20-25, 2023 (Poster presentation, P1-B0057, pag. 574). https://iupac2023.org/ ;  https://iupac2023.org/wp-content/uploads/2023/08/IUPAC-Abstractbook_11aug.pdf
  8. Mangalagiu, I.I.; Oniciuc, L.; Antoci, V.; Mangalagiu, V. Heptacyclic Benzo[f]quinoline Derivatives: a NMR Study Concerning Structure Determination, Adriatic NMR 2023, Mali Ston, Croatia, June 1-4, 2023 (Poster presentation, P09, pag. 54).https://adriatic-nmr-conference.hkd.hr/   ;   https://adriatic-nmr-conference.hkd.hr/Adriatic_NMR_2023_Book_of_Abstracts.pdf
  9. Mangalagiu, V.; Amariucai-Mantu, D.; Mangalagiu, I.I. A NMR Study Concerning Conformational Equilibria of Some Pyridazinones Derivatives, Adriatic NMR 2023, Mali Ston, Croatia, June 1-4, 2023 (Poster presentation, P10, pag. 55). https://adriatic-nmr-conference.hkd.hr/   ;   https://adriatic-nmr-conference.hkd.hr/Adriatic_NMR_2023_Book_of_Abstracts.pdf
  10. Mangalagiu, I.I.; Amariucai-Mantu, D.; Mangalagiu, V. Diazine with antimicrobial activity, Six and five member ring azaheterocycles of interest as antimicrobials and anticancer potential drugs, International Meet on Pharmaceutics and Drug Delivery Systems – PHARMAMEET 2023, Porto, Portugal, February 9-11, 2023. (Poster, pag.25).https://www.albedomeetings.com/cms/pdfs/PHARMAMEET2023-tentative-program.pdf https://www.albedomeetings.com/cms/pdfs/PHARMAMEET2023_abstract_book.pdf
  11. Diaconu, D.; Mangalagiu, V.; Mangalagiu, I.I. Six and five member ring azaheterocycles of interest as antimicrobials and anticancer potential drugs, International Meet on Pharmaceutics and Drug Delivery Systems – PHARMAMEET 2023, Porto, Portugal, February 9-11, 2023. (Conference, pag.18-19).https://www.albedomeetings.com/cms/pdfs/PHARMAMEET2023-tentative-program.pdf https://www.albedomeetings.com/cms/pdfs/PHARMAMEET2023_abstract_book.pdf

Project leader,

Prof.dr. Ionel Mangalagiu