2022 Report

Stage II.  Synthesis, structural analysis and biological evaluation of newly hybrid azaheterocycles derivatives having in the same molecule a 1,2-diazine (pyridazine and phthalazine) and a di- or tri- azole heterocycles..

In this stage there was brought contributions to objectives O3, O4, O8-O12.

A.II.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.II.2. Synthesis of newly hybrid azaheterocycles derivatives (type Q8 and Q9) having in the same molecule a π–deficient diazine heterocycle (pyridazine, phthalazine) and triazole (π–reach) molecule, anchored with diverse substituents, including anthracene fluorophore.

Using pyridazine and phthalazine (as π–deficient azine) and triazole (as π–reach azole), rationally substituted (including anthracene fluorophore), the hybrid classless of compounds type diazino-linker-triazole Q8 and diazino-pyrrolo-triazol Q9 was obtained. The reactions schemes are depicted bellow:

A.II.3. Synthesis of newly hybrid azaheterocycles derivatives (type Q10) having in the same molecule a π–deficient bis-pyridazine, triazole (π molecule, anchored with diverse substituents, including anthracene fluorophore.

Using bis-pyridazine and triazole, rationally substituted (including fluorophores), the hybrid classless of compounds type bis-pyridazine-linker-triazole Q10 was obtained. Initially there have been done test reactions on simple pyridazine derivatives, when the hybrid classless of compounds type pyridazine-linker-triazole Q10’ was obtained. Then, using a similar strategy the desired classless of compounds type bis-pyridazine-linker-triazole Q10 was obtained. The reactions schemes are depicted bellow:

A.II.4. Synthesis of newly hybrid azaheterocycles derivatives (type Q11, Q12) having in the same molecule bis-pyridazine and azine (π–deficient), and a triazole (π–reach) molecule, anchored with diverse substituents.

Using π–deficient bis-pyridazine and azine, π–reach triazole, and variously linker/spacer (alkyl hydrazide, alkyl amine, alkyl-ureil), the hybrid classless of compounds type bis-pyridazine-linker-triazole linker-azino Q11, bis-pyridazine-linker-triazole-linker ureil- azine Q12, was obtained. The reactions schemes are depicted bellow:

A.II.5. Synthesis of hybrid compounds type Q8-Q12 using eco-friendly setup procedures.

Synthesis presented above on activities A.II.1-A.II.4., will be performed by green setup procedures, using MW and/or US technology.

Synthesis presented above on activities A.II.1-A.II.4., was performed by green setup procedures, using MW and/or US technology. As a result, some important clues have to be underlined:

– under MW and/or US irradiation the reaction time decrease substantially, from days or hours under conventional thermal heating (TH) to minutes under MW and/or US irradiation

– the energy consumed under MW and/or US irradiation is substantially lower comparative with conventional TH

– the amount of the used solvents under MW and/or US irradiation is substantially lower (4 to 5 folds) comparative with conventional TH; in some cases, it was possible to replace the toxic organic solvents with other non-toxic, environmentally friendly, solvents as water or ethanol

– the yields and reaction selectivity are considerably improved under MW and/or US irradiation comparative with conventional TH As a result, these new setup procedures could be considered as environmentally friendly methods.

A.II.6. Evaluation of the antimicrobial activity.

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 azaheterocycle compounds have a very good antibacterial activity against gram positive germ Staphylococcus aureus and against gram negative germ Escherichia coli.

The antifungal assay reveals that the majority of our azaheterocycle compounds have no activity against fungus Candida albicans, only few of azaheterocycles having a moderate activity. Analysis of the biological data reveals some interesting SAR correlations between structure and antimicrobial activity.

A.II.7. Elemental and structural analysis of the obtained structures. Final stage report.

The structure of the newly compounds was proven through elemental and structural analysis: IR, NMR, UV-Vis and fluorescence, 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:

– 6 ISI papers were published (2 paper in Q1 journals, 3 papers in Q2 journals and 1 in Q4);

– 10 papers were published in proceedings;

– 15 papers were presented to Scientific Meetings (2 invited conferences, 10 oral presentation, 3 posters).

Achievements

  • Results Disseminations

    • ISI papers published in the year 2022: 6

  1. Amariucai-Mantu, D.; Mangalagiu, V.; Bejan, I.; Aricu, A.; Mangalagiu, I.I.* Hybrid Azine Derivatives: A useful Approach for Antimicrobial Therapy. Pharmaceutics 2022, 14, 2026. MDPI, ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND. ISSN:1999-4923 Pharmacology & Pharmacy (JCR)-Q1, 39/279 / Pharmacology & Pharmacy (JCI)-Q1, 30/361 https://doi.org/10.3390/pharmaceutics14102026 6.52/5 FI= 6.25
  2. Diaconu, D.; Antoci, V.; Mangalagiu, V.; Amariucai-Mantu, D.; Mangalagiu, I.I.* Quinoline – imidazole/benzimidazole derivatives as dual- / multi- targeting hybrids inhibitors with anticancer and antimicrobial activity. Scientifc Reports 2022, 12, 16988 (pp 1-15). Publisher: Nature Publishing Group, ISSN: 2045-2322 Multidisciplinary Science (JCR)-Q2, 19/73; / Multidisciplinary Sciences (JCI)-Q1, 19/134; https://doi.org/10.1038/s41598-022-21435-6 FI= 4.99
  3. Zbancioc, G.; Mangalagiu, I.I.; Moldoveanu, C. A Review on the Synthesis of Fluorescent Five- and Six- Mem-bered Ring Azaheterocycles. Molecules 2022, 27, 6321. Publisher: Molecular Diversity Preservation International, CODEN: MOLEFW ISSN: 1420-3049 Chemistry, Multidisciplinary (JCR)-Q2, 65/179; / Chemistry, Multidisciplinary (JCI)-Q2, 82/224; https://doi.org/10.3390/molecules27196321 FI= 4.92
  4. Zbancioc, G.; Ciobanu, C.I.; Mangalagiu, I.I.; Moldoveanu, C. Ultrasound-Assisted Synthesis of Fluorescent Azatetracyclic\Derivatives: An Energy-Efficient Approach. Molecules 2022, 27, 3180 (pp 1-10). Publisher: Molecular Diversity Preservation International, CODEN: MOLEFW ISSN: 1420-3049. Chemistry, Multidisciplinary (JCR)-Q2, 65/179; / Chemistry, Multidisciplinary (JCI)-Q2, 82/224; https://doi.org/10.3390/molecules27103180 FI= 4.492
  5. Diaconu, D.; Amariuci-Mantu, D.; Antoci, V.; Ciorteanu, R.; Mangalagiu, V.; Mangalagiu, I.I.* DESIGN AND SYNTHESIS OF NEW HYBRID PYRIDINE-IMIDAZOLIUM/BENZIMIDAZOLIUM SALTS WITH ANTIBACTERIAL ACTIVITY, Revue Roumaine de Chimie 2022, 67(1-2), 85–88. Publisher: Editura Academiei Romane, CODEN: RRCHAX ISSN: 0035-3930. Chemistry, Multidisciplinary (JCR)-Q4, 175/179; / Chemistry, Multidisciplinary (JCI)-Q4, 210/224; https://doi.org10.33224/rrch.2022.67.1-2.07 FI= 0.41
  6. Amariucai-Mantu, D.; Antoci, V.; Sardaru, M. C.; Al Matarneh, C. M.; Mangalagiu, I.I.; Danac, R. Fused pyrrolo-pyridines and pyrrolo-(iso)quinoline as anticancer agents. Physical Sciences Reviews 2022, 000, 00 (pp1-64). Publisher WALTER DE GRUYTER GMBHGENTHINER STRASSE 13, D-10785 BERLIN, GERMANY. ISSN 2365-6581; eISSN 2365-659X. (JCI)-0 / Multidisciplinary Sciences (JCI)-Q2, 64/134; https://doi.org/10.1515/psr-2021-0030 AIS= 0.34

    • Papers published in proceedings in the year2022: 10

  1. C.M. Al Matarneh, R.M. Amarandi, I. Mangalagiu, R. Danac, New Fused (Iso)quinoline Heterocycles as Potential Anticancer Agents, Ahi Evran 2nd International Conference on Scientific Research, Ahi Evran University, October 21-23, 2022 (oral online presentation). Proceedings Book, ISBN 978-625-8246-37-7, page 807 https://www.ahievranconference.org/_files/ugd/614b1f_4f7efa6812344bdd878fd263a914fb77.pdf
  2. R. Ciorteanu, C.I. Ciobanu, I.I. Mangalagiu, R. Danac, Synthesis of New Indolizinic Derivatives as Potential Antitumor Agents, 7th International New York Conference on Evolving Trends in Interdisciplinary Research&Practices, Manhattan, New York City, October 1-3, 2022 (oral online presentation) Proceedings Book, ISBN 978-1-955094-30-6, page 795 https://www.nyconference.org/_files/ugd/614b1f_de2d82c118c944599affa919b58734e1.pdf
  3. C.M. Al Matarneh, R.M. Amarandi, I. Mangalagiu, R. Danac, New Pyrrolo-Fused Heterocycles with Anticancer Properties, SIVAS International Conference on Scientific and Innovation Research, Sivas,Turkey, October 13-15, 2022. Proceedings Book, ISBN 978-625-8246-21-6, page 97 https://www.iksadkongre.com/_files/ugd/614b1f_13da539fb218458981371bfc52ad6752.pdf
  4. R. Ciorteanu, R. Danac, V. Antoci, C. Ciobanu, I.I. Mangalagiu, Synthesis of 6, 7 and 8-substituted indolizines as potential anticancer agents, EGE International Congress on Natural & Medical Sciences, Izmir, Turkey, September 02-04, 2022 (oral online presentation). Proceedings Book, ISBN 978-625-8213-61-4, pages 253-254 https://www.egekongreleri.org/_files/ugd/614b1f_9dc2707aaf35477d8cc2b5d8062f6839.pdf
  5. Antoci,V.; Amăriucăi-Mantu, D.; Diaconu, D.; Dănac, R.; Mangalagiu, V.; Mangalagiu, I.I. Novel benzo[f]quinoline compounds with vinyl chain: synthesis, characterization and anticancer evaluation, INTERNATIONAL SCIENTIFIC RESEARCH CONGRESS-XII, August 13-14, 2022. Delhi, India (on-line, Oral presentation, nr. 656, pag. 656-657). Proceedings Book, ISBN 978-625-8323-42-9. https://www.umteb.org/_files/ugd/614b1f_e40cb651273c47a0a36a664b1a1ff35a.pdf
  6. Ciorteanu, R.; Danac, R.; Ciobanu, C.; Mangalagiu, I.I.; Amăriucăi-Mantu, D. Synthesis of new indolisinic derivativesas potential anticancer agents, INTERNATIONAL SCIENTIFIC RESEARCH CONGRESS-XII, August 13-14, 2022. Delhi, India (on-line, Oral presentation, nr. 665, pag. 665-666). Proceedings Book, ISBN 978-625-8323-42-9. https://www.umteb.org/_files/ugd/614b1f_e40cb651273c47a0a36a664b1a1ff35a.pdf
  7. Mangalagiu, I.I.; Mangalagiu, V.; Amariucai-Mantu, D.; Antoci, V.: Diaconu, D. New Azaheterocycles Derivatives: Design, Synthesis and Applications, MEDCHEMMEET2022- INTERNATIONAL MEET ON MEDICINAL CHEMISTRY, DRUG DISCOVERY & DRUG DELIVERY, June 23-25, 2022. COPENHAGEN, DENMARK. (Invited (plenary) lecture, I-3, pag. 2). MEDCHEMMEET2022, Abstract Book, pag.8 https://www.albedomeetings.com/cms/pdfs/MEDCHEMMEET2022_abstract_book.pdf
  8. Mangalagiu, V.; Diaconu, D.; Amariucai-Mantu, D.; Antoci, V.; Mangalagiu, I.I. Hybrid Five and Six Membered Ring Nitrogen Heterocycles with Antimicrobial and Anticancer Activity, MEDCHEMMEET2022- INTERNATIONAL MEET ON MEDICINAL CHEMISTRY, DRUG DISCOVERY & DRUG DELIVERY, June 23-25, 2022. COPENHAGEN, DENMARK. (Poster presentation, P4- pag. 3). MEDCHEMMEET2022, Abstract Book, pag.19 https://www.albedomeetings.com/cms/pdfs/MEDCHEMMEET2022_abstract_book.pdf
  9. Mangalagiu, V.; Amariucai-Mantu, D.; Antoci, V.; Diaconu, D.; Danac, R.; Moldoveanu, C.; Zbancioc, Ghe.; Mangalagiu, I.I. Ecologically friendly methods used in heterocyclic chemistry, 7th International Conference Ecological and Environmental Chemistry 2022, March 3-4, 2022, Chisinau, Republic of Moldova. (Plenary lecture, PL, pag. 11).
    EEC-2022 Abstract Book Ecological and environmental chemistry, Ediția 7, Vol.1, 2022, pag 52. DOI: http://dx.doi.org/10.19261/eec.2022.v1
  10. Diaconu, D.; Mangalagiu, V.; Mangalagiu, I.I. New Materials Based on Quinoline Sulfonamide – Metals with Antimicrobial Activity. METAL 2022 – 31st International Conference on Metallurgy and Materials, May 18 – 19, 2022. Brno, Czech Republic, (Poster presentation, PE13- pag. 68). https://www.metalconference.eu/en/topics/ https://www.metalconference.eu/en/conference-programme/471-poster-session-e/

    • Papers presented to Scientific Meetings in the year2022: 10(2 invited conferences, 10 oral presentations, 3 posters)

  1. C.M. Al Matarneh, R.M. Amarandi, I. Mangalagiu, R. Danac, Synthesis and anticancer evaluation of new pyrrolo-fused cycloadducts, 7th Asia Pacific, International Modern Sciences Congress, Jakarta, Indonesia, November 4-5, 2022 (oral online presentation, pag. 17). https://en.iksadasia.org/
  2. Amariucai-Mantu, D.; Antoci, V.; Diaconu, D.; R. Danac, Ciobanu, C.; Mangalagiu, V.; Mangalagiu, I.I.Anthracene imidazolium/ benzimidazolium salts: synthesis, structure, andtimicrobial properties, 7th Asia Pacific, International Modern Sciences Congress, Jakarta, Indonesia, November 4-5, 2022 (oral online presentation, pag. 17). https://en.iksadasia.org/
  3. C.M. Al Matarneh, R.M. Amarandi, I. Mangalagiu, R. Danac, New Fused (Iso)quinoline Heterocycles as Potential Anticancer Agents, Ahi Evran 2nd International Conference on Scientific Research, Ahi Evran University, October 21-23, 2022 (oral online presentation). https://www.ahievranconference.org/
  4. R. Ciorteanu, C.I. Ciobanu, I.I. Mangalagiu, R. Danac, Synthesis of New Indolizinic Derivatives as Potential Antitumor Agents, 7th International New York Conference on Evolving Trends in Interdisciplinary Research&Practices, Manhattan, New York City, October 1-3, 2022 (oral online presentation) https://www.nyconference.org/
  5. Ciorteanu, R.; Ciobanu, C.; Antoci, V.; Mangalagiu, I.I.; Danac, R. Synthesis of new fused azaheterocycles as potential anticancer agents, Sesiunea de comunicări științifice a studenților, masteranzilor și doctoranzilor, Ediția XIII, 28 Octombrie 2022, Iasi, Romania. (Comunicare orală CO-01, pag. 6). https://www.chem.uaic.ro/ro/manifestari/scssmd2022.html
  6. Oniciuc, L.; Antoci, V.; Amariucai-Mantu, D.; Diaconu, D.; Ciobanu, C.; Mangalagiu, V.; Mangalagiu, I.I. Novel benzo[f]quinoline derivatives with antimicrobial properties, Sesiunea de comunicări științifice a studenților, masteranzilor și doctoranzilor, Ediția XIII, 28 Octombrie 2022, Iasi, Romania. (Comunicare orală CO-09, pag. 22) https://www.chem.uaic.ro/ro/manifestari/scssmd2022.html
  7. C.M. Al Matarneh, R.M. Amarandi, I. Mangalagiu, R. Danac, New Pyrrolo-Fused Heterocycles with Anticancer Properties, SIVAS International Conference on Scientific and Innovation Research, Sivas, Turkey, October 13-15, 2022 (oral online presentation). https://www.iksadkongre.com/sivas
  8. R. Ciorteanu, R. Danac, V. Antoci, C. Ciobanu, I.I. Mangalagiu, Synthesis of 6, 7 and 8-substituted indolizines as potential anticancer agents, EGE International Congress on Natural & Medical Sciences, Izmir, Turkey, September 02-04, 2022 (oral online presentation). https://www.egekongreleri.org/_files/ugd/1aed9a_88c662ce9fda4be7856018197b287e44.pdf
  9. Antoci,V.; Amăriucăi-Mantu, D.; Diaconu, D.; Dănac, R.; Mangalagiu, V.; Mangalagiu, I.I. Novel benzo[f]quinoline compounds with vinyl chain: synthesis, characterization and anticancer evaluation, INTERNATIONAL SCIENTIFIC RESEARCH CONGRESS-XII, August 13-14, 2022. Delhi, India (on-line, Oral presentation, nr. 656, pag. 656-657). https://www.umteb.org/
  10. Ciorteanu, R.; Danac, R.; Ciobanu, C.; Mangalagiu, I.I.; Amăriucăi-Mantu, D. Synthesis of new indolisinic derivativesas potential anticancer agents, INTERNATIONAL SCIENTIFIC RESEARCH CONGRESS-XII, August 13-14, 2022. Delhi, India (on-line, Oral presentation, nr. 665, pag. 665-666).
  11. Mangalagiu, I.I.; Mangalagiu, V.; Amariucai-Mantu, D.; Antoci, V.: Diaconu, D. New Azaheterocycles Derivatives: Design, Synthesis and Applications, MEDCHEMMEET2022- INTERNATIONAL MEET ON MEDICINAL CHEMISTRY, DRUG DISCOVERY & DRUG DELIVERY, June 23-25, 2022. COPENHAGEN, DENMARK. (Invited (plenary) lecture, I-3, pag. 2). https://www.albedomeetings.com/cms/pdfs/MEDCHEMMEET2022-tentative-program.pdf
  12. Mangalagiu, V.; Diaconu, D.; Amariucai-Mantu, D.; Antoci, V.; Mangalagiu, I.I. Hybrid Five and Six Membered Ring Nitrogen Heterocycles with Antimicrobial and Anticancer Activity, MEDCHEMMEET2022- INTERNATIONAL MEET ON MEDICINAL CHEMISTRY, DRUG DISCOVERY & DRUG DELIVERY, June 23-25, 2022. COPENHAGEN, DENMARK. (Poster presentation, P4- pag. 3). https://www.albedomeetings.com/cms/pdfs/MEDCHEMMEET2022-tentative-program.pdf
  13. Mangalagiu, V.; Amariucai-Mantu, D.; Antoci, V.; Diaconu, D.; Danac, R.; Moldoveanu, C.; Zbancioc, Ghe.; Mangalagiu, I.I. Ecologically friendly methods used in heterocyclic chemistry, 7th International Conference Ecological and Environmental Chemistry 2022, March 3-4, 2022, Chisinau, Republic of Moldova. (Plenary lecture, PL, pag. 11). http://eec-2022.mrda.md/
  14. Diaconu, D.; Mangalagiu, V.; Mangalagiu, I.I. New Materials Based on Quinoline Sulfonamide – Metals with Antimicrobial Activity. METAL 2022 – 31st International Conference on Metallurgy and Materials, May 18 – 19, 2022. Brno, Czech Republic, (Poster presentation, PE13- pag. 68). https://www.metalconference.eu/en/topics/ https://www.metalconference.eu/en/conference-programme/471-poster-session-e/
  15. Mangalagiu, V.; Zbancioc, Ghe.; Mangalagiu, I.I. Synthesis of Fluorescent Materials with Fused Azaheterocycles Skeleton for Medicinal Application. METAL 2022 – 31st International Conference on Metallurgy and Materials, May 18 – 19, 2022. Brno, Czech Republic, (Poster presentation, PE14- pag. 69). https://www.metalconference.eu/en/topics/ https://www.metalconference.eu/en/conference-programme/471-poster-session-e/

Project leader,

  Prof.dr. Ionel Mangalagiu