2021 Report

Stage I.  Synthesis, structural analysis and biological evaluation of newly hybrid azaheterocycles derivatives having in the same molecule an azine (pyridine or quinoline) and a di- or tri- azole heterocycles.

In this stage there was brought contributions to objectives O1, O2, O8-O12.

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

Synthesis was performed according to the schemes presented bellow. There was synthetized the necessary six π–deficient and five π–rich member ring nitrogen heterocycles, azide derivatives, etc. In this respect, the following main results were obtained:

a. There was obtained the necessary intermediary with 6 member ring π–deficient nitrogen heterocycles:

– acylated aminoquinoline of type 1, alkylated aminoquinoline of type 2, using a stright and efficient route of synthesis

– bis-acylated aminopyridine of type 3 and nono-acylated aminopyridine of type 3’, respectively  bis-alkylated aminopyridine of type 4 and mono-alkylated aminopyridine of type 4’. Again, the reaction pathway was straight and efficient

– bis-pyridazine of type 7; the reaction pathway invole 2 speps: acylation of bis-phenyl ether followed by cyclocondensation with hydrazine

b. azides having in molecule an aryl unit, of type 5, by using the direct alkylation with sodium azide

c. There was obtained the necessary intermediary with 5 member ring π–rich nitrogen heterocycles, belong to the class of imidazole 6’and benzimidazole 6. The reaction pathway was straight and efficient, involving an one step reaction: nitration respectively cyclization

d. There was obtained the necessary intermediary with 6 member ring π–deficient nitrogen heterocycles from the azasteroid category type 4 and 4’ 

e. There was obtained the necessary intermediary with 6 member ring π–deficient nitrogen heterocycles, condensed with a 5 member ring p–rich nitrogen heterocycles, having in molecule the cyano functionality type 6 to 10

f. There was obtained intermediary with β-cyclodextrin structure, that will be used further for obtaining supramolecular host-guest assemblies that could be used as drug delivery systems as well as for retard administration.

A.I.2. Synthesis of newly hybrid azaheterocycles derivatives (type Q1 and Q2) having in the same molecule an azine (π–deficient) heterocycle, one or two (π–rich) imidazole/benzimidazole heterocycle, via diverse aliphatic linker/spacers.

Using variously rationally substituted quinoline and pyridine (as π–deficient azine), (benz)imidazole (as π–rich azole), and alkyl amide linker/spacer, the hybrid classless of compounds type azino-linker-1,3-diazol-salt and azino-linker-pyrrolo-1,3-diazol was obtained, namely Q1, Q2, Q2’, Y,

A.I.3. Synthesis of newly hybrid azaheterocycles derivatives (type Q3 to Q7) having in the same molecule one, two or three azine (π–deficient) heterocycle, one or two triazole (π–rich) molecule, and diverse aliphatic and/or aromatic linker/spacers.

Synthesis was performed according to the schemes presented bellow. Using variously π–deficient azine, π–rich triazole, and variously linker/spacer (alkyl amide, alkyl amine, amido-amino-alkyl, amido-amino-aryl, amido-ureil), the hybrid classless of compounds type azino-linker-triazole-linker-azino Q3 and Q3’, azino-linker-triazole-linker-pyridine-linker-triazole-linker-azino Q4, azino-linker-amino(aliphatic and/or aromatic)-linker-triazole Q5, Q6, azino-linker-triazole-linker(ureil) Q7, was obtained.

A.I.4. Synthesis of hybrid compounds type Q1-Q7 using eco-friendly setup procedures.

Synthesis presented above on activities A.I.1-A.I.3., 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 is 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.I.5. Molecular docking studies.

During the last decades molecular docking became an important tool in medicinal chemistry, furnishing relevant information concerning binding sites, binding energy and ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties. As a result, we decide to perform a computationally (in silico) study concerning these parameters for some of the obtained azaheterocycles. The chemical spaces were also screen for similar compounds with remarkable bioactivity and ADME and drug-like properties. Bioactivity is studied with the aid of a computationally build = receptor-ligand system. The complex is characterized by its energy, hydrogen bonds, and steric constraints. The target (binding site) used for this class of compounds was retrieved from literature (manly the work of Hunter and all.  and Xavier and all.) and using an online service that suggests ligand predilection for a specific target, and are ATP synthase and Topoisomerase II (TOPO II). Target structures were retrieved from the PDB database: 6WLZ for ATP synthase and 3KSB for TOPO II. The PDB structures were energetically minimized, charges corrected, names correct, potential energy recomputed. Cofactors and Aa chains were kept, and ligands and water molecules were removed. Azaheterocycles were introduced computationally as SDF. Files that were energetically minimized and charges corrected. Binding site coordinates (Å) were retrieved from literature and from an algorithm based on expended Van der Walls charges. The maximum number of cavities which was set to be detected was 5, corresponding to the binding site molecular theory. The cavity with the most significant volume (Å3) was chosen for each target

The in silico studies furnished important data concerning pharmacodynamics, pharmacokinetics and ADMET parameters of the studied azaheterocycles. Study of the interaction of each azaheterocycle with ATP synthase in the formed complex, reveal that some of them have the best-fit in complex with ATP synthase. Study of the interaction of azaheterocycles with TOPO II in the formed complex, reveal that some other azaheterocycles have the best-fit in complex with TOPO II. The in silico ADMET studies reveal that some azaheterocycle have excellent drug-like properties, these including a low toxicity profile.

A.I.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 antifungal assay reveals that the majority of our azaheterocycle compounds have an excellent quasi-nonselective antifungal activity against fungus Candida albicans, some of them higher that the control drug Nystatin. The antibacterial assay reveals that the majority of our azaheterocycle compounds have a very good antibacterial activity against gram positive germ Staphylococcus aureus while the activity against gram negative germ Escherichia coli is negligible. Analysis of the biological data reveals some interesting SAR correlations between structure and antimicrobial activity.

A.I.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 (1 paper in Q1 journal and 5 papers in Q2 journals);
  • 8 papers were published in proceedings;
  • 9 papers were presented to Scientific Meetings (1 invited conference, 2 oral presentation, 6 posters).

Achievements

  • Results Disseminations

    • ISI papers published in the year 2021: 6

  1. Antoci, V.; Oniciuc, L.; Amariucai-Mantu, D.; Moldoveanu, C.; Mangalagiu, V.; Amarandei, A.M.; Lungu, C.N.; Dunca, S.; Mangalagiu, I.I.; Zbancioc, G. Benzoquinoline Derivatives: A Straightforward and Efficient Route to Antibacterial and Antifungal Agents, Pharmaceuticals 2021, 14, 335 (1-21). MDPI, ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND ISSN: eISSN: 1424-8247. Pharmacology & Phharmacy- Q1- 49/271; https://doi.org/ 10.3390/ph14040335 FI=5.86
  2. Bucur, S.; Niculaua, M.; Ciobanu, C.I.; Lungu, N.C.; Mangalagiu, I.I.* A Simple Synthesis Route for Selectively Methylated b-Cyclodextrin Using a Copper Complex Sandwich Protecting Strategy. Molecules 2021, 26, 5669 (pp. 1-6). Publisher: Molecular Diversity Preservation International, CODEN: MOLEFW  ISSN: 1420-3049. Chemistry, Multidisciplinary-Q2, 67/152; https://doi.org/10.3390/molecules26185669 FI= 4.41
  1. Moldoveanu, C.; Mangalagiu, I.I.; Zbancioc, G. Fluorescent Azasteroids through Ultrasound Assisted Cycloaddition Reactions. Molecules 2021, 26, 5098 (pp. 1-13). Publisher: Molecular Diversity Preservation International, CODEN: MOLEFW ISSN: 1420-3049. Chemistry, Multidisciplinary-Q2, 67/152; https://doi.org/10.3390/molecules26165098  FI= 4.41
  2. Amariucai‐Mantu, D.; Mangalagiu, V.; Mangalagiu, I.I.* [3 + n] Cycloaddition Reactions: A Milestone Approach for Elaborating Pyridazine of Potential Interest in Medicinal Chemistry and Optoelectronics. Molecules 2021, 26, 3359 (pp. 1-17). Publisher: Molecular Diversity Preservation International, CODEN: MOLEFW  ISSN: 1420-3049. Chemistry, Multidisciplinary-Q2, 67/152;  https://doi.org/10.3390/  molecules26113359  FI= 4.41
  1. Al-Matarneh, M.C.; Amarandi, R.M.; Mangalagiu, I.I.; Danac, R. Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives. Molecules 2021, 26, 2066 (pp. 1-19). Publisher: Molecular Diversity Preservation International, CODEN: MOLEFW ISSN: 1420-3049. Chemistry, Multidisciplinary-Q2, 67/152; https://doi.org/10.3390/ molecules26072066      FI= 4.41
  2. Diaconu, D.; Amariuci-Mantu, D.; Mangalagiu, V.; Antoci, V.; Zbancioc, Ghe.; Mangalagiu, I.I. Ultrasound assisted synthesis of hybrid quinoline-imidazole derivatives: a green synthetic approach. RSC Advanced ( RSC Adv.) 2021, 11, 38297–38301. Publisher Royal Society of Chemistry (United Kingdom), ISSN: 2046-2069, eISSN:2046-2069. DOI: 10.1029/d1ra07484a

    • Papers published in proceedings in the year 2021: 8

  1. Ionel I. Mangalagiu, Dorina Amariucai-Mantu,Vasilichia Antoci, Ramona Danac, Violeta Mangalagiu, Costel Moldoveanu, Gheorghita Zbancioc. Hybrid five- and six-member ring azaheterocycles: synthesis and applications. Progress in Organic and Macromolecular Compounds 28-th Ed., Iasi, Romania, October 7-9, 2021. (Plenary lecture, PL, pag. 25-26). Book of Abstracts / editors: Marcela MIHAI, Radu-Dan RUSU ISSN 2810 – 2347 ISSN – L 2810 – 2126 https://icmpp.ro/macroiasi2021/program.php https://icmpp.ro/macroiasi2021/proceedings.php
  2. Roxana Ciorteanu, Vasilichia Antoci, Dorina Amariucăi-Mantu, Catalina Ciobanu, Violeta Mangalagiu, Ionel I. Mangalagiu. New hybrid quaternary salts with sulfanylamide/benzimidazole skeleton. Progress in Organic and Macromolecular Compounds 28-th Ed., Iasi, Romania, October 7-9, 2021. (Poster presentation, pag. 107-108). Book of Abstracts / editors:  ISSN 2810 – 2347 ISSN – L 2810 – 2126 https://icmpp.ro/macroiasi2021/program.php https://icmpp.ro/macroiasi2021/proceedings.php
  3. Violeta Mangalagiu, Dumitrela Diaconu, Ionel I. Mangalagiu. Quinoline Derivatives: a NMR Structure Elucidation. Adriatic NMR Conference, Primošten, Croatia, 13–15 September 2021. (Poster presentation, pag. 54). Book of Abstracts / editors: Nikola Bregović , Danijel Namjesnik, Predrag Novak, Jelena Parlov Vuković ISSN (print) 2806-6227 https://adriatic-nmr-conference.chem.pmf.hr/
  4. Ionel I. Mangalagiu, Gheorghita Zbancioc, Liliana Oniciuc, Violeta Mangalagiu. Fused Benzo-quinoline Derivatives: NMR Insides Concerning Structure Elucidation. Adriatic NMR Conference, Primošten, Croatia, 13–15 September 2021. (Poster presentation, pag. 55). Book of Abstracts / editors: Nikola Bregović , Danijel Namjesnik, Predrag Novak, Jelena Parlov Vuković ISSN (print) 2806-6227 https://adriatic-nmr-conference.chem.pmf.hr/
  5. Mangalagiu, I.I.; Violeta Mangalagiu, Costel Moldoveanu, Gheorghita Zbancioc, Ramona Danac, Vasilichia Antoci. ANTIMICROBIAL AND ANTICANCER ACTIVITY OF SOME HYBRID AZINE/AZOLE DERIVATIVES, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Oral presentation, pag. 14). http://dx.doi.org/10.19261/nfnpc.2021.ab07 https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021 Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki Editura: Institute of Chemistry ISBN 978-9975-3336-7-2 (PDF). DOI: 10.19261/nfnpc.2021
  6. Vasilichia Antoci, Gheorghiţă Zbancioc, Liliana Oniciuc, Dorina Amăriucăi-Mantu, Costel Moldoveanu, Ramona Dănac, Cătălina Ciobanu, Vioaleta Mangalagiu, Mangalagiu, I.I. BENZO[F]QUINOLINIUM SALTS: ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Poster presentation, pag. 21). http://dx.doi.org/10.19261/nfnpc.2021.ab14 https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021 Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki Editura: Institute of Chemistry ISBN 978-9975-3336-7-2 (PDF). DOI: 10.19261/nfnpc.2021
  7. Roxana Ciorteanu, Dumitrela Diaconu, Vasilichia Antoci, Dorina Amăriucăi-Mantu, Cătălina Ciobanu, Violeta Mangalagiu, Mangalagiu, I.I. NEW HYBRID QUATERNARY SALTS WITH PYRIDINE/BENZIMIDAZOLE SKELETON, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Poster presentation, pag. 23). http://dx.doi.org/10.19261/nfnpc.2021.ab16 https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021 Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki Editura: Institute of Chemistry ISBN 978-9975-3336-7-2 (PDF). DOI: 10.19261/nfnpc.2021
  8. Roxana-Maria Amărandi, Maria-Cristina Al-Matarneh, Lacramioara Popovici, Mangalagiu, I.I., Vasilichia Bejan, Catalina-Ionica Ciobanu, Ramona Danac. PYRROLO-FUSED HETEROCYCLIC DERIVATIVES: DESIGN, SYNTHESIS AND ANTICANCER EVALUATION, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Poster presentation, pag. 24). http://dx.doi.org/10.19261/nfnpc.2021.ab17; https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021 Book of Abstracts / editors: Aculina Arîcu, Veaceslav Kulcițki Editura: Institute of Chemistry, ISBN 978-9975-3336-7-2 (PDF). DOI: 10.19261/nfnpc.2021

  • Papers presented to Scientific Meetings: 9 (1 invited conference, 2 oral presentation, 6 posters)

  1. Mangalagiu, I.I.; Violeta Mangalagiu, Costel Moldoveanu, Gheorghita Zbancioc, Ramona Danac, Vasilichia Antoci. ANTIMICROBIAL AND ANTICANCER ACTIVITY OF SOME HYBRID AZINE/AZOLE DERIVATIVES, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Oral presentation, pag. 14). https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021
  2. Vasilichia Antoci, Gheorghiţă Zbancioc, Liliana Oniciuc, Dorina Amăriucăi-Mantu, Costel Moldoveanu, Ramona Dănac, Cătălina Ciobanu, Vioaleta Mangalagiu, Mangalagiu, I.I. BENZO[F]QUINOLINIUM SALTS: ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Poster presentation, pag. 21). https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021
  3. Roxana Ciorteanu, Dumitrela Diaconu, Vasilichia Antoci, Dorina Amăriucăi-Mantu, Cătălina Ciobanu, Violeta Mangalagiu, Mangalagiu, I.I. NEW HYBRID QUATERNARY SALTS WITH PYRIDINE/BENZIMIDAZOLE SKELETON, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Poster presentation, pag. 23). https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021
  4. Roxana-Maria Amărandi, Maria-Cristina Al-Matarneh, Lacramioara Popovici, Mangalagiu, I.I., Vasilichia Bejan, Catalina-Ionica Ciobanu, Ramona Danac. PYRROLO-FUSED HETEROCYCLIC DERIVATIVES: DESIGN, SYNTHESIS AND ANTICANCER EVALUATION, New frontiers in natural product chemistry, June 4-5, 2021, Chișinău, Moldova. (Poster presentation, pag. 24). https://ichem.md/en/scientific-seminar-new-frontiers-natural-product-chemistry-2021
  5. Mangalagiu, I.I. Ultrasound assisted synthesis of azaheterocycles as green modern tool alternative for synthesis. 30th International Conference Ecology & Safety, August 16-19, 2021, Burgas, Bulgaria. (Oral presentation, OP-129, pag. 13). https://www.sciencebg.net/en/conferences/ecology-and-safety/
  6. Mangalagiu, V. Microwave assisted synthesis of fused azaheterocycles. A green aproach. 30th International Conference Ecology & Safety, August 16-19, 2021, Burgas, Bulgaria. (Poster, P-108, pag. 11). https://www.sciencebg.net/en/conferences/ecology-and-safety/
  7. Ionel I. Mangalagiu, Dorina Amariucai-Mantu,Vasilichia Antoci, Ramona Danac, Violeta Mangalagiu, Costel Moldoveanu, Gheorghita Zbancioc. Hybrid five- and six-member ring azaheterocycles: synthesis and applications. Progress in Organic and Macromolecular Compounds 28-th Ed., Iasi, Romania, October 7-9, 2021. (Plenary lecture, PL, pag. 25-26). https://icmpp.ro/macroiasi2021/program.php
  8. Roxana Ciorteanu, Vasilichia Antoci, Dorina Amariucăi-Mantu, Catalina Ciobanu, Violeta Mangalagiu, Ionel I. Mangalagiu. New hybrid quaternary salts with sulfanylamide/benzimidazole skeleton. Progress in Organic and Macromolecular Compounds 28-th Ed., Iasi, Romania, October 7-9, 2021. (Poster presentation, pag. 107-108). https://icmpp.ro/macroiasi2021/program.php
  9. Amariucai-Mantu, D.; Oniciuc, L.; Diaconu, D.; Ciobanu, C.; Mangalagiu, I.I.; Mangalagiu, V.; Antoci, V.: Novel tetrahyropyrrolo-benzo[f]quinoline compounds: synthesis and characterizations, 4th International Conference on Sustainable Science and Technology (ICSuSaT-2021) 01-02 october 2021, ONLINE-TURKEY, poster 34. (poster presentation).

Project leader,

  Prof.dr. Ionel Mangalagiu