Acta Scientific Pharmaceutical Sciences (ASPS)(ISSN: 2581-5423)

Research Article Volume 7 Issue 7

Development, Synthesis and Antiprotozoal Assessment of New Substituted Diquinolinyl-Pyridine Derivatives as Antiparasitic Agents by Potential G-4 Binding

Rabindra Nath Das1,2, Anita Cohen3, Clotilde Boudot4, Solène Savrimoutou1, Sandra Albenque-Rubio1, Stéphane Moreau1, Jean-Louis Mergny5, Luisa Ronga6, Ioannis Kanavos6, Charles Descamps1, Valentin Verdier1, Patrice Agnamey7, Catherine Mullié7, Bertrand Courtioux4, Pascal Sonnet7 and Jean Guillon1*

1University of Bordeaux, Faculty of Pharmacy, CNRS, INSERM, ARNA, France
2Department of Chemistry, College of Engineering and Technology, Kattankulathur – Chennai, Tamil Nadu, India
3University of Aix-Marseille, IRD, AP-HM, SSA, VITROME, France
4University of Limoges, INSERM U1094, Tropical Neuroepidemiology, Limoges, France; Institute of Neuroepidemiology and Tropical Neurology, France
5Ecole Polytechnique, Laboratoire d’Optique et Biosciences, CNRS, INSERM, Institut Polytechnique de Paris, France
6Université de Pau et des Pays de l'Adour, E2S UPPA, CNRS, IPREM, France
7University of Picardie Jules Verne, Agents Infectieux, Résistance et Chimiothérapie (AGIR), UR 4294, UFR de Pharmacie, France

*Corresponding Author: AJean Guillon, University of Bordeaux, Faculty of Pharmacy, CNRS, INSERM, ARNA, France.

Received: May 16, 2023; Published: June 23, 2023

Abstract

In order to fight malaria, a public health problem for which nearly half of the world’s population is at risk and responsible a life-threatening disease primarily found in tropical countries and for which the estimated number of deaths stood at 619 000 in 2021, an original strategy is to design and synthesize quinoline-based drugs that are not recognized by the protein system involved in the drug efflux. Thus, a series of new 2,6-di-(carbamoyl-2-quinolinyl)pyridine derivatives was considered, synthesized, and evaluated in vitro against three parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Pharmacological results showed antiparasitic activity with IC50 values in the sub and mM range. The in vitro cytotoxicity of these new diquinolinyl-pyridine derivatives was evaluated on human HepG2 cells. The diquinolinyl-pyridine 1e was found as the most potent antimalarial candidate with a ratio of cytotoxic to antiprotozoal activities of 73.5 against the P. falciparum CQ-resistant strain W2. Moreover, derivative 3b was also identified as the most potent antiparasitic compound with a selectivity index (SI) of 21.48 on 3D7 P. falciparum CQ-sensitive strain. In addition, the 2,6-di-(carbamoyl-2-quinolinyl)pyridines 2c and 3b were also identified as the most interesting antitrypanosomal candidate drugs with selectivity index (SI) of 75.9 and 38.94, respectively on T. brucei brucei strain. It has been previously described that the telomeres of parasites P. falciparum and Trypanosoma could be considered as potential targets of this kind of nitrogen heterocycles, thus the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes have been measured through a FRET melting assay.

 Keywords: Diquinolinyl-pyridine; Antimalarial Activity; Antileishmanial Activity; Antitrypanosomal Activity; G-quadruplex.

References

  1. World malaria report 2022 (2023).
  2. WHO Guidelines for malaria hosted on the MAGICapp online platform (2023).
  3. WHO Neglected tropical diseases (2023).
  4. WHO Ending the neglect to attain the sustainable development goals: a rationale for continued investment in tackling neglected tropical diseases 2021-2030 (2023).
  5. Dola VR., et al. "Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy”. Antimicrobial Agents and Chemotherapy 61 (2017): e01152-16.
  6. Manohar S., et al. “4-Aminoquinoline based molecular hybrids as antimalarials: an overview”. Current Topics in Medicinal Chemistry 14 (2014): 1706-1733.
  7. Deshpande S., et al. “4-aminoquinolines: An Overview of Antimalarial Chemotherapy”. Medicinal Chemistry 6 (2016): 1.
  8. Kumar S., et al. “Recent advances in novel heterocyclic scaffolds for the treatment of drug-resistant malaria”. Journal of Enzyme Inhibition and Medicinal Chemistry 31 (2016): 173-186.
  9. Van de Walle T., et al. “Recent contributions of quinolines to antimalarial and anticancer drug discovery research”. European Journal of Medicinal Chemistry 226 (2021): 113865.
  10. Goyal A., et al. “Spotlight on 4‐substituted quinolines as potential anti‐infective agents: Journey beyond chloroquine”. Archiv der Pharmazie (Weinheim) 356 (2023): e2200361.
  11. Hochegger P., et al. “New derivatives of quinoline-4-carboxylic acid with antiplasmodial activity”. Bioorganic and Medicinal Chemistry 25 (2017): 2251-2259.
  12. Baragaña B., et al. “A novel multiple-stage antimalarial agent that inhibits protein synthesis”. Nature 522 (2015): 315-320.
  13. Pandya KM., et al. “Development of Antimicrobial, Antimalarial and Antitubercular Compounds Based on a Quinoline-Pyrazole Clubbed Scaffold Derived via Doebner Reaction”. Chemistry Africa 3 (2020): 89-98.
  14. Guillon J., et al. “Synthesis, antimalarial activity, and molecular modeling of new pyrrolo[1,2-a]quinoxalines, bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines”. Journal of Medicinal Chemistry 47 (2004): 1997-2009.
  15. Guillon J., et al. “Synthesis and antiprotozoal evaluation of new 2,9-bis[(pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline derivatives by targeting G-quadruplex, an interesting pharmacophore against drug efflux”. Acta Scientific Pharmaceutical Sciences 7 (2023): 50-65.
  16. Guillon J., et al. “Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives”. Journal of Enzyme Inhibition and Medicinal Chemistry 32 (2017): 547-563.
  17. Jonet A., et al. “Synthesis and Antimalarial Activity of New Enantiopure Aminoalcoholpyrrolo[ 1,2-a]quinoxalines”. Medicinal Chemistry 14 (2018): 293-303.
  18. Guillon J., et al. “Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives”. Journal of Enzyme Inhibition and Medicinal Chemistry 35 (2020): 432-459.
  19. Dassonville-Klimpt A., et al. “Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity”. European Journal of Medicinal Chemistry 228 (2022): 113981.
  20. Guillon J., et al. “Design, synthesis, and antiprotozoal evaluation of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives”. Chemical Biology and Drug Design 91 (2018): 974-995.
  21. Calvo EP., et al. “G-Quadruplex ligands: Potent inhibitors of telomerase activity and cell proliferation in Plasmodium falciparum”. Molecular and Biochemical Parasitology 207 (2016): 207, 33-38.
  22. Tidwell RR., et al. “Dicationic compounds which selectively recognize G-quadruplex DNA”. (2007): 1792613A2.
  23. Leeder WM., et al. “Multiple G-quartet structures in pre-edited mRNAs suggest evolutionary driving force for RNA editing in trypanosomes”. Scientific Reports 6 (2016): 29810.
  24. Lombrana R., et al. “Transcriptionally Driven DNA Replication Program of the Human Parasite Leishmania major”. Cell Reports 16 (2016): 1774-1786.
  25. Bottius E., et al.Plasmodium falciparum Telomerase: De Novo Telomere Addition to Telomeric and Nontelomeric Sequences and Role in Chromosome Healing”. Molecular and Cellular Biology 18 (1998): 919-925.
  26. Raj DK., et al. “Identification of telomerase activity in gametocytes of Plasmodium falciparum”. Biochemical and Biophysical Research Communications 309 (2003): 685-688.
  27. Das RN., et al. "Design, synthesis and biological evaluation of new substituted diquinolinyl-pyridine ligands as anticancer agents by targeting G-quadruplex". Molecules 23 (2018): 81.
  28. Desjardins RE., et al. “Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique”. Antimicrobial Agents and Chemotherapy 16 (1979): 710-718.
  29. Bennett TN., et al. “Novel, Rapid, and Inexpensive Cell-Based Quantification of Antimalarial Drug Efficacy”. Antimicrobial Agents and Chemotherapy 48 (2004): 1807-1810.
  30. Bacon DJ., et al. “Comparison of a SYBR Green I-Based Assay with a Histidine-Rich Protein II Enzyme-Linked Immunosorbent Assay for In Vitro Antimalarial Drug Efficacy Testing and Application to Clinical Isolates”. Antimicrobial Agents and Chemotherapy 51 (2007): 1172-1178.
  31. Kaddouri H., et al. “Assessment of the Drug Susceptibility of Plasmodium falciparum Clinical Isolates from Africa by Using a Plasmodium Lactate Dehydrogenase Immunodetection Assay and an Inhibitory Maximum Effect Model for Precise Measurement of the 50-Percent Inhibitory Concentration”. Antimicrobial Agents and Chemotherapy 50 (2006): 3343-3349.
  32. Mosmann T. “Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays”. Journal of Immunological Methods 65 (1983): 55-63.
  33. Emami SA., et al. “Inhibitory Activity of Eleven Artemisia Species from Iran against Leishmania Major Parasites”. Iranian Journal of Basic Medical Sciences 15 (2012): 807-811.
  34. Räz B., et al. “The Alamar Blue assay to determine drug sensitivity of African trypanosomes (b. rhodesiense and T.b. gambiense) in vitro”. Acta Tropica 68 (1997): 139-147.
  35. Baltz T., et al. “Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, equiperdum, T. evansi, T. rhodesiense and T. gambiense”. EMBO Journal 4 (1985): 1273-1277.
  36. De Cian A., et al. “Fluorescence-based melting assays for studying quadruplex ligands”. Methods 42 (2007): 183-195.
  37. Buu-Hoï et al. “Nitrogen heterocyclic analogs of polyaryls”. Journal of Heterocyclic Chemistry 2 (1965): 7-10.
  38. Marin I., et al. “Homoleptic and heteroleptic ruthenium(II) complexes based on 2,6-bis(quinolin-2-yl)pyridine ligands-multiple-charged-state modules for potential density memory storage”. European Journal of Inorganic Chemistry 5 (2015): 786-793.
  39. Li C., et al. “Asymmetric Ruthenium-Catalyzed Hydrogenation of Terpyridine-Type N-Heteroarenes: Direct Access to Chiral Tridentate Nitrogen Ligands”. Organic Letters 22 (2020): 6452-6457.

Citation

Citation: Jean Guillon., et al. “Development, Synthesis and Antiprotozoal Assessment of New Substituted Diquinolinyl-Pyridine Derivatives as Antiparasitic Agents by Potential G-4 Binding". Acta Scientific Pharmaceutical Sciences 7.7 (2023): 15-33.

Copyright

Copyright: © 2023 Jean Guillon., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.




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