Jean Guillon¹*, Anita Cohen², Sarah Monic^1,3, Clotilde Boudot⁴, Solène Savrimoutou¹, Sandra Albenque-Rubio¹, Stéphane Moreau¹, Alexandra Dassonville-Klimpt⁵, Jean-Louis Mergny⁶, Luisa Ronga⁷, Mikel Bernabeu de Maria⁷, Nikita Tyurin-Schmitt¹, Paul Parrens¹, Adrien Labarthe¹, Valentin Gomez¹, Serge Moukha^8,9, Pascale Dozolme^8,9, Nadine Azas², Valérie Gabelica¹⁰, Patrice Agnamey⁵, Céline Damiani^5,11, Anne Totet^5,11, Catherine Mullié⁵, Bertrand Courtioux⁴ and Pascal Sonnet⁵

¹University of Bordeaux, Faculty of Pharmacy, CNRS, INSERM, ARNA, UMR 5320, U1212, France
²University of Aix-Marseille, IRD, AP-HM, SSA, VITROME, Marseille, France
³Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom
⁴University of Limoges, INSERM U1094, Tropical Neuroepidemiology, Limoges, France and Institute of Neuroepidemiology and Tropical Neurology, France
⁵University of Picardie Jules Verne, Agents Infectieux, Résistance et Chimiothérapie (AGIR), UR 4294, UFR de Pharmacie, France
⁶Ecole Polytechnique, Laboratoire d’Optique et Biosciences, CNRS, INSERM, Institut Polytechnique de Paris, France
⁷Université de Pau et des Pays de l'Adour, E2S UPPA, CNRS, IPREM, France
⁸Centre de Recherche Cardio-thoracique de Bordeaux (CRCTB), UMR U1045 INSERM, PTIB - Hôpital Xavier Arnozan, France
⁹INRAE Bordeaux Aquitaine, F- 33140 Villenave-d'Ornon, France
¹⁰University of Bordeaux, IECB, CNRS, INSERM, ARNA, France
¹¹Laboratoire de Parasitologie-Mycologie, Centre de Biologie Humaine, CHU Amiens-Picardie, France

*Corresponding Author: Jean Guillon, University of Bordeaux, Faculty of Pharmacy, CNRS, INSERM, ARNA, UMR 5320, U1212, France.

Received: January 07, 2023; Published: January 27, 2023

Abstract

A series of new 2,9-bis[(pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline compounds 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 novel aza derivatives was evaluated on human HepG2 cells. The phenanthroline 1f was noticed as the most potent antimalarial candidate with a ratio of cytotoxic to antiprotozoal activities of 912.4 against the P. falciparum CQ-resistant strain W2. In addition, the phenanthroline 1a was also identified as the most potent antiparasitic derivative with a selectivity index (SI) of 811.8 on P. falciparum CQ-sensitive strain 3D7. Against the promastigote forms of L. donovani, the same phenanthroline 1a was found the most active compounds with an IC₅₀ of 2.08 M. In addition, the phenanthrolines 1f and 1i were also identified as the most promising trypanosomal candidates with selectivity index (SI) of 231.1 and 143.7, respectively on T. brucei brucei strain. As the telomeres of the parasites P. falciparum and Trypanosoma could be considered as possible targets of this kind of aza heterocyclic molecules, their ability to stabilize the parasitic telomeric G-quadruplexes have been measured through the FRET melting assay.

Keywords: Phenanthroline; G-quadruplex; Antimalarial Activity; Antileishmanial Activity; Antitrypanosomal Activity

References

1. World malaria report (2022).
2. WHO Guidelines for malaria (2022).
3. Webinar: Launch of new antimalarial drug resistance strategy for Africa (2022).
4. Global Malaria Programme: Tools for monitoring antimalarial drug efficacy (2022).
5. Belete TM. “Recent progress in the development of new antimalarial drugs with novel targets”. Drug Design, Development and Therapy 14 (2020): 3875-3889.
6. Kim J., et al. “Structure and drug resistance of the Plasmodium falciparum transporter PfCRT”. Nature 576 (2019): 315-320.
7. Alibert-Franco S., et al. “Efflux Mechanism, an Attractive Target to Combat Multidrug Resistant Plasmodium falciparum and Pseudomonas aeruginosa”. Current Medicinal Chemistry 16 (2009): 301-317.
8. Baird JK. “8-Aminoquinoline Therapy for Latent Malaria”. Clinical Microbiology Reviews 32 (2019): e00011-19.
9. 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.
10. Manohar S., et al. “4-Aminoquinoline based molecular hybrids as antimalarials: an overview”. Current Topics in Medicinal Chemistry 14 (2014): 1706-1733.
11. O'Neill PM., et al. “A medicinal chemistry perspective on 4-aminoquinoline antimalarial drugs”. Current Topics in Medicinal Chemistry 6 (2006): 479-507.
12. Krogstad DJ., et al. “Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance”. Science 238 (1987): 1283-1285.
13. Fidock DA., et al. “Mutations in the falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance”. Molecular Cell 6 (2000): 861-871.
14. Roepe PD. “Molecular and physiologic basis of quinoline drug resistance in Plasmodium falciparum malaria”. Future Microbiology 4 (2009): 441-455.
15. Deshpande S., et al. “4-aminoquinolines: An Overview of Antimalarial Chemotherapy”. Medicinal Chemistry 6 (2016): 1.
16. 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.
17. 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.
18. Douglas B., et al. “Attempts to find new antimalarials. Part XXVIII. p-Phenanthroline derivatives substituted in the 4-position”. Journal of the Chemical Society (1949): 1017-1022.
19. Yapi AD., et al. “In Vitro and in Vivo Antimalarial Activity of Derivatives of 1,10-Phenanthroline Framework”. Archiv der Pharmazie - Chemistry in Life Sciences 339 (2006): 201-206.
20. Sall C., et al. “Design, synthesis, and biological activities of conformationally restricted analogs of primaquine with a 1,10-phenanthroline framework”. Bioorganic and Medicinal Chemistry Letters 18 (2008): 4666-4669.
21. Wijayanti MA., et al. “Additive in vitro antiplasmodial effect of N-alkyl and N-benzyl-1,10-phenanthroline derivatives and cysteine protease inhibitor e64”. Malaria Research and Treatment 2010 (2010): 540786.
22. Sholikhah EN., et al. “In vitro antiplasmodial activity and cytotoxicity of newly synthesized N-alkyl and N-benzyl-1,10-phenanthroline derivatives”. Southeast Asian Journal of Tropical Medicine and Public Health 37 (2006): 1072-1077.
23. Zuma AA., et al. “In vitro study of the trypanocidal activity of anilinophenanthrolines against Trypanosoma cruzi”. Parasitology International 83 (2021): 102338.
24. Ending the neglect to attain the sustainable development goals: a road map for neglected tropical diseases 2021–2030.
25. Fernandez-Prada C., et al. “Repurposed molecules: A new hope in tackling neglected infectious diseases”. In “In Silico Drug Design: Repurposing Techniques and Methodologies”. 1^st; Roy, K. Ed.; Elsevier: Amsterdam, (2019): 119-160.
26. Guillon J., et al. “Design, synthesis, and antiproliferative effect of 2,9-bis[4- (pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline derivatives on human leukemic cells by targeting G-quadruplex”. Archiv der Pharmazie (Weinheim) 354 (2021): e2000450.
27. 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.
28. Dassonville-Klimpt A., et al. “Absolute Configuration and Antimalarial Activity of erythro-Mefloquine Enantiomers”. ChemPlusChem 78 (2013): 642-646.
29. 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.
30. Jonet A., et al. “Synthesis and Antimalarial Activity of New Enantiopure Aminoalcoholpyrrolo[1,2-a]quinoxalines”. Medicinal Chemistry 14 (2018): 293-303.
31. 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.
32. 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.
33. 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.
34. Calvo EP., et al. “G-Quadruplex ligands: Potent inhibitors of telomerase activity and cell proliferation in Plasmodium falciparum”. Molecular and Biochemical Parasitology 207 (2016): 33-38.
35. Tidwell RR., et al. “Dicationic compounds which selectively recognize G-quadruplex DNA”. EP 1792613A2 (2007).
36. 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.
37. Lombrana R., et al. “Transcriptionally Driven DNA Replication Program of the Human Parasite Leishmania major”. Cell Reports 16 (2016): 1774-1786.
38. 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.
39. Raj DK., et al. “Identification of telomerase activity in gametocytes of Plasmodium falciparum”. Biochemical and Biophysical Research Communications 309 (2003): 685-688.
40. Desjardins RE., et al. “Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique”. Antimicrobial Agents and Chemotherapy 16 (1979): 710-718.
41. Bennett TN., et al. “Novel, Rapid, and Inexpensive Cell-Based Quantification of Antimalarial Drug Efficacy”. Antimicrobial Agents and Chemotherapy 48 (2004): 1807-1810.
42. 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.
43. 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.
44. Mosmann T. “Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays”. Journal of Immunological Methods 65 (1983): 55-63.
45. 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.
46. 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.
47. 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.
48. De Cian A., et al. “Fluorescence-based melting assays for studying quadruplex ligands”. Methods 42 (2007): 183-195.

Citation

Citation: Jean Guillon., 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 7.2 (2023): 50-65.

Copyright

Copyright: © 2022 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.