Design, synthesis, and antiprotozoal evaluation of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives

Abstract

A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic-to-antiparasitic activities of 107 and 39 against a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G-quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.

Synthesis of 1H-3-{4-[(3-Dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole and Evaluation of Its Antiprotozoal Activity

“…The 3D structural determination of disubstituted indole 2 was established by X-ray crystallography (Figure 1) [21] and confirmed the structure in the solid state as anticipated on the basis of NMR data [19,20]. Condensation of 3-dimethylaminopropylamine with the aldehyde 2 led to the unstable imine 3, which was immediately reduced into the 1H-3-{4-[(3-dimethylaminopropyl)aminomethyl] phenyl}-2-phenylindole (4) using sodium borohydride as a reductive agent in refluxing methanol as previously described by our team [16,17]. The structure of this new synthesized derivative 4 was then confirmed by FTIR, 1 H/ 13 C-NMR and ESI-MS analyses (see Supplementary Materials).…”

“…In this last field, the indole compounds are considered as attractive candidates for antiprotozoal therapy [11][12][13][14]. In the course of our work devoted to discovering new original heterocyclic candidates for use in antiparasitic chemotherapy [15][16][17], and as an extension of our work on the development of new antimalarial indole heterocyclic drugs, we have identified 1H-3-{4-[(3-dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole and found that it is endowed with interesting activity against three protozoan parasites. Thus, we report herein on the synthesis and structural identification of this new indole scaffold, which was then screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei).…”

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8‐Nitroquinolin‐2(1H)‐one Scaffold Using Palladium‐Catalysed Cross‐Coupling Reactions

“…The effects of the test compounds were assessed using the viability marker Alamar Blue assay described by Räz et al . After a 69 h incubation period at 37 °C, Alamar Blue (10 μL, Fisher, France) was added to each well, and the plates were incubated for 5 h . The plates were read using a PerkinElmer (Germany) ENSPIRE microplate reader using an excitation wavelength of 530 nm and an emission wavelength of 590 nm.…”

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

“…Besides the quinoline‐quinoline hybrids mentioned above, some atypical quinoline dimers also possessed considerable activity against drug‐resistant P falciparum strains . Among them, dimer 34 with IC 50 of 71 and 70 nM against CQR W2 and MQ‐resistant 3D7 strains, was no inferior to MQ (IC 50 : 32 and 80 nM against CQR W2 and MQ‐resistant 3D7 strains, respectively) and CQ (IC 50 : 200 and 80 nM, respectively) …”