Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives

Abstract

Novel series of bis-and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC 50 in the lM range. In attempting to investigate the large broadspectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds. ARTICLE HISTORY

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

“…The mono‐aldehydes 11a–b were prepared using 4‐formylphenylboronic acid pinacol ester under mild conditions in the presence of Pd(PPh 3 ) 4 and cesium carbonate as previously described by our team. Reaction of primary amines, such as 3,3′‐diamino‐ N ‐methyldipropylamine or 1,4‐bis(3‐aminopropyl)piperazine), with 11a–b gave the di‐imines 13a–c , which were reduced into the bis{ N ‐[(phenanthrolin‐2‐yl)benzyl]‐3‐aminopropyl}amines 3a–c using sodium borohydride in methanol (Scheme ).…”

“…FRET melting experiments were performed with dual‐labeled oligonucleotides mimicking the Plasmodium telomeric sequences FPf1T [FAM‐ 5 ′(GGGTTTA) 3 ‐GGG 3 ′‐TAMRA] and FPf8T [FAM‐ 5 ′(GGGTTCA) 3 GGG 3 ′‐TAMRA] and the human telomeric sequence F21T [FAM‐(GGGTTA) 3 ‐GGG 3 ′‐TAMRA] . The oligonucleotides were prefolded in 10 m m lithium cacodylate buffer (pH 7.2), with 10 m m KCl and 90 m m LiCl (K + condition).…”

“…In the course of our work devoted to discovery of new heterocyclic compounds for use in anticancer chemotherapy, we prepared a series of substituted 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives (Figure , 1 ) designed to bind to DNA G‐quadruplexes . As these 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthrolines possess the structural parameters required for an antimalarial activity, we decided to synthesize new substituted 1,10‐phenanthroline compounds (Figure ) taking into account our experience in the field of the synthesis of new antiprotozoal heterocyclic compounds . Herein, we describe the design and synthesis of phenanthrolines and bis‐ and tris‐phenanthrolines (Figure , 1–4 ) that are considered as new analogs of compounds A and B .…”

Synthesis of new piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction

“…The pyrrolo [1,2-a]quinoxaline heterocyclic framework constitutes the basis of an important class of compounds possessing interesting biological activities. These compounds have been reported as key intermediates for the assembly of several heterocycles including antipsychotic agent, 18 anti-HIV agent, 19 adenosine A 3 receptor modulator, 20 antiparasitic agents, [21][22][23][24][25] and antitumor agents. [26][27][28][29][30][31] We also previously demonstrated that the pyrrolo [1,2-a]quinoxaline heterocyclic scaffold could lead to the preparation of bacterial multidrug resistance pump inhibitors.…”

G4-iM Grinder: DNA and RNA G-Quadruplex, i-Motif and higher order structure search and analyser tool

“…Even if a higher frequency of a PQS does not mean a stronger tendency of in vitro G4 formation, it does mean that statistically they may be more biologically important or less biologically problematic. Also, higher G4 frequency allows easier and more accessible targets for the current G4-ligands, which in general are not selective between G4s (22)(23)(24). As example, we recently published the results of a PQS search in several parasitic genomes whilst considering frequency, and identified numerous highly recurrent potential G4 candidates (25).…”