Antiprotozoal Activity and DNA Binding of Dicationic Acridones

Abstract

Dicationic acridone derivatives were synthesized and their antiparasitic activity was evaluated. Acridones displayed in vitro nanomolar IC 50 values against Trypanosoma brucei rhodesiense STIB900 with selectivity indices >1000. Compounds 1b, 3a, and 3b were as potent as the reference drug melarsoprol in this assay. Submicromolar-range activities were observed against wild-type (NF54) and resistant (K1) strains of Plasmodium falciparum, whereas no significant activity was detected against Trypanosoma cruzi or Leishmania donovani. Compounds 1a and 1b were curative in the STIB900 mouse model for human African trypanosomiasis. UV spectrophotometric titrations and circular dichroism (CD) experiments with fish sperm (FS) DNA showed that these compounds form complexes with DNA with binding affinities in the 10 4 M −1 range. Biological and biophysical data show that antiparasitic activity, toxicity, and DNA binding of this series of acridones are dependent on the relative position of both imidazolinium cations on the heterocyclic scaffold.

Bioprospecting of Nitrogenous Heterocyclic Scaffolds with Potential Action for Neglected Parasitosis: A Review

“…Subsequently, UV spectrophotometric titrations and circular dichroism (CD) experiments were conducted, revealing binding constants with DNA in the 10 4 M -1 range, and binding mode mainly by intercalation. No apparent correlation was observed between antitrypanosomal activity and DNA binding affinity, which suggests that there may be additional mechanisms of action involved in the activity of these acridone derivatives against T. brucei [194].…”

“…The mechanism of action performed by acridine compounds with antiparasitic activity has been mostly related to their ability to intercalate between the bases of DNA [192][193][194]. This mechanism of action is well-known to acridine compounds with chemotherapeutic action, considering the structure of the nucleus, which characterized as polyaromatic and planar, with a positively charged heteroatom inserted into the ring system, which assists in relocating the molecule to the center of the DNA [195,196].…”

A practical route to arylated dihydroacridine derivatives via nickel boride mediated intramolecular reductive cyclization-concomitant dehydration

“…Acridine and acridone derivatives, found in plants and marine sources, 2 constitute an important class of N-heterocycles of great interest to scientists due to their broad spectrum of pharmaceutical activities and other industrial applications. Acridine derivatives are well recognized for their immense potential as therapeutic agents and often display wide-ranging bioactivities such as antiviral, 3 antimalarial, 4 antileishmanial, 5 anti-inflammatory, 6 antitubercular, 7 anticancer, 8 antimicrobial, 9 antibacterial, 10 antileukemic, 11 antiprotozoal, 12 and fungicidal 13 activities. Acridine is the imperative heterocyclic nucleus of several commercially successful drugs such as proflavine, 14 a mepacrine, 14 b ethacridine, 14 c DACA, 14 d , e nitracine, 14 f and amsacrine 14 g , h to name a few (Fig.…”

High yield synthesis of trans-azoxybenzene versus 2-isopropoxy-4-nitrobenzoic acid: influence of temperature and base concentration

“…During our project dedicated to the design of new dicationic compounds active against kinetoplastid parasites, [1][2][3][4] we needed to prepare 2-isopropoxy-4-nitrobenzoic acid (1). The two-steps synthesis of this compound had been reported earlier by Adler & Hamilton.…”