Antimalarial activity of new acridinone derivatives

Abstract

Malaria is one of the major threats concerning world public health. Resistance to the current antimalarial drugs has led to searches for new antimalarial compounds. Acridinone derivatives have recently demonstrated to be active against malaria parasite. We focused our attention on synthesized new acridinone derivatives, some of them resulting with high antiviral and trypanocidal activity. In this study new derivatives of 10-alyl-, 10-(3-methyl-2-butenyl)- and 10-(1,2-propadienyl)-9(10H)-acridinone were evaluated for their antimalarial activity against Plasmodium falciparum. To assess the selectivity, cytotoxicity was assessed in parallel against human MRC-5 cells. Inhibition of β-hematin formation was determined using a spectrophotometric assay. Mitochondrial bc(1) complexes were isolated from yeast and bovine heart cells to test acridinone inhibitory activity. This study resulted in the identification of three compounds with submicromolar efficacy against P. falciparum and without cytotoxic effects on human cellular line. One compound, IIa (1-fluoro-10-(3-methyl-2-butenyl)-9(10H)-acridinone), can be classified as hit for antimalarial drug development exhibiting IC(50) less than 0.2 μg/mL with SI greater than 100. In molecular tests, no relevant inhibitory activity was obtained for our compounds. The mechanism of acridinones antimalarial action remains unclear.

Acridine‐1,8‐diones: Synthesis and Biological Applications

“…Ulus and companions [104] functionalized MWCNT with carboxylic acid group for improving their catalytic efficiency and exploited them in acridinediones synthesis by condensation of different substituted aromatic amines and aldehydes with dimedone in EtOH solvent and furnished excellent yields. This monodispersed, economical, and biodegradable catalyst is easily recovered, reusable up to six successive runs [Scheme 13,Method 4].…”

“…[6][7][8][9][10] Its electronic properties, bichromophoric structure and interaction ability with various ranges of light are responsible for their keyrole in medicinal, synthetic and photo-physical chemistry. It is used as antimicrobial, antimalarial, antioxidant, anti-cancer, and antihypertensive activities and works as DNA-intercalating agent, carbonic anhydrase inhibitor and free radical scavenger and so on [11][12][13][14][15] [ Scheme 2].…”

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

“…Even though they were all less potent than mefloquine (IC50 = 0.04 ± 0.01 µM, SI = 295), derivative 206 demonstrated IC50 comparable to amsacrine (IC50 = 0.80 ± 0.10 µM, SI = 6.5) and selectivity index 14 times higher, and also proved to be more efficient than primaquine in both aspects (IC50 = 1.70 ± 0.10 µM, SI = 49) (Figure 101) [205]. (209,210,211) were the most potent against both strains, showing values of IC50 ranging from 0.30 to 0.52 µM against 3D7 strain and values on the range of 0.15-0.32 µM against Dd2 strain (Figure 102). Unexpectedly, some derivatives exhibited more potency against CQresistant strain in comparison to CQ-sensitive strain, with values of resistance index in the range of 0.15-0.7.…”

Antibiotics in malaria therapy: which antibiotics except tetracyclines and macrolides may be used against malaria?

“…Recent studies aimed at re-evaluating the acridinones which seem promising, with IC 50  <20 nM [81]. Acridinones, like quinolones, targeted the cytochrome bc 1 complex and also inhibited haem polymerization, as chloroquine does [82]. …”