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  • N-cinnamoylation of antimalarial classics: quinacrine analogues with decreased toxicity and dual-stage activity.

N-cinnamoylation of antimalarial classics: quinacrine analogues with decreased toxicity and dual-stage activity.

ChemMedChem (2014-01-30)
Ana Gomes, Bianca Pérez, Inês Albuquerque, Marta Machado, Miguel Prudêncio, Fátima Nogueira, Cátia Teixeira, Paula Gomes
ABSTRACT

Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N-cinnamoylated quinacrine surrogates, 9-(N-cinnamoylaminobutyl)-amino-6-chloro-2-methoxyacridines, is reported. The compounds were found to be highly potent against both blood-stage P.falciparum, chloroquine-sensitive 3D7 (IC50 =17.0-39.0 nM) and chloroquine-resistant W2 and Dd2 strains (IC50 =3.2-41.2 and 27.1-131.0 nM, respectively), and liver-stage P.berghei (IC50 =1.6-4.9 μM) parasites. These findings bring new hope for the possible future "rise of a fallen angel" in antimalarial chemotherapy, with a potential resurgence of quinacrine-related compounds as dual-stage antimalarial leads.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥98.0% (NT)
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥99%
Sigma-Aldrich
Bovine Serum Albumin, lyophilized powder, ≥96% (agarose gel electrophoresis)
Sigma-Aldrich
6,9-Dichloro-2-methoxyacridine, 97%
Sigma-Aldrich
1,4-Diaminobutane, 99%
Supelco
3,3′,5,5′-Tetramethylbenzidine, standard for GC
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥98% (TLC)
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, tablet, 1 mg substrate per tablet
Supelco
Putrescine, analytical standard
Sigma-Aldrich
Phenol, ≥99%
Sigma-Aldrich
Phenol, BioUltra, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
Phenol, unstabilized, purified by redistillation, ≥99%
Sigma-Aldrich
Phenol, contains hypophosphorous as stabilizer, loose crystals, ACS reagent, ≥99.0%
Sigma-Aldrich
Phenol, puriss., meets analytical specification of Ph. Eur., BP, USP, ≥99.5% (GC), crystalline (detached)
Sigma-Aldrich
Phenol, puriss., meets analytical specification of Ph. Eur., BP, USP, 99.5-100.5% (GC)
Sigma-Aldrich
Phenol, BioUltra, for molecular biology, TE-saturated, ~73% (T)
Sigma-Aldrich
Phenol, ≥96.0% (calc. on dry substance, T)
Sigma-Aldrich
Phenol, puriss. p.a., ACS reagent, reag. Ph. Eur., 99.0-100.5%
Supelco
Phenol solution, 100 μg/mL in acetonitrile, PESTANAL®, analytical standard
Sigma-Aldrich
Phenol, BioXtra, ≥99.5% (GC)
Sigma-Aldrich
Phenol solution, Equilibrated with 10 mM Tris HCl, pH 8.0, 1 mM EDTA, BioReagent, for molecular biology
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Phenol solution, BioReagent, Saturated with 0.01 M citrate buffer, pH 4.3 ± 0.2, for molecular biology
Sigma-Aldrich
Liquified Phenol, ≥89.0%
Sigma-Aldrich
Phenol, for molecular biology
Sigma-Aldrich
Phenol, unstabilized, ReagentPlus®, ≥99%
Supelco
Phenol, PESTANAL®, analytical standard
Sigma-Aldrich
Phenol, JIS special grade, ≥99.0%
Sigma-Aldrich
Phenol, SAJ first grade, ≥98.0%
Sigma-Aldrich
Phenol, ≥99.0%
Sigma-Aldrich
Phenol, ≥99.0%