2-Phenoxy-3-trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

Two-dimensional Exchange 35Cl NQR Spectroscopy of Chloral Hydrate

Two-dimensional exchange 35Cl NQR spectroscopy has been applied for studies of the CCl3- group reorientation processes in chloral hydrate. The experimental results are interpreted on the basis of the 2D-exchange NQR theory, which takes into account the off-resonance irradiation. The pulse-optimisation procedure, which is required by this theory, enabled the detection of the 2D-exchangeNQRspectrum andwas applied to the quantitative study of the exchange processes in chloral hydrate. A temperature dependent study of the exchange rate revealed two different activation processes in the temperature ranges from 240 to 295 K and from 295 to 310 K, respectively

Reorientation of the CCl3 Group in Chloral 4-Chlorobenzylhemiacetal. A Pulsed 35Cl NQR and X-ray Study

The crystal structure of the title compound was determined at 291 K : monoclinic, space group C52h-P21/n, Z = 4, a = 1693.2(1), b = 579.3(1), c = 1232.5(1) pm, and ß = 107.21 (1)°, R = 0.0415. A sharp decrease of of Cl NQR found at T ≳ 270 K for the CCl3 group is attributed to the reorientation of the group over a potential barrier of ca. 50 kJ/mol. Intermolecular interactions between the CCl3 and the neighboring atoms seem to dominate the magnitude of the potential barrier. T1-1 of the 35Cl NQR of the Cl atom on the benzene ring obeyed the T2 law well in the range 80 ≲ T/K ≲ 270, while at T ≳ 280 K it deviated from the T2 law.