Interaction between Antimalarial 2‑Aryl‑3<i>H</i>‑indol-3-one Derivatives and Human Serum Albumin

Binding of drugs to plasma proteins, such as albumin, is a major factor which determines their pharmacokinetics and pharmacological effects. Therefore, the interactions between human serum albumin (HSA) and four antimalarial compounds selected in the 2-aryl-3<i>H</i>-indol-3-one series have been investigated using UV–visible, fluorescence and circular dichroism (CD) spectroscopies. Compounds produced a static quenching of the intrinsic fluorescence of HSA. The thermodynamic parameters have shown that the binding reaction is endothermic for three compounds while exothermic for the 2-phenyl-3<i>H</i>-indol-3-one, <b>3</b>. The interaction is entropically driven with predominant hydrophobic forces with binding affinities of the order of 10⁴ M^–1. The highest binding constant is observed for <b>3</b> (<i>K</i>_{<i>λ=280nm</i>} = 4.53 × 10⁴ M^–1) which is also the less active compound against Plasmodium falciparum. Synchronous fluorescence gave qualitative information on the conformational changes of HSA while quantitative data were obtained with CD. Displacement experiments with site markers indicated that drugs bind to HSA at site I (subdomain IIA). In addition, the apparent binding constant and the binding site number were calculated in the presence of different ions

Atropisomerization in <i>N</i>‑aryl-2(1<i>H</i>)‑pyrimidin-(thi)ones: A Ring-Opening/Rotation/Ring-Closure Process in Place of a Classical Rotation around the Pivot Bond

Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less distorted transition states account for the experimental barrier to atropenantiomerization. In 1988, one of us hypothesized that, in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidin-(thi)­ones, a ring-opening/ring-closure process was contributing to the observed racemization process accounting for the lower barriers in the sulfur analogues than in oxygen analogues. Now, a series of six novel 6-amino-5-cyano-1,4-disubstituted-2­(1<i>H</i>)-pyrimidinones <b>5a</b>–<b>5f</b> and two 6-amino-5-cyano-4-<i>p</i>-tolyl-1-substituted-2­(1<i>H</i>)-pyrimidinethiones <b>6a</b> and <b>6b</b> were synthesized and characterized through spectroscopic and X-ray diffraction studies. Semipreparative HPLC chiral separation was achieved, and enantiomerization barriers were obtained by thermal racemization. The rotational barriers of 6-amino-5-cyano-1-<i>o</i>-tolyl-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5b</b>) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5e</b>) were found to be 120.4 and 125.1 kJ·mol^–1 (<i>n</i>-BuOH, 117 °C), respectively, and those of the corresponding thiones were 116.8 and 109.6 kJ·mol^–1 (EtOH, 78 °C), respectively. DFT calculations of the rotational barriers clearly ruled out the classical rotation around the pivotal bond with distorted transition states in the case of the sulfur derivatives. Instead, the ranking of the experimental barriers (sulfur versus oxygen, and <i>o</i>-tolyl versus 1-naphthyl in both series) was nicely reproduced by calculations when the rotation occurred via a ring-opened form in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidinethiones

Atropisomerization in <i>N</i>‑aryl-2(1<i>H</i>)‑pyrimidin-(thi)ones: A Ring-Opening/Rotation/Ring-Closure Process in Place of a Classical Rotation around the Pivot Bond

Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less distorted transition states account for the experimental barrier to atropenantiomerization. In 1988, one of us hypothesized that, in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidin-(thi)­ones, a ring-opening/ring-closure process was contributing to the observed racemization process accounting for the lower barriers in the sulfur analogues than in oxygen analogues. Now, a series of six novel 6-amino-5-cyano-1,4-disubstituted-2­(1<i>H</i>)-pyrimidinones <b>5a</b>–<b>5f</b> and two 6-amino-5-cyano-4-<i>p</i>-tolyl-1-substituted-2­(1<i>H</i>)-pyrimidinethiones <b>6a</b> and <b>6b</b> were synthesized and characterized through spectroscopic and X-ray diffraction studies. Semipreparative HPLC chiral separation was achieved, and enantiomerization barriers were obtained by thermal racemization. The rotational barriers of 6-amino-5-cyano-1-<i>o</i>-tolyl-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5b</b>) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5e</b>) were found to be 120.4 and 125.1 kJ·mol^–1 (<i>n</i>-BuOH, 117 °C), respectively, and those of the corresponding thiones were 116.8 and 109.6 kJ·mol^–1 (EtOH, 78 °C), respectively. DFT calculations of the rotational barriers clearly ruled out the classical rotation around the pivotal bond with distorted transition states in the case of the sulfur derivatives. Instead, the ranking of the experimental barriers (sulfur versus oxygen, and <i>o</i>-tolyl versus 1-naphthyl in both series) was nicely reproduced by calculations when the rotation occurred via a ring-opened form in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidinethiones