Ludovic Jean

Tetrahydroisoquinoline (THIQ) oximes have been investigated as antidotes for poisoning by toxic organophosphorus compounds. Recent studies have shown that some THIQ oximes induce cytotoxic effects and trigger apoptosis in various cell types. Since this pathway activation is desirable for anticancer drugs, we further explored the effects of three selected THIQ oximes on well-known cancer cell models: breast (MDA-MB-231 and MCF-7), prostate (PC-3) cancer and malignant glioblastoma (U251). The tested THIQ oximes were cytotoxic to breast cancer cells and, to a lesser extent, to glioblastoma cells, but not to PC-3 cells at concentrations up to 200 µM within a 24-h exposure period. The MCF-7 cells exhibited the highest sensitivity, with all three oximes affecting it in a time-dependent manner (IC₅₀ from 7-74 µM). While the membrane integrity of affected cells was maintained after treatment with the tested THIQ oximes, they disrupted mitochondrial membrane potential and activated caspase 9 indicating triggering of the mitochondria-mediated apoptosis. Overall, these findings suggest that the THIQ oxime scaffold could be a foundation for developing targeted therapies, especially for breast cancer, and other derivatives may be worthier of exploration.

This study reports a series of novel heterocyclic hemiindigos (Het‐HI) synthesized via the condensation of indoxyl acetate with various heteroaromatic aldehydes. The influence of electron‐rich and electron‐poor heterocycles on the photochemical and photophysical properties of these compounds has been investigated. Our findings reveal that several Het‐HIs exhibit noteworthy photoswitching behavior, including enhanced absorption at the visible region. Notably, certain derivatives respond efficiently to green and red light, achieving good conversions to the metastable E ‐isomer and displaying prolonged half‐lives of up to 53 days in a polar solvent. The results highlight the potential of these photoswitches for applications in molecular devices and responsive materials.

Hemiindigo photoswitches, a class of chromophores derived from the well‐known indigo dye, have attracted considerable interest over the past two decades. These compounds are unique in their ability to absorb light in the visible region of the spectrum in both isomeric states, making them ideal for applications where high‐energy UV light is not tolerated. A particularly attractive feature of hemiindigoids is that, despite their rigid structures, they undergo significant and controllable changes during the photoisomerisation process. Moreover, they exhibit a combination of high thermal bistability, pronounced photochromism, and fast, efficient photoisomerisation, positioning hemiindigoid photoswitches as versatile chromophores. This review summarises the current developments and advances in hemiindigoid photoswitches, including their synthesis, photoswitching performance, and applications, with a strong focus on their practical use as reversible triggers in fields ranging from photopharmacology to advanced materials.

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

Thioaurone chromophores, part of the indigoid family and commonly named hemithioindigos, have recently gained attention due to their interesting photoswitching properties. The study focuses on heterocyclic hemithioindigos (Het‐HTIs) and investigates their synthesis using electron‐rich and electron‐poor heterocycles and modifications to the thioindigo moiety. Furthermore, it aims to evaluate the photoswitching performances of these synthesised compounds, with a particular emphasis on the influence of the heterocycles on the photoisomerization capabilities, which was found to be more prominent than the modifications made to the thioindigo moiety. Among the 44 Het‐HTIs tested, several exhibited highly efficient photoswitchable properties, demonstrating Z‐to‐E photoisomerization in the blue region, and E‐to‐Z photoisomerization in the green or the red regions. Additionally, the metastable E‐isomer displayed an impressive half‐life of up to 54 days in a polar solvent (DMSO). These results suggest that heterocyclic hemithioindigos hold great promise as photoswitches for researchers interested in light‐controlled molecular mechanisms.

The amine‐promoted rearrangement of 3‐halogenated and 3‐tosylated flavones into amino‐substituted aurones is a reliable but little‐explored method in aurone synthesis. We extend it to 8‐azaflavones, readily prepared from 3‐cyano‐2‐pyridones by the Baker‐Venkataraman methodology. They rearrange into 7‐azaaurones under mild conditions in the presence of a broad range of aliphatic primary and secondary amines, including bulky amines for which steric hindrance issues are overcome by Lewis base organocatalysis. Primary amines selectively give the E configuration through an intramolecular stabilising hydrogen bond between the amino substituent and the carbonyl oxygen. Suppressing such hydrogen bonds by N‐acylation allows accessing the Z configuration by simple photoisomerization. Thus, we propose a methodology that allows access to the 7‐azaaurone scaffold and allows controlling the E / Z configuration by switching from an amino to an amido substituent at the double bond. Finally, the rearrangement‐acylation‐photoisomerization sequence is successfully extended to 2‐ethylidenefuropyridin‐3‐ones.

Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood–brain barrier. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their in vitro reactivation efficacy on inhibited human acetylcholinesterase, the crystal structure of two compounds in complex with the enzyme, their protective index on intoxicated mice, and their pharmacokinetics. We then evaluated their endothelial permeability coefficients with a human in vitro model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the glucose transporter located at the blood–brain barrier.

Sulfur-containing CWA simulants of yperite (CEES) and VX (PhX) are neutralized with Oxone, in solid or liquid form, in flow systems.

The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.