A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA in Mycobacterium tuberculosis.

A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.

Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity.

A series of isoniazid derivatives bearing a phenolic or heteroaromatic coupled frame were obtained by mechanochemical means. Their pH stability and their structural (conformer/isomer) analysis were checked. The activity of prepared derivatives against Mycobacterium tuberculosis cell growth was evaluated. Some compounds such as phenolic hydrazine 1a and almost all heteroaromatic ones, especially 2, 5 and 7, are more active than isoniazid, and their activity against some M. tuberculosis MDR clinical isolates was determined. Compounds 1a and 7 present a selectivity index >1400 evaluated on MRC5 human fibroblast cells. The mechanism of action of selected hydrazones was demonstrated to block mycolic acid synthesis due to InhA inhibition inside the mycobacterial cell.

2-Phenylbenzoxazole derivatives: a family of robust emitters of solid-state fluorescence.

The derivatives of 2-phenylbenzoxazole (PBO) are popular fluorescent organic dyes for use in solution or after dispersion in an appropriate matrix. Their spectroscopic behavior in the solid state is, unjustly, not so well known. Many of them are strongly emissive as pure solid dyes, due to a favorable crystal packing mode. The PBO fragment lends itself well to relatively simple modifications of its chemical structure, aimed at enlarging the conjugated π-electron system. Many molecules thus designed show aggregation-induced emission (AIE). Furthermore, the derivatives of 2-(2'-hydroxyphenyl)benzoxazole (HBO) are familiar excited-state intramolecular proton transfer (ESIPT) dyes. They are particularly well suited for solid-state sensing. Mechanofluorochromism is also observed in complexes and closely-related compounds. Regarding their self-association properties, the general tendency of many PBO derivatives is to give elongated nano and microparticles. Very small chemical changes are enough to tune the shape and size of these particles. Nanofibers may be obtained by simple preparation methods and are of great value for wave-guiding. For all these reasons, as well as for its robustness and high photo- and thermal stability, the PBO fragment is an attractive building block to access new molecules that will be particularly well adapted for developments in the field of photoluminescent materials.

Conjugates of Benzoxazole and GFP Chromophore with Aggregation-Induced Enhanced Emission: Influence of the Chain Length on the Formation of Particles and on the Dye Uptake by Living Cells.

Six conjugates of benzoxazole and green fluorescent protein chromophore that differ by the length of their alkyl chain (from C1 to C16) are investigated. They exhibit rigidofluorochromism and clear aggregation-induced emission enhancement (AIEE) behavior with emission in the orange-red that is specific to the solid state. A preparation method based on solvent exchange is used to prepare particles. The self-association properties of these molecules depend on the length of the alkyl chain. Microfibers, platelets, and rounded microparticles are successively obtained by increasing the chain length. The same method is used to prepare nanoparticles (NPs) that are fully characterized. In particular, homogeneous populations of stable NPs measuring around 70 nm are obtained with the analogs whose chains contain four to eight carbon atoms. The behavior with respect to living cells is also influenced by the nature of the compounds. Only the dyes with intermediate hydrophobicity are efficiently uptaken by both normal and tumor cells, and fluorescence only originates from dispersed dye molecules. There is no evidence for incorporation of NPs into cells. This work shows that small variations of the chemical structure must be taken into account for making the best use of AIEE compounds in view of precise applications.

A comparative study of nine berberine salts in the solid state: optimization of the photoluminescence and self-association properties through the choice of the anion.

The arrangement of an ionic fluorophore in the crystalline state was regulated by the presence of various counter-ions and the effect on spectroscopic and self-association properties was studied. To do so, nine salts of berberine (i.e. a fluorescent natural alkaloid) were investigated. Most of them contained organic anions and were prepared using an ion-exchange process. Berberine chloride and hemisulfate were also used for the sake of comparison. The diffuse reflectance and photoluminescence spectra were recorded on powder compounds. All salts were emissive in the solid state and the emission efficiency was increased seven-fold with the nature of the anion. The optical properties were tentatively discussed on the basis of the crystal-packing mode. The possibility of implementing a bottom-up approach to generate microparticles was investigated using the reprecipitation method. Salts that contain the most hydrophobic anions gave a large number of homogeneous, elongated microparticles. This study showed that most of the berberine salts could be used as fluorescent materials, but proper choice of the anion allows using the self-association properties to best advantage.

Synthesis and evaluation of antioxidant phenolic diaryl hydrazones as potent antiangiogenic agents in atherosclerosis.

A series of bis-hydrazones derived from diaryl and diaryl ether hydroxybenzaldehyde frames 1 and 2 have been synthesized as potential antioxidant and antiangiogenic agents, two properties required to limit atherogenesis and cardiovascular events. These compounds were evaluated for their ability to neutralize free radical formation, to block endothelial cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS), an essential step in atherogenesis, and subsequent toxicity, to prevent angiogenesis evoked by low oxidized LDL concentration (monitored by the formation of capillary tubes on Matrigel) and to inhibit intracellular ROS increase involved in the angiogenic signaling. A structure/activity study has been carried out and finally allowed to select the phenolic diaryl ether hydralazine derivative 2a, sharing all these protective properties, as a promising hit for further development.

Synthesis, antioxidant and cytoprotective evaluation of potential antiatherogenic phenolic hydrazones. A structure-activity relationship insight.

A novel series of hydrazones derived from substituted benzaldehydes have been synthesized as potential antiatherogenic agents. Several methods were used for exploring their antioxidant and cytoprotective properties, such as their scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, the inhibition of superoxide anion (O2(·-)) generation and the measurement of cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS). The cytoprotective efficacy was also evaluated by measuring the cell viability (monitored by the MTT assay) in the presence of cytotoxic oxidized LDL. In this report, we discuss the relationship between the chemical structure of phenolic hydrazones and their antioxidant and cytoprotective activities, for subsequent application as antiatherogenic agents. This SAR study confirms that the phenolic frame is not the only prerequisite for antioxidant activity and N-methylbenzothiazole hydrazone moiety magnifies the dual required properties in two most interesting derivatives.