We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (K = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.

Nano-sized metal–organic frameworks (nanoMOFs), with engineered surfaces to enhance the targeting of the drug delivery, have proven efficient as drug nanocarriers.

Metal-organic framework nanoparticles (nanoMOFs) are novel porous drug delivery systems whose features include high drug loading capacity, versatile functionalization, biocompatibility, and biodegradability. However, little knowledge about the nature of nanoMOFs degradation mechanism is one of many reasons that prevents their clinical use. MIL-100 (MIL stands for Matériaux de l'Institut Lavoisier) is among the most studied nanoMOF for drug delivery.Here, we investigate at the atomic scale the degradation mechanism of metal(III)-trimesate nanoMIL-100 drug carrier in biological-mimicking phosphate medium. By using solid-state NMR (ssNMR) spectroscopy, we found that the first step of nanoMIL-100(Al) degradation is the substitution of labile water ligands, resulting in new coordination bonds between Al(III) and phosphate ions, followed by the substitution of trimesate ligands leading to their release. The data indicated that the reaction-limiting step most likely is the formation of an inorganic aluminophosphate layer at the nanoparticle surface and that drug encapsulation and surface coating affect the nanoMIL-100(Al) degradation. X-ray Absorption Near Edge Structure (XANES) spectroscopy study of nanoMIL-100(Fe) degradation corroborates the hypothesized alteration mechanism of nanoMIL-100(Al). From the ensemble of data, a stepwise degradation mechanism representative for the nanoMIL-100 drug delivery system is proposed.