Aurones and derivatives as promising New Delhi metallo-ß-lactamase (NDM-1) inhibitors.

Bacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-ß-lactamases (MBLs) able to hydrolytically inactivate ß-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-ß-lactamase-1 (NDM-1) is still considered as one of the most relevant targets for inhibitor development. Following a fragment-based strategy to find new NDM-1 inhibitors, we identified aurone as a promising scaffold. A series of 60 derivatives were then evaluated and two of them were identified as promising inhibitors with Ki values as low as 1.7 and 2.5 µM. Moreover, these two most active compounds were able to potentiate meropenem in in vitro antimicrobial susceptibility assays. The molecular modelling provided insights about their likely interactions with the active site of NDM-1, thus enabling further improvement in the structure of this new inhibitor family.

Design and synthesis of 4-amino-2',4'-dihydroxyindanone derivatives as potent inhibitors of tyrosinase and melanin biosynthesis in human melanoma cells.

Melanogenesis inhibition constitutes a privileged therapeutic solution to treat skin hyperpigmentation, a major dermatological concern associated with the overproduction of melanin by human tyrosinase (hsTYR). Despite the existence of many well-known TYR (tyrosinase) inhibitors commercialized in skin formulations, their hsTYR-inhibition efficacy remains poor since most of them were investigated over mushroom tyrosinase (abTYR), a model with low homology relative to hsTYR. Considering the need for new potent hsTYR inhibitors, we designed and synthesized a series of indanones starting from 4-hydroxy compound 1a, one of the two most active derivatives reported to date against the human enzyme, together with marketed thiamidol. We observed that analogues featuring 4-amino and 4-amido-2',4'-dihydroxyindanone motifs showed two-to ten-fold increase in activity over human melanoma MNT-1 cell lysates, and a ten-fold improvement in a 4-days whole-cell experiment, compared to parent analogue 1a. Molecular docking investigation was performed for the most promising 4-amido derivatives and suggested a plausible interaction pattern with the second coordination sphere of hsTYR, notably through hydrogen bonding with Glu203, confirming their impact in the binding mode with hsTYR active site.

Resorcinol-based hemiindigoid derivatives as human tyrosinase inhibitors and melanogenesis suppressors in human melanoma cells.

Human tyrosinase (hsTYR) catalyzes the key steps of melanogenesis, making it a privileged target for reducing melanin production in vivo. However, very few hsTYR inhibitors have been reported so far in the literature, whereas thousands of mushroom tyrosinase (abTYR) inhibitors are known. Yet, as these enzymes are actually very different, including at their active sites, there is an urgent need for new true hsTYR inhibitors in order to enable human-directed pharmacological and dermocosmetic applications without encountering the inefficiency and toxicity issues currently triggered by kojic acid or hydroquinone. Starting from the two most active compounds reported to date, i.e. a 2-hydroxypyridine-embedded aurone and thiamidol, we combined herein key structural elements and developed new nanomolar hsTYR inhibitors with cell-based activity. From a complete series of thirty-eight synthesized derivatives, excellent inhibition values were obtained for two compounds in both human melanoma cell lysates and purified hsTYR assays, and a promising improvement was observed in whole cell experiments.

Advances in the Design of Genuine Human Tyrosinase Inhibitors for Targeting Melanogenesis and Related Pigmentations.

Human tyrosinase (hsTYR) is the key enzyme ensuring the conversion of l-tyrosine to dopaquinone, thereby initiating melanin synthesis, i.e., melanogenesis. Although the protein has long been familiar, knowledge about its three-dimensional structure and efficient overexpression protocols emerged only recently. Consequently, for decades medicinal chemistry studies aiming at developing skin depigmenting agents relied almost exclusively on biological assays performed using mushroom tyrosinase (abTYR), producing a plethoric literature, often of little useful purpose. Indeed, several recent reports have pointed out spectacular differences in terms of interaction patterns and inhibition values between hsTYR and abTYR, including for widely used standard tyrosinase inhibitors. In this review, we summarize the last developments regarding the potential role of hsTYR in human pathologies, the advances in recombinant expression systems and structural data retrieving, and the pioneer generation of true hsTYR inhibitors. Finally, we present suggestions for the design of future inhibitors of this highly attractive target in pharmacology and dermocosmetics.

Aurone derivatives as promising antibacterial agents against resistant Gram-positive pathogens.

A set of variously substituted aurones was synthesized and evaluated against Methicillin-Resistant S. aureus (MRSA) and P. aeruginosa. Several analogues were found active against MRSA, but no effect was recorded against P. aeruginosa. Compounds 27, 30 and 33 showed low cytotoxicity, and were tested against a full range of bacterial (Gram-positive and Gram-negative) and fungal species, including resistant strains. These aurones displayed a selective inhibition of Gram-positive bacteria with excellent Therapeutic Index values, while showing no significant action on several Gram-negative strains, H. pylori and V. alginolyticus being the only susceptible strains among the Gram-negative bacteria tested. A permeabilization assay showed that the antibacterial activity of at least some of the aurones could be linked to alterations of the bacterial membrane. Overall, this study endorses the use of the aurone scaffold for the development of new potent and selective antibacterial agents.