Tyrosinase inhibition is a key strategy to reduce melanogenesis in vivo, making the enzyme an attractive target for cosmetic and dermatological applications. Despite the large number of reported compounds, many inhibitors show limited efficacy against the human enzyme, such as kojic acid, or instead act as alternative substrates or pseudo-substrates, such as hydroquinone. Given the controversial activity of polyphenolic scaffolds on tyrosinase, we designed a new series of hemiindigoid derivatives by replacing the classical resorcinol moiety with functional groups known for their copper-binding potential, including amines, halogens, non-oxidizable phenols and hydroxamic acids. Among the 43 compounds evaluated, para- and meta-hydroxamic acid derivatives afforded the best results, demonstrating nanomolar inhibition of both mushroom tyrosinase and human tyrosinase from cell lysates. Structural and kinetic studies provided insight into their inhibition mechanism and binding geometry, while whole cell assays confirmed their ability to suppress melanogenesis in the micromolar range.

Myocardial infarction (MI) is the leading cause of death worldwide. The extent of infarct size, determined by the degree of cardiomyocyte death, is a major factor in post-MI functional recovery. Therefore, cardioprotective strategies focus on limiting infarct size. Among the mechanisms involved in the MI response, Hypoxia Inducible Factor-1 (HIF-1) plays a complex role that can be either beneficial or detrimental depending on the nature of its activation (i.e., acute or chronic). Given the potential cardioprotective effects of curcumin through HIF-1 modulation, we investigated the impact of hydroxylated aurone derivatives on cardiomyoblasts (H9C2) incubated with cobalt chloride (CoCl2, 1 mM for 2 h), which mimics hypoxia by stabilizing HIF-1 alpha. Cell viability was measured using the methyl thiazolyl tetrazolium (MTT) assay, and HIF-1 alpha expression was assessed by western blot. Interestingly, only the three 7-hydroxyaurones enhanced cell viability under CoCl2-induced stress, showing efficiencies comparable to curcumin (120-140 % improvement at 100 & micro;M). However, they exhibited divergent effects on HIF-1 alpha expression: 2 '- and 3 '-hydroxyaurones led to a reduction, whereas 4 '-hydroxyaurone caused an increase. This study thus identifies a new class of molecules capable of modulating HIF-1 activity and preventing cardiac cell death. These findings open new perspectives, as these aurones could potentially be developed for strategies aiming to reduce infarct size by regulating HIF-1 expression, either increasing HIF-1 alpha in the context of MI alone or suppressing its expression under chronic conditions such as obstructive sleep apnea syndrome (OSA).

Bacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-beta-lactamases (MBLs) able to hydrolytically inactivate beta-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-beta-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 K-i values as low as 1.7 and 2.5 mu M. 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.

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.

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 com-pounds 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.

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.

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.

La peau est la première barrière de défense contre les agressions environnementales. En effet, la mélanine, un pigment cutané, est responsable de cette protection contre les rayons UV et les radicaux libres. Cependant, sa surexpression entraîne à la fois des troubles cutanés et des problèmes de multirésistance du mélanome contre toutes les thérapies anticancéreuses traditionnelles.L'inhibition de la tyrosinase humaine (hsTY) constitue la stratégie la plus simple et la plus classique pour réduire la production de mélanine, mais l’état de l’art concernant le développement d’inhibiteurs de hsTY n'en est qu'à ses débuts. Par conséquent, dans cette étude, nous étudions l'effet de dérivés aurones sur la tyrosinase humaine, à partir d'un composé parent : le 2-hydroxypyridine-N-oxide-6-hydroxyaurone (aurone - HOPNO) précédemment identifié (Ki = 0,35 µM) qui souffre cependant de problèmes de solubilité et de pénétration cellulaire. L'identification du 4-butylrésorcinol et du thiamidol en tant qu'inhibiteurs puissants de hsTY nous a inspiré pour le développement d'une série de composés avec un groupement résorcinol (sur le cycle B), capable de chélater le centre à cuivre du site actif. Des modifications sur les cycles C et B ont été effectuées simultanément pour interagir avec des résidus hsTY spécifiques éloignés du centre à cuivre, assurant une sélectivité élevée. Les composés synthétisés ont été évalués pour déterminer leur capacité à inhiber la production de mélanine à partir de cellules de mélanome MNT-1. Jusqu'à présent, il semble que les substitutions polyphénoliques sur le cycle A favorisent les interactions avec des résidus clés, améliorant ainsi l’activité. Dans l'ensemble, cette étude montre l'intérêt de l’utilisation de squelettes de type hémiindigoïde pour le développement de nouveaux inhibiteurs plus actifs et sélectifs de la tyrosinase.