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The development of Tyrosinase inhibitors (TYRIs) could represent an efficacious strategy for pharmacological intervention on skin pathologies related to aberrant production of melanin. Based on in silico studies we designed and tested a library of twenty-four compounds bearing the 4-(4-fluorobenzyl) piperazin-1-yl]-fragment. As result, we identified several compounds with excellent inhibit effects at low micromolar concentration against TYR from Agaricus bisporus (TyM). Among them, compound 25 (IC 50 ¼ 0.96 mM) proved to be~20-fold more potent than the reference compound kojic acid (IC 50 ¼ 17.76 mM) having wide applications in the cosmetics and pharmaceutical industries. The mode of interaction of active inhibitor 25 was deciphered by means of crystallography as well as molecular docking and these results were consistent with kinetic experiments. Moreover, the identified compound 25 exhibited no considerable cytotoxicity and showed anti-melanogenic effects on B16F10 melanoma cells. Therefore, a combination of computational and biochemical approaches could represent a rational guidelines for further structural modification of this class of compounds as future anti-melanogenic agents.

The inhibition of tyrosinase (Ty, EC 1.14.18.1) represents an efficient strategy of decreasing melanogenesis and skin hyperpigmentation. A combination of crystallographic and docking studies on two different tyrosinases, that from Bacillus megaterium (TyBm) and that from a mushroom (TyM), has contributed to increasing our knowledge about their structural information and translating that information to the most druggable human Ty (TyH) isozyme. In particular, we designed and synthesized a series of 1-(4-fluorobenzyl)piperazine and 1-(4-fluorobenzyl)piperidine derivatives showing inhibitory activities on TyM at micromolar ranges and more potency than that of the reference compound, kojic acid. The crystal structures of TyBm with inhibitor 3 (IC value of 25.11 μM) and 16 (IC value of 5.25 μM) were solved, confirming the binding poses hypothesized by in silico studies and revealing the main molecular determinants for the binding recognition of the inhibitors.

A conceptually novel, high‐yielding, mono‐ or bis‐homologation was realized with lithium halocarbenoids and enables the one‐step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the homologation event, carried out with two different carbenoids (LiCH 2 Cl and LiCH 2 F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.

The transfer of a reactive nucleophilic CH2X unit into a preformed bond enables the introduction of a fragment featuring the exact and desired degree of functionalization through a single synthetic operation. The instability of metallated α-organometallic species often poses serious questions regarding the practicability of using this conceptually intuitive and simple approach for forming C-C or C-heteroatom bonds. A deep understanding of processes regulating the formation of these nucleophiles is a precious source of inspiration not only for successfully applying theoretically feasible transformations (i.e. determining how to employ a given reagent), but also for designing new reactions which ultimately lead to the introduction of molecular complexity via short experimental sequences.

The acylation of α-substituted carbanion-type reagents (MCR1R2X; X = halogen, OR, SR, NR3R4, SeR, etc.) with Weinreb amides constitutes a highly versatile and flexible approach for accessing α-functionalized ketones. In this short review we will present a series of transformations—from our own and the work of others—documenting the general applicability of the methodology. Chemoselectivity is uniformly manifested including for critical substrates featuring additional electrophilic functionalities or sterically demanding elements. Importantly, the stereochemical information contained in the Weinreb amides can be fully transferred to the targeted ketones without affecting the optical purity. The protocol is also applicable to chiral carbanions generated through sparteine-mediated asymmetric deprotonation: the careful design of the experimental procedure allows recycling of the sparteine and the Weinreb ‘amine’ (N,O-dimethylhydroxylamine), thus improving the sustainability perspective of the processes.1 Introduction1.1 The Problem of the Synthesis of α-Substituted Ketones1.2 Weinreb Amides: General Features and Preparation2 Synthesis of α-Substituted Ketones2.1 α-Haloketones2.2 Synthesis of α-Cyanoketones2.3 Synthesis of α-Oxyketones2.4 Synthesis of β-Oxo Thioethers (α-Thioketones)2.5 Synthesis of Chiral α-Oxy and α-Nitrogen Ketones via the Sparteine-Mediated Generation of Optically Active Organolithiums2.6 Synthesis of α-Selenomethyl Ketones2.7 Reactivity of α-Phosphorus Carbanions with Weinreb Amides2.8 Modification of the Weinreb Amide Core: The CLAmP Reagent3 Competing Attack of Nucleophiles at More Reactive Electrophilic Sites than Weinreb Amides4 Conclusions

There is a considerable attention for the development of inhibitors of tyrosinase (TYR) as therapeutic strategy for the treatment of hyperpigmentation disorders in humans. Continuing in our efforts to identify TYR inhibitors, we describe the design, synthesis and pharmacophore exploration of new small molecules structurally characterized by the presence of the 4-fluorobenzylpiperazine moiety as key pharmacophoric feature for the inhibition of TYR from Agaricus bisporus (AbTYR). Our investigations resulted in the discovery of the competitive inhibitor [4-(4-fluorobenzyl)piperazin-1-yl]-(3-chloro-2-nitrophenyl)methanone 26 (IC 50 = 0.18 μM) that proved to bẽ 100-fold more active than reference compound kojic acid (IC 50 = 17.76 μM). Notably, compound 26 exerted antimelanogenic effect on B16F10 cells in absence of cytotoxicity. Docking analysis suggested its binding mode into AbTYR and into modelled human TYR.

Melanogenesis controls the formation of melanin pigment whose overproduction is related to various hyperpigmentary disorders in humans. Tyrosinase is a type‐3 copper enzyme involved in the rate limiting step of melanin synthesis, therefore its inhibition could represent an efficient way for the development of depigmenting agents. In this work, a combination of pharmacophore and docking‐based studies has been employed to screen two in‐house 3D compound databases containing about 2,000 molecules from natural and synthetic sources. As result we selected two “hit compounds” which proved to inhibit tyrosinase activity showing IC50 values in the micromolar range.