Transdermal drug delivery (TDD) presents many advantages compared to other conventional routes of drug administration, yet its full potential has not been achieved. The administration of drugs through the skin is hampered by the natural barrier properties of the skin, which results in poor permeation of most drugs. Several methods have been developed to overcome this limitation. One of the approaches to increase drug permeation and thus to enable TDD for a wider range of drugs consists in the use of chemical permeation enhancers (CPEs), compounds that interact with skin to ultimately increase drug flux. Amino acid derivatives show great potential as permeation enhancers, as they exhibit high biodegradability and low toxicity. Here we present an overview of amino acid derivatives investigated so far as CPEs for the delivery of hydrophilic and lipophilic drugs across the skin, focusing on the structural features which promote their enhancement capacity.

The synthesis of chalcones commonly relies on the Claisen–Schmidt condensation, an attractive reaction owing to its operational simplicity and favorable atom economy. However, its application to acetophenones bearing multiple hydroxy substituents can be problematic, often requiring hydroxy protection and subsequent deprotection, thereby diminishing the sustainability advantages of the approach. In this work, density functional theory (DFT) calculations were performed at the CAM-B3LYP/6-311++G(d,p) level to provide a qualitative electronic rationale for the factors that may account for this limitation. The nucleophilic behavior of the starting species was examined under basic, acidic, and metal-assisted conditions, using molecular models both with and without the hydroxy groups to evaluate the hypothesis that competing nucleophilic sites could interfere with the desired condensation and hinder the reaction. The results indicated that strong basic conditions favor extensive phenol deprotonation, generating several competing nucleophiles. In this situation, the resulting phenolate species were more nucleophilic than the corresponding enolates, favoring undesired reaction pathways. Coordination of lithium or calcium to the two phenolate groups decreased their nucleophilicity but failed to suppress the unwanted reactivity of the remaining phenolate. In contrast, under acidic conditions, the enol species exhibited greater nucleophilic character than the phenolic groups, providing no support for the proposed competition between phenolates and enolates as the sole explanation for the unsuccessful reaction. Nevertheless, the acidic environment may facilitate isomerization of the bischalcone products, which could subsequently promote degradation and/or undesired cyclization processes. Taken together, experimental and computational results indicate that the failure of the reaction arises from multiple competing factors rather than from a single mechanistic limitation. Among the conditions investigated, the acid-mediated pathway appears to be the most promising starting point for further optimization of the synthesis of polyhydroxylated bischalcones.

Chalcones, a class of compounds characterized by two aromatic rings linked through a three carbon α,β-unsaturated carbonyl system, aroused widespread interest due to their (bio)synthesis and broad biological activities. However, less attention has been given to a subcategory of chalcones, bis-chalcones, despite some studies suggesting that they have improved bioactivities in comparison to their mono derivatives. Their synthesis is relatively less explored and typically requires longer reaction times and harder purifications, especially for derivatives with free hydroxy groups. This issue is relevant because several activities of bis-chalcones have been associated with the presence of hydroxy groups in the structure. In this context, the objectives of this work were to establish an efficient methodology for the synthesis of novel polyhydroxylated bis-chalcones and bis-chalcones containing other substituent groups such as halogen, methoxy, and prenyl groups and explore their chemical reactivity for further transformation into other potentially bioactive flavonoids. Herein, we report our most recent results on the synthesis of bis-chalcones and their transformation into bis-flavones. Bis-chalcones were obtained in good yields (50–80%) by basic catalyzed Claisen–Schmidt condensation of methoxymethyl (MOM)/Me-protected bis-acetophenones with aromatic aldehydes, followed by deprotection of MOM groups in an acidic medium. In turn, a prenylated bis-chalcone was prepared by O-prenylation of the hydroxylated bis-acetophenone followed by Claisen rearrangement and Claisen–Schmidt condensation with 4-methoxymethylbenzaldehyde. Afterwards, some unprotected bis-chalcones were successfully cyclized into bis-flavones through cyclodehydrogenation with I₂/ dimethyl sulfoxide (DMSO). In the future we intend to evaluate the anti-inflammatory activity of these compounds.

Chemi-/bioluminescence are phenomena in which chemical energy is converted into electronically excited singlet states, which decay with light emission. Given this feature, along with high quantum yields and other beneficial characteristics, these systems have gained numerous applications in bioanalysis, in biomedicine, and in the pharmaceutical field. Singlet chemiexcitation is made possible by the formation of cyclic peroxides (as dioxetanones) as thermolysis provides a route for a ground state reaction to produce singlet excited states. However, such thermolysis can also lead to the formation of triplet states. While triplet states are not desired in the typical applications of chemi-/bioluminescence, the efficient production of such states can open the door for the use of these systems as sensitizers in photocatalysis and triplet-triplet annihilation, among other fields. Thus, the goal of this study is to assess the effect of heavy atom addition on the thermolysis and triplet chemiexcitation of a model dioxetanone. Monobromination does not affect the thermolysis reaction but can improve the efficiency of intersystem crossing, depending on the position of monobromination. Addition of bromine atoms to the triplet state reaction product has little effect on its properties, except on its electron affinity, in which monobromination can increase between 3.1 and 8.8 kcal mol⁻¹.