In recent years, a great deal of attention has been paid to natural compounds due to their many biological effects. Polyphenols are a class of plant derivatives that have been widely investigated for preventing and treating many oxidative stress-related pathological conditions, such as neurodegenerative and cardiovascular diseases, cancer, diabetes mellitus and inflammation. Among these polyphenols, resveratrol (RSV) has attracted considerable interest owing to its high antioxidant and free radical scavenging activities. However, the poor water solubility and rapid metabolism of RSV lead to low bioavailability, thus limiting its clinical efficacy. After discussing the main biochemical mechanisms involved in RSV biological activities, this review will focus on the strategies attempted to improve RSV effectiveness, both for systemic and for topical administration. In particular, technological approaches involving RSV incorporation into different delivery systems such as liposomes, polymeric and lipid nanoparticles, microemulsions and cyclodextrins will be illustrated, highlighting their potential clinical applications. In addition, chemical modifications of this antioxidant aimed at improving its physicochemical properties will be described along with the results of in vitro and in vivo studies.

A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT 1A and 5-HT 2A serotonergic, alpha 1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT 1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT 1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT 1A receptor was used to explain the influence of spacer length on ligands affinity.

Since their discovery as distinct receptor proteins, the specific physiopathological role of sigma receptors (σRs) has been deeply investigated. It has been reported that these proteins, classified into two subtypes indicated as σ 1 and σ 2 , might play a pivotal role in cancer growth, cell proliferation, and tumor aggressiveness. As a result, the development of selective σR ligands with potential antitumor properties attracted significant attention as an emerging theme in cancer research. This perspective deals with the recent advances of σR ligands as novel cytotoxic agents, covering articles published between 2010 and 2020. An up-to-date description of the medicinal chemistry of selective σ 1 R and σ 2 R ligands with antiproliferative and cytotoxic activities has been provided, including major pharmacophore models and comprehensive structure–activity relationships for each main class of σR ligands.

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In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.

The aim of this review is to highlight the advances in the field of heme oxygenase-1 (HO-1) inhibitors over the past years, particularly from a medicinal chemistry point of view; progresses made in the field strongly helped to clarify physiological roles of the heme oxygenase (HO) system. HO is a family of ubiquitously expressed enzymes which regulate the regiospecific catabolism of heme leading to the formation of equimolar amounts of carbon monoxide (CO), ferrous iron (Fe⁺⁺), and biliverdin. HO exists in two distinct, catalytically active isoforms: HO-1 and HO-2. HO-1 is an inducible 32-kDa protein, while HO-2 is a constitutively synthesized 36-kDa protein and generally is unresponsive to any of the inducers of HO-1. A third isoform, HO-3, is still an elusive protein. The HO system, along with its catabolism products, is involved in a variety of crucial physiological functions, including cytoprotection, inflammation, anti-oxidative effects, apoptosis, neuro-modulation, immune-modulation, angiogenesis, and vascular regulation. The use of selective HO inhibitors is a very important tool to clarify the role of the HO system and the mechanisms underlying its physiological effects and pathological involvement; due to the inducible nature of HO-1, selective inhibition of HO-1 isoform is generally preferable. Notably, HO-1 inhibitors may be also beneficial in therapeutic applications and have been mainly studied for treatment of hyperbilirubinemia and certain types of cancer. Historically, the first molecules used as non selective HO-1 inhibitors were metalloporphyrins (Mps). The subsequent development of the imidazole-dioxolane derivatives afforded the first generation of non-porphyrin based, isozyme selective HO-1 inhibitors.

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