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α-Lipoic acid is a sulfur-containing nutrient endowed with pleiotropic actions and a safe biological profile selected to replace the unsaturated alkyl acid of capsaicin with the aim of obtaining lipoic amides potentially active as a TRPV1 ligand and with significant antioxidant properties. Thus, nine compounds were obtained in good yields following a simple synthetic procedure and tested for their functional TRPV1 activity and radical-scavenger activity. The safe biological profile together with the protective effect against hypoxia damage as well as the in vitro antioxidant properties were also evaluated. Although less potent than capsaicin, almost all lipoic amides were found to be TRPV1 agonists and, specifically, compound 4, the lipoic analogue of capsaicin, proved to be the best ligand in terms of efficacy and potency. EPR experiments and in vitro biological assays suggested the potential protective role against oxidative stress of the tested compounds and their safe biological profile. Compounds 4, 5 and 9 significantly ameliorated the mitochondrial membrane potential caused by hypoxia condition and decreased F2-isoprostanes, known markers of oxidative stress. Thus, the experimental results encourage further investigation of the therapeutic potential of these lipoic amides. [ABSTRACT FROM AUTHOR]

[Display omitted] • Artificial intelligence accelerates the drug discovery. • O -substituted morin derivatives show interesting vasorelaxant activity. • Ca V 1.2 channels seem to be the main targets involved in the vasorelaxant activity. • The pentamethyl derivative 5a reveals a multi-target activity. Morin is a vasorelaxant flavonoid, whose activity is ascribable to Ca V 1.2 channel blockade that, however, is weak as compared to that of clinically used therapeutic agents. A conventional strategy to circumvent this drawback is to synthesize new derivatives differently decorated and, in this context, morin-derivatives able to interact with Ca V 1.2 channels were found by employing the potential of PLATO in target fishing and reverse screening. Three different derivatives (5a - c) were selected as promising tools, synthesized, and investigated in in vitro functional studies using rat aorta rings and rat tail artery myocytes. 5a - c were found more effective vasorelaxant agents than the naturally occurring parent compound and antagonized both electro- and pharmaco-mechanical coupling in an endothelium-independent manner. 5a , the series' most potent, reduced also Ca2+ mobilization from intracellular store sites. Furthermore, 5a ≈ 5c > 5b inhibited Ba2+ current through Ca V 1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of K Ca 1.1 channel currents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design, synthesis and evaluation of a new library based on 3-amino-1,2-propanediol skeleton. • Nitrogen was functionalized as phenyl urea and hydroxyl groups as substituted benzoyl esters or triazoles. • Seven compounds showed high anti-HAdV activity (IC 50 2.47–5.75 µM) and low cytotoxicity. • Predicted mechanisms of action involve different steps on the HAdV replicative cycle. Nowadays there is not an effective drug for the treatment of infections caused by human adenovirus (HAdV) which supposes a clinical challenge, especially for paediatric and immunosuppressed patients. Here, we describe the design, synthesis and biological evaluation as anti-adenovirus agents of a new library (57 compounds) of diester, monoester and triazole derivatives based on 3-amino-1,2-propanediol skeleton. Seven compounds (17 , 20 , 26 , 34 , 44 , 60 and 66) were selected based on their high anti-HAdV activity at low micromolar concentration (IC 50 from 2.47 to 5.75 µM) and low cytotoxicity (CC 50 from 28.70 to >200 µM). In addition, our mechanistic assays revealed that compounds 20 and 44 might be targeting specifically the HAdV DNA replication process, and compound 66 would be targeting HAdV E1A mRNA transcription. For compounds 17 , 20 , 34 and 60 , the mechanism of action seems to be associated with later steps after HAdV DNA replication. [ABSTRACT FROM AUTHOR]