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Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy as they are able to boost the immune response and to work in synergy with other immunotherapeutic agents. Despite the fact that no IDO1 inhibitor has been approved so far, recent studies have shed light on the additional roles that IDO1 mediates beyond its catalytic activity, conferring new life to the field. Here we present a novel class of compounds originated from a structure-based virtual screening made on IDO1 active site. The starting hit compound is a novel chemotype based on a [1,2,4]triazolo[4,3-a]pyridine scaffold, so far underexploited among the heme binding moieties. Thanks to the rational and in silico-guided design of analogues, an improvement of the potency to sub-micromolar levels has been achieved, with excellent in vitro metabolic stability and exquisite selectivity with respect to other heme-containing enzymes.

Activation of the phosphoinositide 3‐kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on‐target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life‐threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so‐far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan‐PI3K inhibitor.

The estrogen receptors, responsible for the effects of this hormone, are known to be able to recognize nonsteroidogenic molecules, and this has led to the development of molecules with therapeutic potential. The phenomenon of nonsteroidal ligands of the estrogen receptors is also thought to play a major role in food and environmental sciences, with the winepolyphenol resveratrol and the insecticide DDT thought to act as estrogenic substances. It is therefore evident that it is of great interest to develop specific nonsteroidal substances that interfere with the estrogen receptors in a receptor-specific and/or tissue-specific manner and that display agonistic, antagonistic, or partial agonistic properties. Indeed, a number of strategies have been or could be employed to generate new structures, namely the screening of existing chemical libraries, the screening of natural compound libraries, novel modifications of known compounds with estrogenic potential, or the de novo generation of chemical libraries using rapid synthetic methods. Click chemistry is an increasingly common method for rapid synthesis of novel biologically active compounds. This term, coined by Barry K. Sharpless, now refers to reactions yielding the product in high yield without the need for further purification, without generating offensive byproducts, and operating in a benign solvent, usually water. In this way, it is possible to generate a plethora of new compounds reliably and thereby accelerate the process of drug discovery. Briefly, the paradigmatic “click” reaction is the [3+2] cycloaddition between an azide and an alkyne in the presence of copper (I) salts which generate the 1,4 disubstituted 1H-1,2,3-triazole ring in excellent yield. Three distinct observations have drawn our attention to the possibility of applying click chemistry to the synthesis of ER ligands: 1) reports that a pyrazole core can be used to build compounds that are ER ligands, 2) the successful bioisosteric replacement of pyrazole with a triazole in fibronil, an insecticide acting as a GABA receptor antagonist, and 3) our report that several resveratrol analogues synthesized by click chemistry retain estrogen-like activity. We have therefore used the archetypical [3+2] azide-alkyne cycloaddition to link two phenol rings, bearing the hydroxyl moieties in different positions, with a distance comparable to estradiol or diethylstilbestrol. Azides (1–3, Figure 1) were obtained by reacting commercially available amine phenols, via diazonium salt, with sodium azide. The desired ethynyl phenols (4–6, Figure 1) were ob