Alzheimer’s disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aβ) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it is urgent to explore all the opportunities available to combat this illness. Among them, the discovery of new heterocyclic scaffolds binding different receptors involved in AD should offer structural diversity and new therapeutic solutions. In this context, this work describes new triazolopyridopyrimidine easily prepared in good yields showing anticholinesterase inhibition and strong antioxidant power, particularly the most balanced: 6-amino-5-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1′,5′:1,6] pyrido[2,3-d]pyrimidine-4-carbonitrile(3c) with IC50 equal to 1.32 μM against AChE and oxygen radical absorbance capacity (ORAC) value equal to 4.01 Trolox equivalents (TE); thus representing a new and very promising hit-triazolopyridopyrimidine for AD therapy.

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Herein we report the reaction of 2‐(5‐aryl‐4H‐1,2,4‐triazol‐3‐yl)acetonitriles 1 a,b with appropriate Michael acceptors 2–4 to give novel [1,2,4]triazolo[1,5‐a]pyridines 5–8, whose antioxidant properties have been investigated. A plausible reaction mechanism, supported by DFT calculations, has been proposed to explain the total observed regioselective formation of [1,2,4]triazolo[1,5‐a]pyridine derivatives depending on the type of substituents on the Michael acceptor. Triazoles are well‐known agents exhibiting antimicrobial,[1] antitumor,[2] anti‐inflammatory,[3] antihypertensive,[4] anticonvulsant,[5] antiviral[6] and analgesic[7] biological activities. On the other hand, pyridine is the key core of heterocyclic derivatives showing a variety of pharmacological properties.[8–12] Several studies have revealed that a combination of different bioactive molecules, having different mechanisms of action, is a current strategy affording useful therapeutic agents.[13] This is the case of the [1,2,4]triazolo[1,5‐a] pyridine heterocyclic motif,[14] present in a number of bioactive compounds,[15] and largely used in materials chemistry.[16] Accordingly, diverse synthetic methods have been described for the synthesis of differently substituted [1,2,4]triazolo[1,5‐a]pyridines.[17–24] Our group has recently reported the ultrasound‐promoted facile and convenient “one‐pot” procedure for the synthesis of novel [1,2,4]triazolo[1,5‐a]pyridines in short reaction times and high yields, based on the reaction of 2‐(5‐aryl‐4H‐1,2,4‐triazol‐3‐yl)acetonitriles, malononitrile (or ethyl cyanoacetate) and aromatic aldehydes, in absolute ethanol, in the presence of IRA‐400.[25]

Herein we report the synthesis of (E)‐3‐aryl‐2‐(5‐aryl‐4H‐1,2,4‐triazol‐3‐yl)acrylonitriles 3 a–k whose fluorescence properties have been investigated for the first time. A plausible reaction mechanism has been proposed to explain the total observed stereospecific formation of the E‐isomers of compounds 3 a–k. The fluorescence analysis of compounds 3a‐f has revealed relatively low values of the fluorescence emission quantum yields in a range of ∼1 to 10 %, depending in the nature of the substituents.