Synthesis and structure-activity relationship study of a library of 1-substituted [1,2,4]triazolo[4,3- <i>a</i> ]quinolines as valuable chemical probes for paraxonase-2 (PON2)

A plethora of studies have demonstrated the pathophysiological roles played by paraxonase 2 (PON2) in oxidative stress control, inhibition of apoptosis, infections, and the progression of various types of malignancies. The continuous interest in PON2 has not gone hand in hand with the development of its inhibitors. Indeed, only one inhibitor for PON2, namely TQ416, is known, although neither its preparation nor a systematic structure-activity relationship analysis has been so far reported. Herein, we outline the first study aimed at the definition of structure-activity relationships of TQ416 by the preparation of a small library of its analogues. Successfully, we identified some [1,2,4]triazolo[4,3-<i>a</i>]quinoline derivatives more potent than TQ416 as PON2 inhibitors, and among them one endowed with an IC₅₀ value in the nanomolar range. We tested the parent TQ416 and its most effective congener <b>2</b> in cells showing their effectiveness and complex behaviour.