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

a plethora of studies have demonstrated the pathophysiological roles played byparaxonase 2 (PON2) in oxidative stress control, inhibition of apoptosis, infections, andthe progression of various types of malignancies. the continuous interest in PON2 hasnot gone hand in hand with the development of its inhibitors. indeed, only oneinhibitor for PON2, namely tQ416, is known, although neither its preparation nor asystematic structure-activity relationship analysis has been so far reported. herein, weoutline the first study aimed at the definition of structure-activity relationships of tQ416by the preparation of a small library of its analogues. successfully, we identified some[1,2,4]triazolo[4,3-a]quinoline derivatives more potent than tQ416 as PON2 inhibitors,and among them one endowed with an ic50 value in the nanomolar range. We testedthe parent tQ416 and its most effective congener 2 in cells showing their effectivenessand complex behaviour