Design, molecular docking and synthesis of pyrazino[1,2-a] indole derivatives via tandem Ugi-4CR/intramolecular cyclization as potential urease inhibitor agents

Abstract

In the present paper, a novel series of pyrazino[1,2-a]indole derivatives 6(a-k) were synthesized by Ugi four-component reaction (U-4CR), followed by an intramolecular cyclization of the Ugi products in the presence of DBU as a catalyst, Subsequently, we assessed their inhibitory activity against Jack bean's urease enzyme in vitro, and some of these derivatives exhibited potent urease inhibition. Notably, compounds 6e (IC50 = 3.55 ± 1.11 µM), 6g (IC50 = 3.18 ± 0.42 µM), and 6j (IC50 = 3.80 ± 0.65 µM) demonstrated urease inhibitory effects comparable to the reference compound, thiourea. Additionally, our docking study corroborated these experimental results, confirming that the pyrazino[1,2-a]indole derivatives (6a-k) effectively interacted with the urease enzyme's active site, exhibiting proper binding energies and modes.