Hydantoin based dual inhibitors of ALR2 and PARP-1: Design, synthesis, in-vitro and in-vivo evaluation

Abstract

Diabetic nephropathy is one of the most dreadful diabetic complications (DCs). The polyol pathway and unified mechanism are two important pathways implicated in the progression of DCs. In this regard, targeting the key enzymes i.e., aldose reductase (ALR2) and poly (ADP-ribose) polymerase-1 (PARP-1), of these pathways can be a relevant strategy. Thus, in this study, the pharmacophoric requirements necessary for the dual inhibition of these two enzymes i.e., ALR2 and PARP-1 were identified and consequently, some hydantoin based molecules were designed. The designed molecules were subjected to structure-based molecular modelling analysis including molecular docking analysis and molecular dynamic simulations. The promising molecules were duly synthesized and examined for their ALR2 and PARP-1 dual inhibitory activities and selectivity over aldehyde reductase (ALR1) using in vitro enzymatic assays. Based on the results of in silico analysis and in vitro assays, the best three molecules were evaluated in vivo for their nephroprotective effect and antioxidant potential in the high-fat diet-streptozotocin induced diabetic rat model. The results showed that the compounds FM6B, FM7B and FM9B were having low micromolar inhibitory potential against ALR2 (IC₅₀; 1.02, 1.14 and 1.08 μM, respectively) and PARP-1 (IC₅₀; 0.95, 0.81 and 1.42 μM, respectively) with selectivity over ALR1 (selectivity index; 43.63, 37.03 and 45.14, respectively).

Keywords: ALR2 inhibitors; Dual inhibitors; PARP-1 inhibitor.