Synthesis and biological (in vitro and in silico) screening of the 4-aryl-fused pyranopyrazole derivatives as enzyme (α-amylase, α-glucosidase, acetylcholinesterase & proteinase) inhibitors with anti-oxidant and cytotoxic activities

Abstract

The development of single compound targeting dual/multiple proteins is an efficient approach to avoid the combined drug administration. Herein, based on the modification of the previously reported lead compound A, we synthesized a new series of dihydropyranopyrazolone 7a-g and dihydro-pyrazolopyranopyrimidin-5-amine 8. The compounds were evaluated for their inhibitory in vitro enzymatic potential against α-amylase, α-glucosidase, acetylcholinesterase & proteinase. Also, the in vitro antioxidant evaluation and cytotoxicity assays were performed for all the final compounds. Interestingly, compound 8 possessed moderate activity against α-amylase (25.38 %) and α-glucosidase (29.37 %) compared to acarbose (75.43 % and 52.79 %, respectively). On the other hand, compound 7f showed a moderate anti-cholinesterase activity (46 ± 0.03 % inhibition) compared to donepezil used as a reference standard drug (67.28 ± 0.61 %). Compound 7d exhibited a moderate anti-arthritic activity (proteinase denaturation (42.21 ± 0.04 %), inhibition of proteinase (38.09 ± 0.04 %)) compared to diclofenac sodium used as a reference (47.93 ± 0.01, 44.96 ± 0.02, respectively). Compound 8 exhibited significant antioxidant activity in TAC assay and increased ABTS scavenging activity. Compounds 7 and derivative 8 exhibited reduced or no toxicity against the normal skin fibroblast thus confirming their safety at least in vitro. The in silico ADMET (absorption, distribution, metabolism, elimination and toxicity) profile of all final compounds implied their acceptability as oral bioavailable drug-likeness property. The anti-hyperglycemic activity was emphasized by the molecular docking of compound 8 showing good interactions in the acarbose binding site of both α-amylase and α-glucosidase enzymes. This study presents the dihydropyrazolopyranopyrimidin-5-amine derivative (compound 8) as a promising scaffold for future modification to design and develop derivatives with increased inhibitory effect against α-amylase and α-glucosidase for the management of type 2 diabetes mellitus (T2DM).