Drug Design, Development and Therapy (Jun 2020)
Comparative Cholinesterase, α-Glucosidase Inhibitory, Antioxidant, Molecular Docking, and Kinetic Studies on Potent Succinimide Derivatives
Abstract
Ashfaq Ahmad,1,2 Farhat Ullah,2 Abdul Sadiq,2 Muhammad Ayaz,2 Muhammad Saeed Jan,2 Muhammad Shahid,2 Abdul Wadood,3 Fawad Mahmood,2 Umer Rashid,4 Riaz Ullah,5 Muhammad Umar Khayam Sahibzada,1 Ali S Alqahtani,5 Hafiz Majid Mahmood6 1Department of Pharmacy, Sarhad University of Science & Technology, Peshawar, KPK, Pakistan; 2Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000, KP, Pakistan; 3Department of Biochemistry, UCS, Shankar Abdul Wali Khan University, Mardan 23200, Pakistan; 4Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; 5Department of Pharmacognosy, Medicinal, Aromatic and Poisonous Plants Research Center (MAPRC), College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 6Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaCorrespondence: Abdul SadiqDepartment of Pharmacy,Faculty of Biological Sciences, University of Malakand, Chakdara 18000, KP, PakistanTel +92 301-2297-102Email [email protected] AhmadDepartment of Pharmacy, Sarhad University of Information Technology, Peshawar, PakistanEmail [email protected]: The current study was designed to synthesize derivatives of succinimide and compare their biological potency in anticholinesterase, alpha-glucosidase inhibition, and antioxidant assays.Methods: In this research, two succinimide derivatives including (S)-1-(2,5-dioxo-1-phenylpyrrolidin-3-yl) cyclohexanecarbaldehyde (Compound 1) and (R)-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-phenylpropanal (Compound 2) were synthesized using Michael addition. Both the compounds, ie, 1 and 2 were evaluated for in-vitro acetylcholinesterase (AChE), butyrylctcholinesterase (BChE), antioxidant, and α-glucosidase inhibitory potentials. Furthermore, molecular docking was performed using Molecular Operating Environment (MOE) to explore the binding mode of both the compounds against different enzymes. Lineweaver–Burk plots of enzyme inhibitions representing the reciprocal of initial enzyme velocity versus the reciprocal of substrate concentration in the presence of synthesized compounds and standard drugs were constructed using Michaelis–Menten kinetics.Results: In AChE inhibitory assay, compounds 1 and 2 exhibited IC50 of 343.45 and 422.98 μM, respectively, against AChE enzyme. Similarly, both the compounds showed IC50 of 276.86 and 357.91 μM, respectively, against BChE enzyme. Compounds 1 and 2 displayed IC50 of 157.71 and 471.79 μM against α-glucosidase enzyme, respectively. In a similar pattern, compound 1 exhibited to be more potent as compared to compound 2 in all the three antioxidant assays. Compound 1 exhibited IC50 values of 297.98, 332.94, and 825.92 μM against DPPH, ABTS, and H2O2 free radicals, respectively. Molecular docking showed a triple fold in the AChE and BChE activity for compound 1 compared with compound 2. The compound 1 revealed good interaction against both the AChE and BChE enzymes which revealed the high potency of this compound compared to compound 2.Conclusion: Both succinimide derivatives exhibited considerable inhibitory activities against cholinesterases and α-glucosidase enzymes. Of these two, compound 1 revealed to be more potent against all the in-vitro targets which was supported by molecular docking with the lowest binding energies. Moreover, compound 1 also proved to have antiradical properties.Keywords: succinimides, Alzheimer’s disease, cholinesterase, antioxidant, glucosidase, molecular docking
