Comparative in-vitro anti-inflammatory, anticholinesterase and antidiabetic evaluation: computational and kinetic assessment of succinimides cyano-acetate derivatives

Aini Pervaiz; Muhammad Saeed Jan; Syed Muhammad Hassan Shah; Ali Khan; Rehman Zafar; Bushra Ansari; Muhammad Shahid; Fida Hussain; Mohammad Ijaz Khan; Anwar Zeb; Syed Muhammad Mukarram Shah

doi:10.1080/07391102.2022.2069862

Comparative in-vitro anti-inflammatory, anticholinesterase and antidiabetic evaluation: computational and kinetic assessment of succinimides cyano-acetate derivatives

J Biomol Struct Dyn. 2022 May 4:1-14. doi: 10.1080/07391102.2022.2069862. Online ahead of print.

Affiliations

¹ Department of Pharmacy, University of Swabi, Swabi, KP, Pakistan.
² School of Pharmacy, University of Nottingham, Nottingham, UK.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
⁴ Department of Pharmacy, Abdul Wali Khan University, Mardan, KP, Pakistan.
⁵ Department of Pharmacy, Institute of Integrative Biosciences, CECOS University of IT and Emerging Sciences, Peshawar, KP, Pakistan.

PMID: 35507043
DOI: 10.1080/07391102.2022.2069862

Abstract

This research was planned to synthesize cyano-acetate derivatives of succinimide and evaluate its comparative biological efficacy as anti-inflammatory, anti-cholinesterase and anti-diabetic, which was further validated by molecular docking studies. The three cyano-acetate derivatives of succinimide including compound 23 Methyl 2-cyano-2-(2,5-dioxopyrrolidin-3-yl)acetate, compound 31 Methyl 2-cyano-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)acetate and compound 44 Methyl 2-cyano-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl) acetate were synthesized. The mentioned compounds were checked for in vitro anti-inflammatory, anti-cholinesterase and anti-diabetic (α-amylase inhibition) activity. To validate the in vitro results, computational studies were carried out using molecular operating environment to analyse the BE, i.e. binding energies of all synthesized compounds against the respective enzymes. The Compounds 23, 31, 44 exhibited anti-inflammatory via inhibiting COX-2 (IC₅₀ value of 204.08, 68.60 and 50.93 µM, respectively), COX-1 (IC₅₀ value of 287, 185, and 143 µM, respectively) and 5-LOX (IC₅₀ value of 138, 50.76 and 20, 87 µM respectively)_. They exhibited choline-mimetic potential, such as compound 23, 31 and 44 inhibited AChE enzyme (IC₅₀ value of 240, 174, and 134 µM, respectively) and BChE enzyme (IC₅₀ value of 203, 134 and 97 µM, respectively). The Compounds 23, 31, 44 exhibited anti-diabetic effect via inhibiting α-amylase enzyme (IC₅₀ values of 250, 106 and 60 µM, respectively). Molecular docking studies revealed that the synthesized compounds have good binding affinity in the binding pockets of AChE, BChE, COX-2, 5-LOX and α-amylase enzyme and showed high binding energies. The synthesized succinimide derivatives, i.e. compound 23, 31, 44 showed marked inhibitory activities against cyclooxygenase, lipoxygenase, α-amylase and cholinesterase enzymes. Among these three, compound 44 and 31 showed strong anti-inflammatory and anti-diabetic activity while they displayed moderate anti-cholinesterase activity supported by molecular docking results.Communicated by Ramaswamy H. Sarma.

Keywords: AChE; BChE; Succinimides; computational studies; inflammation; α-amylase.