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

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.

Antidiabetic potential of flavonoids from Artemisia macrocephalla Jaquem in streptozotocin-induced diabetic rats: Pharmacological and biochemical approach.

Plants belongs to Asteraceae family are reported to be rich in major phytochemical including flavonoids and are documented to acquire antidiabetic response. Antidiabetic effects of salvigenin, eupatilin and cirsilineol were screened on in-vitro enzyme inhibition and in-vivo streptozotocin animal models. Administration of salvigenin, eupatilin and cirsilineol (7.5 and 15mg/kg) produced antidiabteic responses in streptozotocin model for diabetes. All natural flavonoids reduces the blood glucose level to a significant level (*P<0.05, **P<0.01, ***P<0.001, n=8) but promising results were observed in eupatilin at dose of 7.5mk/kg (364.12±4.3 to 128.41±4.2mg/dL, n=8) and at dose of 7.5mk/kg 363.65±4.8 to 126.14±5.1mg/dL, n=8). Administration of salvigenin, eupatilin and cirsilineol (7.5 and 15mg/kg) for 28 days showed a substantial fall (*P<0.05, **P<0.01, ***P<0.001, n=8) in total cholesterol, LDL and triglcerides (TGs) in comparison to diabetic model. The isolated flavonoids reduced considerably the serum ALP, SGPT and SGOT in rats intoxicated with streptozotocin. The results indicate that the flavonoids may be useful in the development of new antidiabetic drugs.