Quinoline- and Isoindoline-Integrated Polycyclic Compounds as Antioxidant, and Antidiabetic Agents Targeting the Dual Inhibition of α-Glycosidase and α-Amylase Enzymes

Abstract

Novel analogs of quinoline and isoindoline containing various heterocycles, such as tetrazole, triazole, pyrazole, and pyridine, were synthesized and characterized using FT-IR, NMR, and mass spectroscopy, and their antioxidant and antidiabetic activities were investigated. The previously synthesized compound 1 was utilized in conjugation with ketone-bearing tetrazole and isoindoline-1,3-dione to synthesize Schiff’s bases 2 and 3. Furthermore, hydrazide 1 was treated with aryledines to provide pyrazoles 4a–c. Compound 5 was obtained by treating 1 with potassium thiocyanate, which was then cyclized in a basic solution to afford triazole 6. On the other hand, pyridine derivatives 7a–d and 8a–d were synthesized using 2-(4-acetylphenyl)isoindoline-1,3-dione via a one-pot condensation reaction with aryl aldehydes and active methylene compounds. From the antioxidant and antidiabetic studies, compound 7d showed significant antioxidant activity with an EC50 = 0.65, 0.52, and 0.93 mM in the free radical scavenging assays (DPPH, ABTS, and superoxide anion radicals). It also displayed noteworthy inhibitory activity against both enzymes α-glycosidase (IC50: 0.07 mM) and α-amylase (0.21 mM) compared to acarbose (0.09 mM α-glycosidase and 0.25 mM for α-amylase), and higher than in the other compounds. During in silico assays, compound 7d exhibited favorable binding affinities towards both α-glycosidase (−10.9 kcal/mol) and α-amylase (−9.0 kcal/mol) compared to acarbose (−8.6 kcal/mol for α-glycosidase and −6.0 kcal/mol for α-amylase). The stability of 7d was demonstrated by molecular dynamics simulations and estimations of the binding free energy throughout the simulation session (100 ns).

In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic

“…Schiff base-bearing pyrazole skeleton 13 is an example of in vivo antiviral activity that exhibited protection, inhibition, and therapeutic effects against tobacco mosaic virus (TMV) [25] (Figure 2). As a result of the foregoing facts about the pharmaceutical and medicinal applications of Schiff bases, pyrazole scaffold, and Schiff bases bearing pyrazole scaffold as well as the importance of multi-target compounds in medicinal chemistry [26][27][28][29][30][31][32][33][34], also, based on the concept of the multi-target drug, and in continuation of our cooperation program [35], thus the goal of the current manuscript is to: During the last decade, Schiff bases bearing pyrazole scaffold have attracted growing interest in the pharmaceutical and medicinal fields because of their varied biological effectiveness [21]. Schiff base-bearing pyrazole derivative 10 was shown to be an effective antibacterial for Salmonella typhimurium and had anticancer properties against the HeLa cancer cell line [22].…”

“…21), respectively, in ethanol absolute [37] as represented in synthetic Scheme 2. (21), respectively, in ethanol absolute [37] as represented in synthetic Scheme 2.…”

“…Synthesis of 5-aminopyrazoles 19a, b. The target compounds, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b), were produced by the one-step reaction strategy, where 5-aminopyrazoles 19a, b were reacted with 2, 5-dimethoxybenzaldehyde (20) or 4-chloro-3-nitrobenzaldehyde(21), respectively, in ethanol absolute[37] as represented in synthetic Scheme 2.The 1 H NMR spectra of the target compounds, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b), were characterized by a single signal around at δ = 8.64-8.76 ppm for the -N=CH-proton. Also, they were characterized by three signals around at δ = 9.13-9.47, 9.79-10.18, and 11.74-13.01 ppm for the three NH protons which are exchangeable by D 2 O[37] (see Supplementary Material).…”