Design, Synthesis, and Neuroprotective Effects of a Series of Pyrazolines against 6-Hydroxydopamine-Induced Oxidative Stress

Abstract

Parkinson’s disease (PD) is a chronic, progressive, and age-related neurodegenerative disorder characterized by the loss of midbrain dopaminergic neurons caused by the accumulation of free radicals and oxidative stress. Based on the neuroprotective properties of 2-pyrazoline derivatives, in the current work, 1-(phenyl/4-substituted phenyl)-3-(2-furanyl/thienyl)-5-aryl-2-pyrazolines (3a–i, 4a–i) were synthesized via the cyclization of the chalcones (1, 2) with suitable phenylhydrazine hydrochloride derivatives. All these compounds were investigated for their neuroprotective effects using an in vitro 6-hydroxydopamine (6-OHDA)-induced neurotoxicity model of PD in the rat pheochromocytoma (PC-12) Adh cell line. In addition, some different pharmacokinetic parameters of all compounds were in silico predicted by the QikProp module of Schrödinger’s Maestro molecular modeling package. 4-Methylsulfonylphenyl substituted compounds 3h (20%) and 4h (23%) were determined as the most promising neuroprotective agents related to their inductive roles in cell viability when compared with the 6-OHDA-positive control group (43% and 42%, respectively). Moreover, in silico pharmacokinetic results indicated that all compounds were within the acceptable range intended for human use. According to both in vitro and in silico studies, compounds 3h and 4h draw attention as potential orally bioavailable therapeutic drug candidates against neurodegeneration in PD.

Isobornylchalcones as Scaffold for the Synthesis of Diarylpyrazolines with Antioxidant Activity

“…Amongst these heterocyclic ring-containing scaffolds, pyrazolines as a class of electron-rich nitrogen heterocyclic compounds play an important role due to their extensive use as pharmacophore and synthon. Interestingly, 2-pyrazoline derivatives synthesized from chalcones have shown a variety of biological activities, such as antibacterial, antitumor, antifungal, anti-inflammatory, antioxidant, and antimalarial [18][19][20][21][22][23][24]. Previously it has been reported that 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-(multi-substituted-4-hydroxyphenyl)-2-pyrazoli nes showed significant human LDL-antioxidant activities (Figure 1) [25].…”

Structure-activity relationship with pyrazoline-based aromatic sulfamates as carbonic anhydrase isoforms I, II, IX and XII inhibitors: Synthesis and biological evaluation

“…Pyrazoline ring is a privileged structure in medicinal chemistry because of its wide spectrum of pharmacological activities. A number of pyrazoline derivatives have been reported for their antibacterial [1], antimalarial [2,3], anti-inflammatory [4], MAO inhibitory [5,6], antioxidant [7,8], neuroprotective [9], antidepressant [10] and anticancer activity [11][12][13][14][15][16][17][18]. Furthermore, several series of pyrazoline derivatives displayed carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity [19][20][21][22][23][24][25].…”

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy

“…Appropriate nHBD (0 to 4) and nHBA (3.7 to 7.2) values of all compounds within the limits (0 to 6 and 2 to 20, respectively) also supported the outcomes of the molecular docking study. Solvent accessible surface area (SASA) is defined as the accessibility of the residue to the solvent; either it is between lipid or water accessibility and it is also essential to BBB permeability [42]. The SASA values of all compounds were in an optimal range of the specified values (300 to 1000).…”