Synthesis, DFT Study, and In Vitro Evaluation of Antioxidant Properties and Cytotoxic and Cytoprotective Effects of New Hydrazones on SH-SY5Y Neuroblastoma Cell Lines

Abstract

A series of ten new hydrazide–hydrazone derivatives bearing a pyrrole ring were synthesized and structurally elucidated through appropriate spectral characteristics. The target hydrazones were assessed for radical scavenging activity through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests, with ethyl 5-(4-bromophenyl)-1-(2-(2-(4-hydroxy-3,5-dimethoxybenzylidene)hydrazine-yl)-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (7d) and ethyl 5-(4-bromophenyl)-1-(3-(2-(4-hydroxy-3,5-dimethoxybenzylidene) hydra zine-yl)-3-oxopropyl)-2-methyl-1H-pyrrole-3-carboxylate (8d) highlighted as the best radical scavengers from the series. Additional density functional theory (DFT) studies have indicated that the best radical scavenging ligands in the newly synthesized molecules are stable, do not decompose into elements, are less polarizable, and with a hard nature. The energy of the highest occupied molecular orbital (HOMO) revealed that both compounds possess good electron donation capacities. Overall, 7d and 8d can readily scavenge free radicals in biological systems via the donation of hydrogen atoms and single electron transfer. The performed in vitro assessment of the compound’s protective activity on the H2O2-induced oxidative stress model on human neuroblastoma cell line SH-SY5Y determined 7d as the most perspective representative with the lowest cellular toxicity and the highest protection.

In Silico and Chromatographic Methods for Analysis of Biotransformation of Prospective Neuroprotective Pyrrole-Based Hydrazone in Isolated Rat Hepatocytes

“…experimental conditions allowing evaluation of these properties are a promising rejection of the least drug-like molecule prior to progression into the lead-discove in order to justify a drug discovery effort. Some of our preliminary experiments with compounds possessing a centra ring and a hydrazide-hydrazone fragment pointed our attention to their promisin in neurodegeneration therapy research [12][13][14]. This determined as most scien interesting the structure of compound 11b, presented in Figure 1 and show multiple points of biotransformation related to molecules based on an Nhydrazide-hydrazone moiety.…”

Evaluation of the inhibition performance of pyrrole derivatives against CYP450 isoforms

“…Therefore, an initial evaluation toward the CYP450 activity for each active molecule is required in the process of drug development (Manikandan et al 2018). The examined structures were initially synthesized by Tzankova et al 2023. The series MI_a-e and MII_a-e were studied for possible inhibitory effects on some isoforms of Cytochrome P450 -CY-P1A2; CYP2D6, which revealed genetic polymorphism; and CYP3A4, which metabolized over 60 % of the drugs on the market.…”

“…In the current study, the initial compounds were previously synthesized and evaluated for their DPPH, ABTS and MAO activities (Tzankova et al 2023). The general structure of the pyrrole-based compounds is given in Fig.…”