Design, microwave-assisted synthesis, biological evaluation, molecular docking and ADME studies of pyrrole-based hydrazide-hydrazones as potential antioxidant agents

Abstract

In this study, one novel N-pyrrolyl carboxylic acid (3), the corresponding N-pyrrolyl hydrazide (5), and four new hydrazide-hydrazones (5a-d) bearing electron donating moieties were designed, synthesized, and fully elucidated by 1H NMR, FT-IR, and HRMS. The hydrazide-hydrazones were produced in five steps, which were optimized by applying microwave heating. The microwave-assisted synthesis significantly decreased the reaction times and increased the yields of the title molecules. In addition, all novel compounds were assessed for their radical scavenging properties by employing DPPH and ABTS assays. The most promising agent was obtained after condensation of the title hydrazide (5) with a 3,5-dimetoxy-4-hydroxybenzaldehyde (5d). The latter compound showed better antioxidant properties than Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and could serve as a prominent lead structure for future optimization as an antioxidant agent. A possible binding conformation of 5d in the active site of NADPH oxidase was also identified through molecular docking simulations. Analysis of the major interactions showed the importance of the hydroxyl moiety for the antioxidant activity. Finally, the virtual calculations of the ADME properties of the synthesized compounds displayed good drug-like properties. Overall, an optimized synthetic protocol through MW irradiation was employed. The newly synthesized ethyl (E)-5-(4-bromophenyl)-1-(1-(2-(4-hydroxy-3,5-dimethoxybenzylidene)hydrazineyl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate (5d) was found to possess the most prominent radical-scavenging capacity, which identifies it as a promising lead compound for the development of novel antioxidants.

Synthesis, Biological Evaluation, Molecular Docking and ADME Studies of Novel Pyrrole-Based Schiff Bases as Dual Acting MAO/AChE Inhibitors

“…Values of effective permeability coefficient Pe, presented in terms of -logPe, are given in Table 4 for the evaluated compounds. * 5a and 5d were reported in our recent work [28]. 1 ACD Labs, v.9.08; 2 SwissADME [30].…”

“…to produce the tryptophan-based N-pyrrolyl carboxylic acid (3) through the MW-assisted approach. After a work-up, an esterification of 3 with excess of thionyl chloride and ethanol was carried out [28].…”

“…Since good blood-brain penetration is strongly desirable for CNS active compounds, the PAMPA-BBB assay was used to investigate the passive diffusion of 5j across the bloodbrain barrier. Two earlier synthesized hydrazone congeners (5a and 5d) [28] were also tested to probe the effectiveness of the chosen structural modification on the BBB permeability.…”

“…of tryptophan were dissolved in 10 mL of glacial acetic acid. The mixture was heated by a microwave reactor for 55 min as per synthetic conditions reported by our research group in Mateev et al [28].…”

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

“…Moreover, the hydrazide–hydrazones condensed with 4-dimethylamino benzaldehyde and 7a and 8a demonstrated moderate ABTS scavenging capacities of 22% and 48%, respectively. The drastic differences between the two assays could be related to the ability of the ABTS test to examine both hydrophobic and hydrophilic compounds, as well as to test bulky structures [ 30 ]. However, the application of the DPPH assay is still used by numerous research groups to produce significant and comparable antioxidant results [ 31 ].…”