Neurotoxicity, Neuroprotection, In Vitro MAOA/MAOB Inhibitory Activity Assessment, Molecular Docking, and Permeability Assay Studies of Newly Synthesized Hydrazones Containing a Pyrrole Ring.

Neurodegenerative diseases such as Parkinson's and Alzheimer's continue to be some of the most significant challenges in modern medicine. Recent research related to the molecular mechanisms of parkinsonism has opened up new approaches to antiparkinsonian therapy. In response to this, we present the evaluation of the potential neuroprotective and MAOA/MAOB inhibitory effects of newly synthesized hydrazones, containing a pyrrole moiety in the carboxyl fragment of the structure. The substances were studied on different brain subcellular fractions, including rat brain synaptosomes, mitochondria, and microsomes. The single application of 50 µM of each compound to the subcellular fractions showed that all substances exhibit a weak neurotoxic effect, with , , and being the least neurotoxic representatives. The corresponding neuroprotective and antioxidant effects were also evaluated in different injury models on subcellular fractions, single out , , and as the most prominent derivatives. A 1 µM concentration of each molecule from the series was also studied for potential MAOA/MAOB inhibitory effects. The results revealed a lack of MAOA activity for all evaluated structures and the appearance of MAOB effects, with compounds , , and showing effects similar to those of selegiline. The best MAOB selectivity index (>204) was determined for and , distinguishing these two representatives as the most promising molecules for further studies as potential selective MAOB inhibitors. The performed molecular docking simulations defined the appearance of selective MAOB inhibitory effects based on the interaction of the tested molecules with Tyr398, which is one of the components of the aromatic cage of MAOB and participated in π-π stabilization with the aromatic pyrrole ring. The preliminary PAMPA testing indicated that in relation to the blood-brain barrier (BBB) permeability, the tested pyrrole-based hydrazones may be considered as high permeable, except for and , which were established to be permeable in the medium range with -logP of 5.268 and 5.714, respectively, compared to the applied references.