Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs

Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors

The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (<i>h</i>MAO-A and <i>h</i>MAO-B). The structure–activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were <i>N</i>-(3′-chlorophenyl)-4-oxo-4<i>H</i>-chromene-3-carboxamide (<b>20</b>) (IC₅₀ = 403 pM) and <i>N</i>-(3′,4′-dimethylphenyl)-4-oxo-4<i>H</i>-chromene-3-carboxamide (<b>27</b>) (IC₅₀ = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme–inhibitor interactions and a rationale for the observed selectivity and potency. Compound <b>27</b> stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood–brain barrier permeability, thus being a valid candidate for subsequent animal studies

Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks

Although the lipophilic triphenylphosphonium (TPP+) cation is widely used to target antioxidants to mitochondria, TPP+-based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2) cells, decreasing intracellular adenosine triphosphate (ATP) levels, leading to mitochondrial membrane depolarization and reduced mitochondrial mass after 24 h. We surpassed this concern using nitrogen-derived cationic carriers (Mito.PICO, Mito.ISOQ, and Mito.IMIDZ). As opposed to Mito.TPP, these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells up to 50 μM and after 24 h of incubation. All of the cationic derivatives accumulated inside the mitochondrial matrix and acted as neuroprotective agents against iron(III), hydrogen peroxide, and tert-butyl hydroperoxide insults. The overall data showed that nitrogen-based cationic carriers can modulate the biological performance of mitochondria-directed antioxidants and are an alternative to the TPP cation

Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks

Although the lipophilic triphenylphosphonium (TPP+) cation is widely used to target antioxidants to mitochondria, TPP+-based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2) cells, decreasing intracellular adenosine triphosphate (ATP) levels, leading to mitochondrial membrane depolarization and reduced mitochondrial mass after 24 h. We surpassed this concern using nitrogen-derived cationic carriers (Mito.PICO, Mito.ISOQ, and Mito.IMIDZ). As opposed to Mito.TPP, these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells up to 50 μM and after 24 h of incubation. All of the cationic derivatives accumulated inside the mitochondrial matrix and acted as neuroprotective agents against iron(III), hydrogen peroxide, and tert-butyl hydroperoxide insults. The overall data showed that nitrogen-based cationic carriers can modulate the biological performance of mitochondria-directed antioxidants and are an alternative to the TPP cation