Fernando Cagide

Abstract The increasing interest in utilizing psychedelics for therapeutic purposes demands the development of tools capable of efficiently monitoring and accurately identifying these substances, thereby supporting medical interventions. 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) has gained significant popularity as one of the most widely used psychedelic compounds in non-medical settings. In this study, we aimed to create a material with selective recognition of 2C-B by synthesizing a series of molecularly imprinted polymers (MIP) using 2C-B as the template and varying ratios of methacrylic acid (MAA) as the functional monomer (1:2, 1:3, and 1:4). Both thermal and microwave-assisted polymerization processes were employed. The molar ratio between the template molecule (2C-B) and functional monomer (MAA) was 1:4, utilizing a microwave-assisted polymerization process. Isotherm studies revealed a Langmuir's maximum absorption capacity (Bmax) value of 115.6 mu mol center dot mg-1 and Kd values of 26.7 mu M for this material. An imprint factor of 4.2 was determined for this material, against the corresponding non-imprinted polymer. The good selectivity against 14 other new psychoactive substances highlighted the material's potential for applications requiring selective recognition. These findings can contribute to the development of tailored materials for the detection and analysis of 2C-B, supporting advancements in non-medical use monitoring and potential therapeutic models involving psychedelics.

Abstract Substituted phenethylamines including 2C (2,5-dimethoxyphenethylamines) and NBOMe (N-(2-methoxybenzyl)phenethylamines) drugs are potent psychoactive substances with little to no knowledge available on their toxicity. In the present in vitro study, we explored the mechanisms underlying the neurotoxicity of six substituted phenethylamines: 2C-T-2, 2C-T-4, 2C-T-7 and their corresponding NBOMes. These drugs were synthesized and chemically characterized, and their cytotoxicity (0-1000 mu M) was evaluated in differentiated SH-SY5Y cells and primary rat cortical cultures, by the NR uptake and MTT reduction assays. In differentiated SH-SY5Y cells, mitochondrial membrane potential, intracellular ATP and calcium levels, reactive oxygen species production, and intracellular total glutathione levels were also evaluated. All the tested drugs exhibited concentration-dependent cytotoxic effects towards differentiated SH-SY5Y cells and primary rat cortical cultures. The NBOMe drugs presented higher cytotoxicity than their counterparts, which correlates with the drug's lipophilicity. These cytotoxic effects were associated with mitochondrial dysfunction, evident through mitochondrial membrane depolarization and lowered intracellular ATP levels. Intracellular calcium imbalance was observed for 2C-T-7 and 25T7-NBOMe, implying a disrupted calcium regulation. Although reactive species levels remained unchanged, a reduction in intracellular total GSH content was observed. Overall, these findings contribute to a deeper understanding of these drugs, shedding light on the mechanisms underpinning their neurotoxicity.

Abstract A new library of non-nitrocatechol compounds (HetCAMs) was developed and their efficacy was compared to tolcapone, a standard COMT inhibitor for PD. Compound 9 emerged as the most potent inhibitor, showing selective inhibition of brain (IC50 = 24 nM) and liver (IC50 = 81 nM) MB-COMT over liver S-COMT (IC50 = 620 nM) isoforms. Although compound 9 presented higher IC50 values than tolcapone, it was more selective for brain MB-COMT than liver S-COMT. Unlike tolcapone, compound 9 is not a tight-binding inhibitor and is less cytotoxic to HepG2 and SK-N-SH cells. Additionally, compound 9 is predicted to cross the blood-brain barrier (BBB) by passive diffusion and chelate divalent metals like Fe(II) and Cu(II). The results demonstrate the potential of this rational drug design strategy for developing new CNS-active drug candidates, offering symptom relief via COMT inhibition that can provide a long-term, disease-modifying outcome (chelation of divalent metals) in PD.

Abstract Antimicrobial resistance (AMR) poses a global threat to human health, as exemplified by the devastating impact of ESKAPE pathogens, reducing treatment options, increasing disease burden, and elevating death rates due to treatment failure. This looming health threat has rekindled interest in the development of new antimicrobial therapies. In this study, a library of 49 structurally related quaternary heteronium salts (QHSs), such as quaternary ammonium and phosphonium compounds, was screened at a concentration of 32 mu g/mL against five ESKAPE pathogens (methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli), as well as the yeast -like fungus Candida albicans. The preliminary high -throughput screening (HTS) data revealed that QHSs with longer alkyl chain lengths (>= 12 carbons) exhibited broad-spectrum antimicrobial activity, with the C14-C16 homologous demonstrating the highest potency. The alkyl-triphenylphosphonium salts 1a-g exhibited the most significant antimicrobial activity among all tested compound series. The compounds identified as active in the initial HTS underwent confirmation assays to determine minimum inhibitory concentration (MIC) and cytotoxicity, following established protocols. Confirmatory assays identified 33 hits (MIC <= 16 mu g/mL), with 78% effective at very low concentrations (<= 0.25 mu g/mL). Seven hits showed safety profiles against HEK-293 cells and red blood cells at concentrations below 32 mu g/mL. Based on a comparative analysis of their potency against pathogenic microorganisms and cell toxicity, the salts of triphenylphosphonium and quinolinium with linear C8 hydrocarbon substituents (compounds 1b and 5b, respectively), and isoquinolinium, methylpyridinium and triethylammonium with linear C18 hydrocarbon substituents (compounds 3g, 4g, and 7g, respectively) have emerged as the most promising candidates for microbial growth control.