Degree: Doctor

Affiliation(s):

CIQUP

Bio

Carlos Fernandes graduated in Chemistry (2011) and finished his Master’s in chemistry in 2012 at the Faculty of Sciences University of Porto (FCUP) with a final classification of 18 (out of 20). After that, CF was awarded with 3 fellowships to work in 3 research groups (REQUIMTE – 2012, CIQUP and LEPABE – 2013). In 2014, CF was awarded for an international PhD fellowship by Foundation for Science and Technology (FCT). In 2018, CF was awarded with the European Doctorate title, and his PhD research was recognized by the prestigious Paul Ehrlich MedChem Network (http://www.pehrlichmedchem.eu/) as one of the best European PhD thesis in the Medicinal Chemistry field.

Afterwards, CF was awarded with a Post-doctoral fellowship (2018) and hired by FCUP as principal researcher of a project funded by FCT (2019). In 2020, CF was hired as a doctorate researcher in a pharmaceutic/cosmetic company (MitoTAG), where he was responsible for the production of antioxidant compounds. In 2021, he was awarded with a 6-year contract in the IV call of Scientific Employment Stimulus funded by FCT (2021.04016.CEECIND). From 2020 up to now, CF has been lecturing BSc and MSc classes within the curricular units at the FCUP and during the years of 2022 and 2023, he was invited by FCUP as assistant professor to give “Drug transport systems for intracellular delivery” classes. He is a member of the Researchers Committee of the Department of Chemistry and Biochemistry, FCUP (2023-now) and also an integrated member of the CIQUP-IMS (Chemistry Research Center-Institute of Molecular Sciences) research unit.

He was a guest editor of a special issues of Molecules and actively collaborates as a referee in several journals in the Medicinal Chemistry and Nanomedicine areas.

Projects
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Publications
Showing 5 latest publications. Total publications: 14
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1. The role of mitochondrial dysfunction and calcium dysregulation in 2C-I and 25I-NBOMe-induced neurotoxicity, Gil-Martins, E; Cagide, F; Borer, A; Barbosa, DJ; Fernandes, C Chavarria, D; Remiao, F; Borges, F; Silva, R in CHEMICO-BIOLOGICAL INTERACTIONS, 2025, ISSN: 0009-2797,  Volume: 411, 
Article,  Indexed in: crossref, scopus, wos  DOI: 10.1016/j.cbi.2025.111425 P-018-10M
Abstract New psychoactive substances (NPS) are designed to evade legal regulation while mimicking the effects of classic illicit drugs such as 3,4-methylenedioxymethamphetamine (MDMA). This category includes phenethylamine derivatives, such as the psychedelic 2C and NBOMe drugs. Given the lack of data regarding the toxicological profile of these substances, the goal of this study was to evaluate the neurotoxicity of 2C-I and 25I-NBOMe and explore their neurotoxic pathways. Lower EC50 values, in both NR uptake and MTT reduction assays in differentiated SH-SY5Y cells and primary rat cortical cultures, revealed that 25I-NBOMe is significantly more cytotoxic than 2C-I, likely due to its higher lipophilicity. Both drugs triggered severe mitochondrial dysfunction, characterized by decreased intracellular ATP levels and mitochondrial membrane depolarization, although no significant changes in intracellular ROS/RNS levels were observed. Additionally, 25I-NBOMe increased the intracellular Ca2* levels. Apoptosis was an observed mechanism of cell death for both drugs, as demonstrated by a significant increase in the number of cells undergoing early apoptosis (AnV+/PI-) and late apoptosis/necrosis (AnV+/PI+). However, only 2C-I induced autophagy and strongly triggered caspase-3 activation. This suggests that 2C-I induces caspase-3-dependent apoptosis, whereas 25I-NBOMe may also induce apoptosis through a caspase-3-independent pathway, possibly involving increased intracellular Ca2* levels and direct mitochondrial damage. These findings underscore the complex interplay between mitochondrial dysfunction, calcium dysregulation, and cell death pathways, highlighting the central role of mitochondria in the cytotoxicity of 2C-I and 25INBOMe.

2. Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment, Aguiar, B; Alfenim, AR; Machado, CS; Moreira, J; Pinto, M; Otero-Espinar, FJ; Borges, F; Fernandes, C in INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2025, ISSN: 1661-6596,  Volume: 26, 
Article,  Indexed in: crossref, scopus, wos  DOI: 10.3390/ijms26052146 P-018-C8V
Abstract Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 degrees C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.

3. Efficacy of Novel Quaternary Ammonium and Phosphonium Salts Differing in Cation Type and Alkyl Chain Length against Antibiotic-Resistant Staphylococcus aureus, Nunes, B; Cagide, F; Fernandes, C Borges, A Borges, F; Simoes, M in INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2024, ISSN: 1661-6596,  Volume: 25, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.3390/ijms25010504 P-00Z-SVS
Abstract Antibacterial resistance poses a critical public health threat, challenging the prevention and treatment of bacterial infections. The search for innovative antibacterial agents has spurred significant interest in quaternary heteronium salts (QHSs), such as quaternary ammonium and phosphonium compounds as potential candidates. In this study, a library of 49 structurally related QHSs was synthesized, varying the cation type and alkyl chain length. Their antibacterial activities against Staphylococcus aureus, including antibiotic-resistant strains, were evaluated by determining minimum inhibitory/bactericidal concentrations (MIC/MBC) <= 64 mu g/mL. Structure-activity relationship analyses highlighted alkyl-triphenylphosphonium and alkyl-methylimidazolium salts as the most effective against S. aureus CECT 976. The length of the alkyl side chain significantly influenced the antibacterial activity, with optimal chain lengths observed between C-10 and C-14. Dose-response relationships were assessed for selected QHSs, showing dose-dependent antibacterial activity following a non-linear pattern. Survival curves indicated effective eradication of S. aureus CECT 976 by QHSs at low concentrations, particularly compounds 1e, 3e, and 5e. Moreover, in vitro human cellular data indicated that compounds 2e, 4e, and 5e showed favourable safety profiles at concentrations <= 2 mu g/mL. These findings highlight the potential of these QHSs as effective agents against susceptible and resistant bacterial strains, providing valuable insights for the rational design of bioactive QHSs.

4. Rescuing a Troubled Tolcapone with PEGylated PLGA Nanoparticles: Design, Characterization, and Hepatotoxicity Evaluation, Pinto, M Machado, CS; Barreiro, S; Otero-Espinar, FJ; Remiao, F; Borges, F Fernandes, C in ACS APPLIED MATERIALS & INTERFACES, 2024, ISSN: 1944-8244,  Volume: 16, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.1021/acsami.4c00614 P-010-B1R
Abstract Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor used as adjuvant therapy in Parkinson's disease. However, it has a highly hepatotoxic profile, as recognized by the U.S. Food and Drug Administration. As a possible solution, nanoscience brought us several tools in the development of new functional nanomaterials with tunable physicochemical properties, which can be part of a solution to solve several drawbacks, including drug's short half-life and toxicity. This work aims to use PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a stable carrier with lower hydrodynamic size and polydispersity to encapsulate tolcapone in order to overcome its therapeutic drawbacks. Using the nanoprecipitation method, tolcapone-loaded nanoparticles with a DLC% of 5.7% were obtained (EE% of 47.0%) and subjected to a lyophilization optimization process to obtain a final shelf-stable formulation. Six different cryoprotectants in concentrations up to 10% (w/v) were tested. A formulation of PLGA nanoparticles with 3% hydroxypropyl-beta-cyclodextrin (HP beta CD) as a cryoprotectant (PLGA-HP@Tolc), presenting sub-200 nm sizes and low polydispersity (PdI < 0.200) was selected. Cytotoxicity assays, namely, MTT and SRB, were used to study the metabolic activity and cell density of tolcapone and PLGA-HP@Tolc-treated cells. In both assays, a hepatocarcinoma cell line (HepG2) growing in glucose or glucose-free media (galactose-supplemented medium) was used. The results demonstrated that the treatment with the PLGA-HP@Tolc formulation led to a decrease in cytotoxicity in comparison to free tolcapone-treated cells in both media tested. Moreover, the elected formulation also counteracted ATP-depletion and excessive ROS production induced by tolcapone. The results suggest that HP beta CD might have a dual function in the formulation: cryoprotectant and anticytotoxic agent, protecting cells from tolcapone-induced damage. Using an in vitro COMT inhibition assay, the PLGA-HP@Tolc formulation demonstrated to inhibit COMT as efficiently as free tolcapone. Overall, the results suggest that tolcapone-loaded PLGA NPs could be an interesting alternative to free tolcapone, demonstrating the same in vitro efficacy in inhibiting COMT but with a safer cytotoxic profile.

5. Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives, Pinto, M Silva, TB; Sardao, VA; Simoes, R; Albuquerque, B; Oliveira, PJ; Valente, MJ; Remiao, F; Soares-da-Silva, P; Fernandes, C Borges, F in ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, 2024, ISSN: 2575-9108,  Volume: 7, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.1021/acsptsci.4c00124 P-010-DCZ
Abstract Nitrocatechols are the standard pharmacophore to develop potent tight-binding inhibitors of catechol O-methyltransferase (COMT), which can be used as coadjuvant drugs to manage Parkinson's disease. Tolcapone is the most potent drug of this class, but it has raised safety concerns due to its potential to induce liver damage. Tolcapone-induced hepatotoxicity has been attributed to the nitrocatechol moiety; however, other nitrocatechol-based COMT inhibitors, such as entacapone, are safe and do not damage the liver. There is a knowledge gap concerning which mechanisms and chemical properties govern the toxicity of nitrocatechol-based COMT inhibitors. Using a vast array of cell-based assays, we found that tolcapone-induced toxicity is caused by direct interference with mitochondria that does not depend on bioactivation by P450. Our findings also suggest that (a) lipophilicity is a key property in the toxic potential of nitrocatechols; (b) the presence of a carbonyl group directly attached to the nitrocatechol ring seems to increase the reactivity of the molecule, and (c) the presence of cyano moiety in double bond stabilizes the reactivity decreasing the cytotoxicity. Altogether, the fine balance between lipophilicity and the chemical nature of the C1 substituents of the nitrocatechol ring may explain the difference in the toxicological behavior observed between tolcapone and entacapone.