Degree: Doctor

Affiliation(s):

CIQUP

Bio

Daniel Chavarria obtained his BSc (2012) and MSc (2014) in Biochemistry from the Faculty of Sciences, University of Porto (FCUP, Portugal), and a PhD in Pharmaceutical Sciences (2020) from the Faculty of Pharmacy, University of Porto (FFUP, Portugal). His PhD was labeled as European Doctorate, and his PhD Thesis received an award of excellence from the Paul Ehrlich MedChem Euro-PhD in Medicinal Chemistry. Part of his PhD was performed at USC (Spain) under the supervision of Prof. Eugenio Uriarte. As a post-doc researcher, he also performed 2 secondments: one at Mediagnost GmbH (Germany), funded by project H2020-MSCA-RISE-2016-734719 and supervised by Dr Andrea Normann, and the other at the University of Montpellier (France), funded by project MitoTARGET4AD (2022.15117.CBM) and supervised by Prof Tangui Maurice.

Daniel is currently a post-doc researcher at CIQUP-IMS. His research has been focused on the development of new chemical entities with potential therapeutic application towards neurodegenerative diseases, infectious diseases, and cancer. Daniel is/was the (co)-PI of two FCT-funded exploratory projects (project NOXIOUS, EXPL/BIA-BQM/0492/2021, 18 months, 50K; project DeFend, 2022.04633.PTDC, 18 months, 50K).

Some CV indicators: A) author of 29 peer-reviewed scientific publications (1st author; 12; corresponding author: 1); B) h-index = 12, citations = 539 (Scopus, July 2024); C) Oral communications: 18 (7 as 1st author), Poster communications: 48 (16 as 1st autor; 4 as last author); D) organization of 4 international science dissemination activities (scientific meetings, workshops) and 1 course in Medicinal Chemistry; E) integration of 14 research projects from national (FCT, NORTE2020) and European (FEDER) agencies; F) supervision/tutoring of national PhD (2), MSc (3) and BSc students (5), BSc/MSC fellows (2), mentoring of international Post-doc researchers (1), PhD (1) and MSc students (2).

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Publications
Showing 5 latest publications. Total publications: 12
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1. Drug Development for Alzheimer's and Parkinson's Disease: Where Do We Go Now?, Sequeira, L Benfeito, S; Fernandes, C; Lima, I; Peixoto, J; Alves, C; Machado, CS; Gaspar, A; Borges, F; Chavarria, D in PHARMACEUTICS, 2024, ISSN: 1999-4923,  Volume: 16, 
Review,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.3390/pharmaceutics16060708 P-010-NPQ
Abstract Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases' progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop new, disease-modifying drugs to treat AD and PD, describing as representative examples some advances in the development of drug candidates targeting oxidative stress and adenosine A2A receptors.
2. Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction, Carradori, S; Chavarria, D Provensi, G; Leri, M; Bucciantini, M; Carradori, S; Bonardi, A; Gratteri, P; Borges, F Nocentini, A; Supuran, CT in JOURNAL OF MEDICINAL CHEMISTRY, 2024, ISSN: 0022-2623,  Volume: 67, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.1021/acs.jmedchem.4c00045 P-010-2GH
Abstract 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-beta-peptide (A beta)-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 (K(I)s 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 A beta-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.
3. Mechanistic Insights into the Neurotoxicity of 2,5-Dimethoxyphenethylamines (2C) and Corresponding N-(2-methoxybenzyl)phenethylamine (NBOMe) Drugs, Gil-Martins, E; Cagide-Fagín, F; Martins, D; Borer, A; Barbosa, DJ; Fernandes, C; Chavarria, D Remiao, F; Borges, F Silva, R in JOURNAL OF XENOBIOTICS, 2024, ISSN: 2039-4705,  Volume: 14, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.3390/jox14020044 P-010-NPN
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.
4. Targeting Lewy body dementia with neflamapimod-rasagiline hybrids, Albertini, C; Petralla, S; Massenzio, F; Monti, B; Rizzardi, N; Bergamini, C; Uliassi, E; Borges, F Chavarria, D Fricker, G; Goettert, M; Kronenberger, T; Gehringer, M; Laufer, S; Bolognesi, ML in ARCHIV DER PHARMAZIE, 2024, ISSN: 0365-6233,  Volume: 357, 
Article in Press,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.1002/ardp.202300525 P-010-2HG
Abstract Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38 alpha, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6-dichlorophenyl ring of 1, generating neflamapimod-propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N-methyl-N-propargyl derivative 4 showed a nanomolar p38 alpha-MAPK inhibitory activity (IC50 = 98.7 nM), which is only 2.6-fold lower compared to that of the parent compound 1, while displaying no hepato- and neurotoxicity up to 25 mu M concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5 mu M concentration, 4 demonstrated a neuroprotective effect against dexamethasone-induced reactive oxygen species production in neuronal cells that was higher than that of 1.
5. Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?, Mesiti, F; Gaspar, A Chavarria, D Maruca, A; Rocca, R; Martins, EG; Barreiro, S; Silva, R; Fernandes, C; Gul, S; Keminer, O; Alcaro, S; Borges, F in JOURNAL OF MEDICINAL CHEMISTRY, 2021, ISSN: 0022-2623,  Volume: 64, 
Article,  Indexed in: crossref, wos  DOI: 10.1021/acs.jmedchem.1c00510 P-00V-5MW
Abstract Chromone-3-phenylcarboxamides (Crom-1 and Crom-2) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (hMAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure-activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for hMAO-B inhibitory activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC50 = 1.52 +/- 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In in vitro ADME-toxicity studies, compound 31 showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound 31 also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound 31 as the first-in-class and a suitable candidate for in vivo preclinical investigation.