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Pharmaceuticals
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State of the Art of Medicinal Chemistry in Portugal
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State of the Art of Medicinal Chemistry in Portugal

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 24 May 2024 | Viewed by 4793

Special Issue Editors

Dr. Luís M. T. Frija

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Guest Editor
Centro de Química Estrutural, Instituto Superior Técnico - Universidade de Lisboa, Lisbon, Portugal
Interests: organic chemistry; tetrazoles, thiazoles and thiadiazoles; nitrogen ligands; organocatalysis; metal catalysis; selective chelators for metals on biological medium; leads for cancer chemotherapy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria Matilde Soares Duarte Marques

E-Mail Website
Guest Editor
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Interests: chemical toxicology; drug design; MS-based OMICS; biomarkers; organic synthesis; epigenetic drugs; HK2 inhibitors; drug repurposing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pharmaceutical research in Portugal has for decades been an extremely dynamic area embraced by a multidisciplinary panorama that has allowed it to achieve sustainable development. The international recognition of this research is not limited to the academic environment, with several successful multinational pharmaceutical companies currently intensifying their activities in Portugal. Pharmaceutical researchers spread across the country and in several international research centers are developing their work and dedicating themselves diligently to projects that aim at a practical application.

The topics of pharmaceutical research actually being explored by the country's scientific community are quite numerous. These include, with great emphasis, research aimed at fighting cancer and neurodegenerative and infectious diseases.

This Special Issue, called “State of the Art of Medicinal Chemistry in Portugal”, aims to compile recent works of proven impact and led by Portuguese researchers in the field of medicinal chemistry. It is particularly hoped that this disclosure can serve as a source of inspiration for other scientific communities and scientists at the beginning of their careers.

Dr. Luís M. T. Frija
Prof. Dr. Maria Matilde Soares Duarte Marques
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • medicinal chemistry in Portugal
  • anticancer research and therapies
  • neurodegenerative diseases
  • infectious diseases
  • drug design and drug discovery
  • chemical biology

Published Papers (3 papers)

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Research

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27 pages, 5870 KiB  
Article
Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues
by Daniel Martins, Eva Gil-Martins, Fernando Cagide, Catarina da Fonseca, Sofia Benfeito, Carlos Fernandes, Daniel Chavarria, Fernando Remião, Renata Silva and Fernanda Borges
Pharmaceuticals 2023, 16(8), 1158; https://doi.org/10.3390/ph16081158 - 15 Aug 2023
Cited by 2 | Viewed by 1915
Abstract
Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is [...] Read more.
Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is still poorly understood, despite several reports highlighting cases of acute intoxication, with brain and liver toxicity. Thus, in this study, mescaline, 2C-N (insertion of a nitro in the para position of the 2C phenethylamines aromatic ring) and 2C-B (insertion of a bromide in the para position of the 2C phenethylamines aromatic ring) and their corresponding NBOMe counterparts, mescaline-NBOMe, 25N-NBOMe and 25B-NBOMe, were synthetized and the in vitro neuro- and hepatocytotoxicity evaluated in differentiated SH-SY5Y and HepG2 cell lines, respectively. Cytotoxicity, oxidative stress, metabolic and energetic studies were performed to evaluate the main pathways involved in their toxicity. Our results demonstrated that the presence of the N-2-methoxybenzyl group significantly increased the in vitro cytotoxicity of 2C phenethylamines drugs in both cell lines, with the NBOMe drugs presenting lower EC50 values when compared to their counterparts. Consistently, our data showed a correlation between the drug’s lipophilicity and the EC50 values, except for 2C-B. The 2C-B presented higher cytotoxic effects in both cell lines than mescaline-NBOMe, a result that can be explained by its higher passive permeability. All the NBOMe derivatives were able to cross the blood–brain barrier. Considering metabolic studies, the cytotoxicity of these drugs was shown to be influenced by inhibition of cytochrome P450 (CYP), which suggests a potential role of this enzyme complex, especially CYP3A4 and CYP2D6 isoenzymes in SH-SY5Y cells, in their detoxification or bioactivation. Furthermore, in differentiated SH-SY5Y cells, the drugs were able to induce mitochondrial membrane depolarization, and to disrupt GSH and ATP intracellular levels, these effects being concentration dependent and more pronounced for the NBOMe derivatives. No ROS overproduction was detected for any of the drugs in the tested experimental conditions. A correlation between a drug’s lipophilicity and the EC50 values in both cell lines, except for 2C-B, was also obtained. In summary, the introduction of a NBOMe moiety to the parent drugs significantly increases their lipophilicity, brain permeability and cytotoxic effects, with GSH and ATP homeostasis disruption. The inhibition of CYP3A4 and CYP2D6 emphasized that CYP-mediated metabolism impacts the toxicity of these drugs. Full article
(This article belongs to the Special Issue State of the Art of Medicinal Chemistry in Portugal)
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14 pages, 1842 KiB  
Article
3-(1,2,3-Triazol-4-yl)-β-Carbolines and 3-(1H-Tetrazol-5-yl)-β-Carbolines: Synthesis and Evaluation as Anticancer Agents
by João L. P. Ribeiro, Joana B. Loureiro, Susana M. M. Lopes, Lucília Saraiva and Teresa M. V. D. Pinho e Melo
Pharmaceuticals 2022, 15(12), 1510; https://doi.org/10.3390/ph15121510 - 03 Dec 2022
Cited by 2 | Viewed by 1302
Abstract
Herein, the synthesis and anticancer activity evaluation of a series of novel β-carbolines is reported. The reactivity of nitrosoalkenes towards indole was explored for the synthesis of novel tryptophan analogs where the carboxylic acid was replaced by a triazole moiety. This tryptamine was [...] Read more.
Herein, the synthesis and anticancer activity evaluation of a series of novel β-carbolines is reported. The reactivity of nitrosoalkenes towards indole was explored for the synthesis of novel tryptophan analogs where the carboxylic acid was replaced by a triazole moiety. This tryptamine was used in the synthesis of 3-(1,2,3-triazol-4-yl)-β-carbolines via Pictet–Spengler condensation followed by an oxidative step. A library of compounds, including the novel 3-(1,2,3-triazol-4-yl)-β-carbolines as well as methyl β-carboline-3-carboxylate and 3-tetrazolyl-β-carboline derivatives, was evaluated for their antiproliferative activity against colorectal cancer cell lines. The 3-(1H-tetrazol-5-yl)-β-carbolines stood out as the most active compounds, with values of half-maximal inhibitory concentration (IC50) ranging from 3.3 µM to 9.6 µM against colorectal adenocarcinoma HCT116 and HT29 cell lines. The results also revealed a mechanism of action independent of the p53 pathway. Further studies with the 3-tetrazolyl-β-carboline derivative, which showed high selectivity for cancer cells, revealed IC50 values below 8 μM against pancreatic adenocarcinoma PANC-1, melanoma A375, hepatocarcinoma HEPG2, and breast adenocarcinoma MCF-7 cell lines. Collectively, this work discloses the 3-tetrazolyl-β-carboline derivative as a promising anticancer agent worthy of being further explored in future works. Full article
(This article belongs to the Special Issue State of the Art of Medicinal Chemistry in Portugal)
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Review

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29 pages, 6913 KiB  
Review
Drug Discovery Based on Oxygen and Nitrogen (Non-)Heterocyclic Compounds Developed @LAQV–REQUIMTE/Aveiro
by Joana L. C. Sousa, Hélio M. T. Albuquerque and Artur M. S. Silva
Pharmaceuticals 2023, 16(12), 1668; https://doi.org/10.3390/ph16121668 - 30 Nov 2023
Viewed by 997
Abstract
Artur Silva’s research group has a long history in the field of medicinal chemistry. The development of new synthetic methods for oxygen (mostly polyphenols, e.g., 2- and 3-styrylchromones, xanthones, flavones) and nitrogen (e.g., pyrazoles, triazoles, acridones, 4-quinolones) heterocyclic compounds in order to be [...] Read more.
Artur Silva’s research group has a long history in the field of medicinal chemistry. The development of new synthetic methods for oxygen (mostly polyphenols, e.g., 2- and 3-styrylchromones, xanthones, flavones) and nitrogen (e.g., pyrazoles, triazoles, acridones, 4-quinolones) heterocyclic compounds in order to be assessed as antioxidant, anti-inflammatory, antidiabetic, and anticancer agents has been the main core work of our research interests. Additionally, the synthesis of steroid-type compounds as anti-Alzheimer drugs as well as of several chromophores as important dyes for cellular imaging broadened our research scope. In this review article, we intend to provide an enlightened appraisal of all the bioactive compounds and their biological properties that were synthesized and studied by our research group in the last two decades. Full article
(This article belongs to the Special Issue State of the Art of Medicinal Chemistry in Portugal)
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