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A Commemorative Special Issue in Honor of Professor Carlos Alberto...
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A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases

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

Deadline for manuscript submissions: 25 January 2026 | Viewed by 5949

Special Issue Editors

Dr. Luzineide Tinoco

E-Mail Website
Guest Editor
Laboratory for Analysis and Development of Enzyme Inhibitors, Natural Products Research Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941590, Brazil
Interests: NMR; drug design; FBDD; neglected diseases; natural products
Special Issues, Collections and Topics in MDPI journals
Dr. Pedro De Sena Murteira Pinheiro

E-Mail Website
Guest Editor
Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio®), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941590, Brazil
Interests: SBDD; bioinformatics; cheminformatics; drug design; SAR exploration

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to Professor Carlos Alberto Manssour Fraga for his invaluable contribution to the field of medicinal chemistry and pharmaceutical sciences. Professor Carlos Alberto Manssour Fraga was working as an Editorial Board Member of Pharmaceuticals before he passed away in May 2024.

A graduate of the Federal University of Rio de Janeiro (UFRJ), where he also served as a full professor at the Institute of Biomedical Sciences, Professor Fraga was known for his impactful research at the Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio®). His work has resulted in over 230 international journal articles and 26 patents, significantly advancing drug discovery and development.

Professor Fraga's academic career was distinguished by his dedication to teaching and research. He shaped the minds of countless students and left an imprint on the next generation of scientists. Recognized as one of the most influential researchers worldwide, Professor Fraga received a prestigious Level 1A productivity scholarship from CNPq and was honored as a "Scientist of Our State" by FAPERJ.

This Special Issue, titled "A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases" will be published in Pharmaceuticals.

Complex diseases arise from multifaceted interactions among genetic, environmental, and lifestyle factors. They are challenging to treat due to their heterogeneous nature and often unclear molecular underpinnings. These diseases, which include conditions such as cardiovascular diseases, diabetes, cancer, and neurodegenerative disorders (e.g., Alzheimer's and Parkinson's disease), place an immense burden on global health systems. The intricate pathophysiology of complex diseases means that traditional therapeutic approaches may fall short, underscoring the need for novel bioactive molecules designed with a deep understanding of their disease mechanisms.

This Special Issue seeks to spotlight recent advances in medicinal chemistry that drive the discovery and development of bioactive molecules aimed at combating these challenging conditions. We invite contributions in the following areas:

  • The Identification of Novel Drug Targets and Mechanistic Insights: Discovering new molecular targets and understanding the specific pathways to combating complex diseases, including multi-target approaches where relevant;
  • Synthetic Approaches to Bioactive Molecules: Developing innovative synthetic methods to create molecules with enhanced activity, stability, and selectivity, tailored for the unique demands of complex disease treatment;
  • Lead Optimization and Structure–Activity Relationship (SAR) Studies: Refining lead compounds to improve pharmacological profiles, therapeutic efficacy, and safety through SAR analyses;
  • Advanced Screening Technologies: Leveraging high-throughput screening, computational methods, and systems biology approaches to accelerate the discovery of effective bioactive compounds;
  • Preclinical and Early Clinical Evaluations: Assessing pharmacokinetics, toxicity, and efficacy in preclinical and early clinical studies to validate the therapeutic potential of newly discovered compounds.

Dr. Luzineide Tinoco
Dr. Pedro De Sena Murteira Pinheiro
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
  • bioactive molecules
  • complex diseases
  • cardiovascular diseases
  • diabetes
  • cancer
  • neurodegenerative disorders
  • drug discovery
  • synthetic chemistry
  • target identification
  • structure–activity relationship
  • preclinical evaluation

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Published Papers (5 papers)

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Research

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14 pages, 2837 KiB  
Article
Design, Synthesis, and Bioactivity Assessment of Modified Vemurafenib Analog
by Fabiana Sélos Guerra, Rosana Helena Coimbra Nogueira de Freitas, Florina Moldovan, David Rodrigues da Rocha, Renato Sampaio Carvalho and Patricia Dias Fernandes
Pharmaceuticals 2025, 18(8), 1161; https://doi.org/10.3390/ph18081161 - 5 Aug 2025
Abstract
Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAFV600E mutation, for which vemurafenib, a selective BRAFV600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often [...] Read more.
Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAFV600E mutation, for which vemurafenib, a selective BRAFV600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAFV600E-mutated A375 cells, with RF-86A displaying the lowest IC50 value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. Full article
(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)
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30 pages, 3204 KiB  
Article
Design, Synthesis, and Evaluation of Antinociceptive Properties of Novel CBD-Based Terpene-Cinnamoyl-Acyl-Hydrazone Analogues
by Mikaela Lucinda de Souza, João Pedro Barros de Paiva, Graziella dos Reis Rosa Franco, Vanessa Silva Gontijo, Marina Amaral Alves, Hygor Marcos Ribeiro de Souza, Anna Carolina Pereira Lontra, Eduardo Araújo de Oliveira, Thaís Biondino Sardella Giorno, Isabella Alvim Guedes, Laurent Emmanuel Dardenne, Patrícia Dias Fernandes and Claudio Viegas Jr.
Pharmaceuticals 2025, 18(5), 755; https://doi.org/10.3390/ph18050755 - 20 May 2025
Viewed by 1035
Abstract
Background/Objectives: Cannabidiol (CBD) has been reported for its antinociceptive, anti-inflammatory, and neuroprotective activities. However, several legal restrictions on its medicinal uses and even research have contributed to the development of synthetic analogues. Therefore, the aim of this study was the design and [...] Read more.
Background/Objectives: Cannabidiol (CBD) has been reported for its antinociceptive, anti-inflammatory, and neuroprotective activities. However, several legal restrictions on its medicinal uses and even research have contributed to the development of synthetic analogues. Therefore, the aim of this study was the design and synthesis of a novel series of CBD-based structural analogues, and the in vivo evaluation of their potential antinociceptive activity. Methods: Using a two-step synthetic route, 26 new terpene-cinnamoyl acyl-hydrazone analogues were obtained and were submitted to in vivo screening in the classical formalin-induced paw edema and hot plate assays. Results: The compounds PQM-292, PQM-293, PQM-295, PQM-307, PQM-308, and PQM-309 exhibited the best results in the neurogenic phase (first phase) of the formalin-induced licking response, showing comparable results to morphine. Notably, in the inflammatory phase (second phase), compound PQM-292 exhibited the best anti-inflammatory activity. Interestingly, in the hot plate model, six other compounds (PQM-274, PQM-291, PQM-294, PQM-304, PQM-305, and PQM-378) showed the best antinociceptive activity in comparison to morphine, especially PQM-274, which exhibited an antinociceptive effect almost equivalent to the reference drug. Interestingly, these findings suggested that these bioactive compounds, despite their structural similarity, act through different mechanisms, which were investigated by molecular docking with CB1, CB2, and TRPV1 receptors. In silico results indicated that the most active compounds should act through different mechanisms, probably involving interactions with TRPA1. Conclusions: Therefore, due to the promising antinociceptive activity observed for these highlighted compounds, particularly for PQM-292 and PQM-274, without apparent toxicity and psychoactive effects, and the possible involvement of diverse mechanisms of action, these compounds could be considered as promising starting points to the development of new drug candidate prototypes of clinical interest. Full article
(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)
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30 pages, 3776 KiB  
Article
Design and Synthesis of Bis-Chalcones as Curcumin Simplified Analogs and Assessment of Their Antiproliferative Activities Against Human Lung Cancer Cells and Trypanosoma cruzi Amastigotes
by Gabriela Alves de Souza, Lorrane de Souza Chaves, Afonso Santine M. M. Velez, Jorge Lucas F. Lacerda, Paulo Pitasse-Santos, Jayane Clys Conceição dos Santos, Otávio Augusto Chaves, Carlos Serpa, Raphael do Carmo Valente, Leonardo Marques da Fonseca , Marcos André Rodrigues da Costa Santos, Jhenifer Santos dos Reis, Carlos Antônio do Nascimento Santos, Lucia Mendonça-Previato, Jose Osvaldo Previato, Celio Geraldo Freire-de-Lima, Debora Decoté-Ricardo, Leonardo Freire-de-Lima and Marco Edilson Freire de Lima
Pharmaceuticals 2025, 18(4), 456; https://doi.org/10.3390/ph18040456 - 24 Mar 2025
Cited by 1 | Viewed by 875
Abstract
Background: Anticancer therapies represent the primary treatment option for a significant number of cancer patients globally; however, many of these treatments are associated with severe side effects as they target molecular structures present in both cancerous and healthy cells. In a similar context, [...] Read more.
Background: Anticancer therapies represent the primary treatment option for a significant number of cancer patients globally; however, many of these treatments are associated with severe side effects as they target molecular structures present in both cancerous and healthy cells. In a similar context, the treatment of Chagas disease, a neglected tropical illness, is hindered by the high toxicity of the currently available drugs. Researchers are increasingly focusing on the development of safer and more selective alternatives, with natural compounds being studied as potential starting points for the creation of more effective drug candidates with a favorable therapeutic index. Objectives: The aim of this study was to design simplified curcumin-derived structures that preserved or enhanced their therapeutic activity against human lung cancer cell lines and T. cruzi, while also improving bioavailability and minimizing toxicity. Methods: In this study, curcumin and two natural curcuminoids inspired the synthesis of a chalcone and a set of bis-chalcones, compound classes known for their enhanced stability compared with their natural parent derivatives. The synthetic strategy used was the acid-catalyzed aldol condensation reaction. The stability profiles, IC50 values against A549 and H460 tumor cell lines, and trypanocidal activity against T. cruzi amastigotes of these derivatives were assessed. Results: The synthesized derivatives exhibited improved stability compared with the parent compounds, along with lower IC50 values in both A549 and H460 tumor cell lines. Additionally, one of the new analogs showed promising trypanocidal activity against T. cruzi amastigotes. Conclusions: This study provides a potential pathway toward the development of more effective and less toxic treatments for both cancer and Chagas disease. The simplified curcumin derivatives represent a promising foundation for designing new therapeutic agents with improved bioavailability and efficacy. Full article
(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)
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Review

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63 pages, 3732 KiB  
Review
TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease
by Ana Luísa Rodriguez Gini, Pamela Souza Tada da Cunha, Emílio Emílio João, Chung Man Chin, Jean Leandro dos Santos, Esteban Carlos Serra and Cauê Benito Scarim
Pharmaceuticals 2025, 18(6), 919; https://doi.org/10.3390/ph18060919 - 19 Jun 2025
Viewed by 1387
Abstract
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel [...] Read more.
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel therapeutic avenue by leveraging the ubiquitin–proteasome system to selectively degrade essential parasite proteins. This review introduces the conceptual framework of “TrypPROTACs” as a prospective strategy for T. cruzi, integrating a comprehensive analysis of druggable targets across critical biological pathways, including ergosterol biosynthesis, redox metabolism, glycolysis, nucleotide synthesis, protein kinases, molecular chaperones such as heat shock protein 90 (Hsp90), and epigenetic regulators such as T. cruzi bromodomain factor 3 (TcBDF3). It is important to note that no TrypPROTAC compound has yet been synthesized or experimentally validated in T. cruzi; the approach discussed herein remains theoretical and forward-looking. Representative inhibitors for each target class are compiled, highlighting potency, selectivity, and structural features relevant to ligand design. We also examine the parasite’s ubiquitination machinery and compare it to the human system to identify putative E3 ubiquitin ligases. Key aspects of linker engineering and ternary complex stabilization are discussed, alongside potential validation techniques such as the cellular thermal shift assay (CETSA) and bioluminescence resonance energy transfer (NanoBRET). Collectively, these insights outline a roadmap for the rational design of TrypPROTACs and support the feasibility of expanding targeted protein degradation strategies to neglected tropical diseases. Full article
(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)
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35 pages, 7644 KiB  
Review
Drug Discovery for Histone Deacetylase Inhibition: Past, Present and Future of Zinc-Binding Groups
by Gustavo Salgado Pires, Heber Victor Tolomeu, Daniel Alencar Rodrigues, Lídia Moreira Lima, Carlos Alberto Manssour Fraga and Pedro de Sena Murteira Pinheiro
Pharmaceuticals 2025, 18(4), 577; https://doi.org/10.3390/ph18040577 - 16 Apr 2025
Cited by 2 | Viewed by 2124
Abstract
Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC [...] Read more.
Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC inhibitors (HDACis) have gained significant attention, particularly those containing zinc-binding groups (ZBGs), which interact directly with the catalytic zinc ion in the enzyme’s active site. The structural diversity of ZBGs profoundly impacts the potency, selectivity, and pharmacokinetics of HDACis. While hydroxamic acids remain the most widely used ZBGs, their limitations, such as metabolic instability and off-target effects, have driven the development of alternative scaffolds, including ortho-aminoanilides, mercaptoacetamides, alkylhydrazides, oxadiazoles, and more. This review explores the structural and mechanistic aspects of different ZBGs, their interactions with HDAC isoforms, and their influence on inhibitor selectivity. Advances in structure-based drug design have allowed the fine-tuning of HDACi pharmacophores, leading to more selective and efficacious compounds with improved drug-like properties. Understanding the nuances of ZBG interactions is essential for the rational design of next-generation HDACis, with potential applications in oncology, neuroprotection, and immunotherapy. Full article
(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)
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