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Pharmaceuticals
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Methyl-Containing Pharmaceuticals
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Methyl-Containing Pharmaceuticals

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

Deadline for manuscript submissions: closed (29 December 2023) | Viewed by 12168

Special Issue Editors

Dr. Anna Fantinati

E-Mail Website
Guest Editor
Dept. Department of Environmental and Prevention Sciences – DEPS, University of Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
Interests: organic synthesis; catalysis; small molecules
Dr. Davide Illuminati

E-Mail Website
Guest Editor
Dept. of Chemical, Pharmaceutical and Agricultural Sciences – DOCPAS, University of Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
Interests: catalysis; non-natural amino acids; organic synthesis

Special Issue Information

Dear Colleagues,

Discovering and developing new pharmaceuticals is the main goal of medicinal chemistry research. For this Special Issue, we will consider manuscripts focused on any type of target involved in pharmaceutical methyl-containing profiles, from peptides to anti-fungal/anti-tumoral targets, considering a broad spectrum of applications. For example, there are pharmaceuticals targeting GPCRs (multiple G protein-coupled receptors), that are present on the cell surface of every cell type to regulate key physiological events. They mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants, and so they have potential as therapeutic targets for a broad spectrum of diseases. Even the smallest modification of a molecule can lead to the discovery of an important therapeutic effect. The methyl effect is well acknowledged in medicinal chemistry; the insertion of the smallest alkyl group could have important implications in modulating the biological activity, selectivity, solubility, metabolism and pharmacokinetic/pharmacodynamic properties of the bioactive molecules already highlighted. The purpose of this Special Issue is to combine synthetic strategies to methylate potential drug profiles with the identification of pharmaceuticals through significant lead optimization processes to create new biologically active compounds because, as highlighted, a minimal structural substitution could result in significant and unexpected behavioral modifications.

Dr. Anna Fantinati
Dr. Davide Illuminati
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

  • pharmaceuticals
  • ligands
  • methylation
  • modulators
  • drugs discovery
  • selectivity

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Published Papers (6 papers)

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Editorial

Jump to: Research, Review

2 pages, 180 KiB  
Editorial
Methyl-Containing Pharmaceuticals
by Davide Illuminati and Anna Fantinati
Pharmaceuticals 2024, 17(5), 563; https://doi.org/10.3390/ph17050563 - 28 Apr 2024
Cited by 1 | Viewed by 816
Abstract
This Special Issue, which focused on methyl-containing pharmaceuticals, collected different papers and reviews on this topic [...] Full article
(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)

Research

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34 pages, 30095 KiB  
Article
A Computational Method for the Binding Mode Prediction of COX-1 and COX-2 Inhibitors: Analyzing the Union of Coxibs, Oxicams, Propionic and Acetic Acids
by Estefany Bello-Vargas, Mario Alberto Leyva-Peralta, Zeferino Gómez-Sandoval, Mario Ordóñez and Rodrigo Said Razo-Hernández
Pharmaceuticals 2023, 16(12), 1688; https://doi.org/10.3390/ph16121688 - 4 Dec 2023
Cited by 1 | Viewed by 1776
Abstract
Among the biological targets extensively investigated to improve inflammation and chronic inflammatory conditions, cyclooxygenase enzymes (COXs) occupy a prominent position. The inhibition of these enzymes, essential for mitigating inflammatory processes, is chiefly achieved through Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). In this work, we introduce [...] Read more.
Among the biological targets extensively investigated to improve inflammation and chronic inflammatory conditions, cyclooxygenase enzymes (COXs) occupy a prominent position. The inhibition of these enzymes, essential for mitigating inflammatory processes, is chiefly achieved through Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). In this work, we introduce a novel method—based on computational molecular docking—that could aid in the structure-based design of new compounds or the description of the anti-inflammatory activity of already-tested compounds. For this, we used eight crystal complexes (four COX-1 and COX-2 each), and each pair had a specific NSAID: Celecoxib, Meloxicam, Ibuprofen, and Indomethacin. This selection was based on the ligand selectivity towards COX-1 or COX-2 and their binding mode. An interaction profile of each NSAID was compiled to detect the residues that are key for their binding mode, highlighting the interaction made by the Me group. Furthermore, we rigorously validated our models based on structural accuracy (RMSD < 1) and (R2 > 70) using eight NSAIDs and thirteen compounds with IC50 values for each enzyme. Therefore, this model can be used for the binding mode prediction of small and structurally rigid compounds that work as COX inhibitors or the prediction of new compounds that are designed by means of a structure-based approach. Full article
(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)
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14 pages, 1575 KiB  
Article
(L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation
by Davide Illuminati, Claudio Trapella, Vinicio Zanirato, Remo Guerrini, Valentina Albanese, Chiara Sturaro, Simona Stragapede, Davide Malfacini, Greta Compagnin, Martina Catani and Anna Fantinati
Pharmaceuticals 2023, 16(11), 1592; https://doi.org/10.3390/ph16111592 - 10 Nov 2023
Viewed by 1243
Abstract
The enormous influence in terms of bioactivity, affinity, and selectivity represented by the replacement of (L)-2,6-dimethyl tyrosine (Dmt) instead of Phenylalanine (Phe) into Nociceptin/orphanin (N/OFQ) neuropeptide analogues has been well documented in the literature. More recently, the non-natural amino acid (L)-2-methyl tyrosine (Mmt), [...] Read more.
The enormous influence in terms of bioactivity, affinity, and selectivity represented by the replacement of (L)-2,6-dimethyl tyrosine (Dmt) instead of Phenylalanine (Phe) into Nociceptin/orphanin (N/OFQ) neuropeptide analogues has been well documented in the literature. More recently, the non-natural amino acid (L)-2-methyl tyrosine (Mmt), with steric hindrance included between Tyr and Dmt, has been studied because of the modulation of steric effects in opioid peptide chains. Here, we report a new synthetic strategy to obtain Mmt based on the well-known Pd-catalyzed ortho-C(sp2)–H activation approach, because there is a paucity of other synthetic routes in the literature to achieve it. The aim of this work was to force only the mono-ortho-methylation process over the double ortho-methylation one. In this regard, we are pleased to report that the introduction of the dibenzylamine moiety on a Tyr aromatic nucleus is a convenient and traceless solution to achieve such a goal. Interestingly, our method provided the aimed Mmt either as N-Boc or N-Fmoc derivatives ready to be inserted into peptide chains through solid-phase peptide synthesis (SPPS). Importantly, the introduction of Mmt in place of Phe1 in the sequence of N/OFQ(1-13)-NH2 was very well tolerated in terms of pharmacological profile and bioactivity. Full article
(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)
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18 pages, 2989 KiB  
Article
Towards Symmetric Thioamides: Microwave-Aided Synthesis of Terephthalic Acid Derivatives
by Andrzej Bak, Violetta Kozik, Aleksandra Swietlicka, Wojciech Baran, Adam Smolinski and Andrzej Zięba
Pharmaceuticals 2023, 16(7), 984; https://doi.org/10.3390/ph16070984 - 9 Jul 2023
Cited by 1 | Viewed by 1618
Abstract
The multistep synthesis of novel bis-terephthalthioamides based on methyl esters of amino acids (AAs) was proposed using conventional heating and microwave-assisted approaches. In fact, the comparative case study on the thionation of new symmetrical diamides with Lawesson’s reagent (LR) was performed. The [...] Read more.
The multistep synthesis of novel bis-terephthalthioamides based on methyl esters of amino acids (AAs) was proposed using conventional heating and microwave-assisted approaches. In fact, the comparative case study on the thionation of new symmetrical diamides with Lawesson’s reagent (LR) was performed. The microwave-accelerated small-scale methodology was successfully employed on the whole pathway from substrates (Gly, Ala, Val, Tyr, Ser) to products (symmetrical dithioamides of terephthalic acid), resulting in significantly reduced reaction time, energy requirements, and slightly increased reaction yields when compared to conventional heating. Moreover, the intermolecular similarity of novel terephthalic acid derivatives was estimated in the multidimensional space (mDS) of the structure/property-related in silico descriptors using principal component analysis (PCA) and hierarchical clustering analysis (HCA). The distance-oriented structure/property distribution was also correlated with the experimental lipophilic data. Full article
(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)
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15 pages, 4957 KiB  
Article
Selenylated Imidazo [1,2-a]pyridine Induces Apoptosis and Oxidative Stress in 2D and 3D Models of Colon Cancer Cells
by Giovana Bicudo Gomes, Claudia Stutz Zubieta, Jhefferson dos Santos Guilhermi, Mônica Cristina Toffoli-Kadri, Adilson Beatriz, Jamal Rafique, Eduardo Benedetti Parisotto, Sumbal Saba and Renata Trentin Perdomo
Pharmaceuticals 2023, 16(6), 814; https://doi.org/10.3390/ph16060814 - 30 May 2023
Cited by 9 | Viewed by 2194
Abstract
Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigenetic alterations that promote drug resistance. Recent studies showed that novel synthetic selenium compounds are more efficient and less toxic than conventional drugs, demonstrating biocompatibility and pro-oxidant effects on tumor [...] Read more.
Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigenetic alterations that promote drug resistance. Recent studies showed that novel synthetic selenium compounds are more efficient and less toxic than conventional drugs, demonstrating biocompatibility and pro-oxidant effects on tumor cells. This study aimed to investigate the cytotoxic effect of MRK-107, an imidazo [1,2- a]pyridine derivative, in 2D and 3D cell culture models of colon cancer (Caco-2 and HT-29). Sulforhodamine B results revealed a GI50 of 2.4 µM for Caco-2, 1.1 µM for HT-29, and 22.19 µM for NIH/3T3 in 2D cultures after 48 h of treatment. Cell recovery, migration, clonogenic, and Ki-67 results corroborated that MRK-107 inhibits cell proliferation and prevents cell regeneration and metastatic transition by selectively reducing migratory and clonogenic capacity; non-tumor cells (NIH/3T3) re-established proliferation in less than 18 h. The oxidative stress markers DCFH-DA and TBARS revealed increased ROS generation and oxidative damage. Caspases-3/7 are activated and induce apoptosis as the main mode of cell death in both cell models, as assessed by annexin V-FITC and acridine orange/ethidium bromide staining. MRK-107 is a selective, redox-active compound with pro-oxidant and pro-apoptotic properties and the capacity to activate antiproliferative pathways, showing promise in anticancer drug research. Full article
(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)
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Review

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22 pages, 10428 KiB  
Review
The Magic Methyl and Its Tricks in Drug Discovery and Development
by Pedro de Sena Murteira Pinheiro, Lucas Silva Franco and Carlos Alberto Manssour Fraga
Pharmaceuticals 2023, 16(8), 1157; https://doi.org/10.3390/ph16081157 - 15 Aug 2023
Cited by 28 | Viewed by 3602
Abstract
One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational [...] Read more.
One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational design and optimization of bioactive molecules. The “methylation effect”, or the “magic methyl” effect, is a factor that stands out due to the number of examples that demonstrate profound changes in either pharmacodynamic or pharmacokinetic properties. In many cases, this has been carried out rationally, but in others it has been the product of serendipitous observations. This paper summarizes recent examples that provide an overview of the current state of the art and contribute to a better understanding of the methylation effect in bioactive small-molecule drug candidates. Full article
(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)
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