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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 33232

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Prof. Dr. Maria Novella Romanelli

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Department of Neuroscience, Psychology, Drug Research and Child’s Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Interests: enzyme modulators; ion channel modulators; multi-target ligands; antihyperalgesic agents; receptor modulators
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Prof. Dr. Silvia Dei

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Department of Neuroscience, Psychology, Drug Research and Child’s Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Interests: anticancer drugs; PGP modulators; antibacterials; multitarget-ligands; receptor modulators
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There are several disorders that cannot be properly treated with the old “one target–one molecule” approach, due to their multifactorial character. The complexity of these diseases suggests exploiting the simultaneous modulation of more than one target, a concept known also as polypharmacology, by using compounds which are able to interact with different macromolecules involved in the disorder under investigation. Even if the success of several drugs can be due to their fortuitous interaction with multiple macromolecules, historically, the design of multitarget-directed ligands was developed to treat Alzheimer’s Disease. Later, this approach was extended to different therapeutic areas, among them cancer, inflammation, pain, and infectious diseases.

This Special Issue aims to collect research papers and short communication to provide an overview on the recent advances in the design, synthesis, and biological evaluation of multitarget ligands for innovative therapeutic treatments.

Prof. Maria Novella Romanelli
Prof. Silvia Dei
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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

Drug design
Multitarget ligands
Dual modulators
Chemical synthesis
Biological activity
Drug targets
Neurodegenerative diseases
Cancer
Epigenetics
Pain
Inflammation
Infectious diseases
Polypharmacology

Published Papers (10 papers)

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Research

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18 pages, 1638 KiB

Open AccessArticle

Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells

by Rossella Fioravanti, Stefano Tomassi, Elisabetta Di Bello, Annalisa Romanelli, Andrea Maria Plateroti, Rosaria Benedetti, Mariarosaria Conte, Ettore Novellino, Lucia Altucci, Sergio Valente and Antonello Mai

Molecules 2020, 25(14), 3122; https://doi.org/10.3390/molecules25143122 - 08 Jul 2020

Cited by 3 | Viewed by 2403

Abstract

Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((E)-3-bromobenzylidene)piperidin-4-one 3 displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis((E)-2-bromobenzylidene) cyclic compounds 4a–n to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of 4a–n exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (4d), benzyl (4e), or acyl (4k–m) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl (4f) and 3-phenylpropyl (4g) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (4h–j). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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14 pages, 7940 KiB

Open AccessArticle

Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors

by Annalisa Maruca, Delia Lanzillotta, Roberta Rocca, Antonio Lupia, Giosuè Costa, Raffaella Catalano, Federica Moraca, Eugenio Gaudio, Francesco Ortuso, Anna Artese, Francesco Trapasso and Stefano Alcaro

Molecules 2020, 25(9), 2174; https://doi.org/10.3390/molecules25092174 - 06 May 2020

Cited by 10 | Viewed by 3355

Abstract

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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12 pages, 2902 KiB

Open AccessArticle

Binding-Site Match Maker (BSMM): A Computational Method for the Design of Multi-Target Ligands

by Jinming Zhou and Jian Hui Wu

Molecules 2020, 25(8), 1821; https://doi.org/10.3390/molecules25081821 - 16 Apr 2020

Cited by 1 | Viewed by 2437

Abstract

Multi-target ligand strategies provide a valuable method of drug design. However, to develop a multi-target drug with the desired profile remains a challenge. Herein, we developed a computational method binding-site match maker (BSMM) for the design of multi-target ligands based on binding site matching. BSMM was built based on geometric hashing algorithms and the representation of a binding-site with physicochemical (PC) points. The BSMM software was used to detect proteins with similar binding sites or subsites. In particular, BSMM is independent of protein global folds and sequences and is therefore applicable to the matching of any binding sites. The similar sites between protein pairs with low homology and/or different folds are generally not obvious to the visual inspection. The detection of such similar binding sites by BSMM could be of great value for the design of multi-target ligands. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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26 pages, 2621 KiB

Open AccessFeature PaperArticle

Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells

by Elisabetta Teodori, Laura Braconi, Silvia Bua, Andrea Lapucci, Gianluca Bartolucci, Dina Manetti, Maria Novella Romanelli, Silvia Dei, Claudiu T. Supuran and Marcella Coronnello

Molecules 2020, 25(7), 1748; https://doi.org/10.3390/molecules25071748 - 10 Apr 2020

Cited by 30 | Viewed by 3178

Abstract

A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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21 pages, 7060 KiB

Open AccessCommunication

Design, Synthesis and Biological Evaluation of New Antioxidant and Neuroprotective Multitarget Directed Ligands Able to Block Calcium Channels

by Irene Pachòn Angona, Solene Daniel, Helene Martin, Alexandre Bonet, Artur Wnorowski, Maciej Maj, Krzysztof Jóźwiak, Tiago Barros Silva, Bernard Refouvelet, Fernanda Borges, José Marco-Contelles and Lhassane Ismaili

Molecules 2020, 25(6), 1329; https://doi.org/10.3390/molecules25061329 - 14 Mar 2020

Cited by 11 | Viewed by 3141

Abstract

We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca²⁺ channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs 3a–t, resulting from the juxtaposition of nimodipine, a Ca²⁺ channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6–dimethyl–4-[4-(prop–2–yn–1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (3a), as an attractive antioxidant (1.75 TE), Ca²⁺ channel antagonist (46.95% at 10 μM), showing significant neuroprotection (38%) against H₂O₂ at 10 μM, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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18 pages, 1340 KiB

Open AccessFeature PaperArticle

New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets

by Chiara Brullo, Matteo Massa, Federica Rapetti, Silvana Alfei, Maria B. Bertolotto, Fabrizio Montecucco, Maria Grazia Signorello and Olga Bruno

Molecules 2020, 25(4), 899; https://doi.org/10.3390/molecules25040899 - 18 Feb 2020

Cited by 14 | Viewed by 2522

Abstract

Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure–activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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11 pages, 1723 KiB

Open AccessFeature PaperArticle

Biological Activity Profiles of Multitarget Ligands from X-ray Structures

by Christian Feldmann and Jürgen Bajorath

Molecules 2020, 25(4), 794; https://doi.org/10.3390/molecules25040794 - 12 Feb 2020

Cited by 2 | Viewed by 2649

Abstract

In pharmaceutical research, compounds with multitarget activity receive increasing attention. Such promiscuous chemical entities are prime candidates for polypharmacology, but also prone to causing undesired side effects. In addition, understanding the molecular basis and magnitude of multitarget activity is a stimulating topic for exploratory research. Computationally, compound promiscuity can be estimated through large-scale analysis of activity data. To these ends, it is critically important to take data confidence criteria and data consistency across different sources into consideration. Especially the consistency aspect has thus far only been little investigated. Therefore, we have systematically determined activity annotations and profiles of known multitarget ligands (MTLs) on the basis of activity data from different sources. All MTLs used were confirmed by X-ray crystallography of complexes with multiple targets. One of the key questions underlying our analysis has been how MTLs act in biological screens. The results of our analysis revealed significant variations of MTL activity profiles originating from different data sources. Such variations must be carefully considered in promiscuity analysis. Our study raises awareness of these issues and provides guidance for large-scale activity data analysis. Full article

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12 pages, 2882 KiB

Open AccessFeature PaperArticle

Identifying Promiscuous Compounds with Activity against Different Target Classes

by Christian Feldmann, Filip Miljković, Dimitar Yonchev and Jürgen Bajorath

Molecules 2019, 24(22), 4185; https://doi.org/10.3390/molecules24224185 - 18 Nov 2019

Cited by 16 | Viewed by 3784

Abstract

Compounds with multitarget activity are of high interest for polypharmacological drug discovery. Such promiscuous compounds might be active against closely related target proteins from the same family or against distantly related or unrelated targets. Compounds with activity against distinct targets are not only of interest for polypharmacology but also to better understand how small molecules might form specific interactions in different binding site environments. We have aimed to identify compounds with activity against drug targets from different classes. To these ends, a systematic analysis of public biological screening data was carried out. Care was taken to exclude compounds from further consideration that were prone to experimental artifacts and false positive activity readouts. Extensively assayed compounds were identified and found to contain molecules that were consistently inactive in all assays, active against a single target, or promiscuous. The latter included more than 1000 compounds that were active against 10 or more targets from different classes. These multiclass ligands were further analyzed and exemplary compounds were found in X-ray structures of complexes with distinct targets. Our collection of multiclass ligands should be of interest for pharmaceutical applications and further exploration of binding characteristics at the molecular level. Therefore, these highly promiscuous compounds are made publicly available. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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Review

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20 pages, 5091 KiB

Open AccessReview

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

by Giambattista Marotta, Filippo Basagni, Michela Rosini and Anna Minarini

Molecules 2020, 25(17), 4005; https://doi.org/10.3390/molecules25174005 - 02 Sep 2020

Cited by 28 | Viewed by 5441

Abstract

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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16 pages, 1167 KiB

Open AccessReview

Novel Multitarget Therapies for Lung Cancer and Respiratory Disease

by Masako Yumura, Tatsuya Nagano and Yoshihiro Nishimura

Molecules 2020, 25(17), 3987; https://doi.org/10.3390/molecules25173987 - 01 Sep 2020

Cited by 14 | Viewed by 3483

Abstract

In recent years, multitarget drugs for neurological diseases such as Alzheimer’s disease have been developed and well researched. Many studies have revealed that multitarget drugs are also useful for lung cancer and respiratory diseases. Pemetrexed is a multitargeted antifolate with strong antitumor activity against mesothelioma and lung adenocarcinoma. Crizotinib is an ATP-competitive tyrosine kinase inhibitor that targets c-MET, ROS1, and ALK. Alectinib is known as an ALK inhibitor but also targets LTK, CHEK2, FLT3, PHKG2, and RET. Sorafenib is a tyrosine kinase inhibitor that targets RAF kinase, KIT, VEGFR, PDGFR1β, FLT3, and RET. Nintedanib is a multiple tyrosine kinase inhibitor that targets FGFR, PDGFR, and VEGFR. In this review, we summarize the mechanisms of action of multitarget therapies and report the results of the latest clinical trials. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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