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Enabling Chemical Technologies in Medicinal Chemistry
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Enabling Chemical Technologies in Medicinal Chemistry

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

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 47874

Special Issue Editors

Prof. Dr. Antimo Gioiello

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
Interests: drug discovery; integrated flow systems for lead discovery; chemical probes for understudied biological targets; enabling chemical technologies to assist complex syntheses; automation; new processing methods for large-scale preparation
Dr. Bruno Cerra

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
Interests: medicinal chemistry; flow chemistry; multistep organic synthesis; steroids; process optimization; biocatalysis

Special Issue Information

Dear Colleagues,

One of the major purposes of medicinal chemistry is the design and synthesis of new lead compounds for druggable targets. Lead discovery and optimization consist of iterative learning cycles, which start with molecular design before moving on to synthesis, testing, and structure–activity/structure–property relationship (SAR/SPR) analysis. Using traditional approaches, a significant time delay may occur from the design hypothesis to actual results, thus limiting the number of compounds that can be advanced into (pre)clinical studies.

Enabling chemical technologies are now offering novel solutions to this issue, as they offer the possibility to expedite medicinal chemistry programs that show a great potential in uncovering leads and drug candidates. These include predictive tools for compound design and synthetic route evaluation, chemical technologies as flow systems, bioreactors, nanotechnologies in catalysis, process control devices for in-line analysis and characterization, and, more recently, autonomous platforms and artificial intelligence. In addition, and just as importantly, the set-up and assessment of novel methods for library building as click chemistry and multicomponent reactions, as well as the process optimization for large-scale synthesis, have a considerable potential, especially when assisted by automation and learning machine.

This Special Issue of Molecules welcomes submissions of review and research articles covering the develoment and implementation of novel strategies and enabling chemical technologies that contribute to the shortening of medicinal chemistry discovery cycles.

Prof. Dr. Antimo Gioiello
Dr. Bruno Cerra
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

  • Flow chemistry
  • Automation
  • Process analytical technologies
  • Novel reaction technologies
  • Method development
  • Learning machine and predictive tools

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Published Papers (9 papers)

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Research

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14 pages, 2632 KiB  
Article
A One-Pot Divergent Sequence to Pyrazole and Quinoline Derivatives
by Guido Gambacorta, David C. Apperley and Ian R. Baxendale
Molecules 2020, 25(9), 2160; https://doi.org/10.3390/molecules25092160 - 5 May 2020
Cited by 4 | Viewed by 3238
Abstract
The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The [...] Read more.
The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The method employs cheap and easy-to-handle building blocks and allows easy isolation. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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16 pages, 2016 KiB  
Article
Parallel Interconnected Kinetic Asymmetric Transformation (PIKAT) with an Immobilized ω-Transaminase in Neat Organic Solvent
by Wesley Böhmer, Lucien Koenekoop, Timothée Simon and Francesco G. Mutti
Molecules 2020, 25(9), 2140; https://doi.org/10.3390/molecules25092140 - 3 May 2020
Cited by 7 | Viewed by 4143
Abstract
Comprising approximately 40% of the commercially available optically active drugs, α-chiral amines are pivotal for pharmaceutical manufacture. In this context, the enzymatic asymmetric amination of ketones represents a more sustainable alternative than traditional chemical procedures for chiral amine synthesis. Notable advantages are higher [...] Read more.
Comprising approximately 40% of the commercially available optically active drugs, α-chiral amines are pivotal for pharmaceutical manufacture. In this context, the enzymatic asymmetric amination of ketones represents a more sustainable alternative than traditional chemical procedures for chiral amine synthesis. Notable advantages are higher atom-economy and selectivity, shorter synthesis routes, milder reaction conditions and the elimination of toxic catalysts. A parallel interconnected kinetic asymmetric transformation (PIKAT) is a cascade in which one or two enzymes use the same cofactor to convert two reagents into more useful products. Herein, we describe a PIKAT catalyzed by an immobilized ω-transaminase (ωTA) in neat toluene, which concurrently combines an asymmetric transamination of a ketone with an anti-parallel kinetic resolution of an amine racemate. The applicability of the PIKAT was tested on a set of prochiral ketones and racemic α-chiral amines in a 1:2 molar ratio, which yielded elevated conversions (up to >99%) and enantiomeric excess (ee, up to >99%) for the desired products. The progress of the conversion and ee was also monitored in a selected case. This is the first report of a PIKAT using an immobilized ωTA in a non-aqueous environment. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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11 pages, 857 KiB  
Article
An Enzymatic Flow-Based Preparative Route to Vidarabine
by Lucia Tamborini, Clelia Previtali, Francesca Annunziata, Teodora Bavaro, Marco Terreni, Enrica Calleri, Francesca Rinaldi, Andrea Pinto, Giovanna Speranza, Daniela Ubiali and Paola Conti
Molecules 2020, 25(5), 1223; https://doi.org/10.3390/molecules25051223 - 9 Mar 2020
Cited by 17 | Viewed by 4939
Abstract
The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl–agarose and EziGTM1 (Opal) were [...] Read more.
The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl–agarose and EziGTM1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of CpUP and AhPNP, the results obtained pave the way to the use of the CpUP/AhPNP-based bioreactor for the preparation of other purine nucleosides. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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11 pages, 1880 KiB  
Article
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines
by Bruno Cerra, Antonio Macchiarulo, Andrea Carotti, Emidio Camaioni, Ina Varfaj, Roccaldo Sardella and Antimo Gioiello
Molecules 2020, 25(3), 640; https://doi.org/10.3390/molecules25030640 - 2 Feb 2020
Cited by 11 | Viewed by 3190
Abstract
In the present work, we illustrate the ability of high-performance liquid chromatography (HPLC) analysis to assist the synthesis of chiral imidazolines within our medicinal chemistry programs. In particular, a Chiralpak® IB® column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 μm silica [...] Read more.
In the present work, we illustrate the ability of high-performance liquid chromatography (HPLC) analysis to assist the synthesis of chiral imidazolines within our medicinal chemistry programs. In particular, a Chiralpak® IB® column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 μm silica gel was used for the enantioselective HPLC analysis of chiral imidazolines synthesized in the frame of hit-to-lead explorations and designed for exploring the effect of diverse amide substitutions. Very profitably, reversed-phase (RP) conditions succeeded in resolving the enantiomers in nine out of the 10 investigated enantiomeric pairs, with α values always higher than 1.10 and RS values up to 2.31. All compounds were analysed with 50% (v) water while varying the content of the two organic modifiers acetonitrile and methanol. All the employed eluent systems were buffered with 40 mM ammonium acetate while the apparent pH was fixed at 7.5. Based on the experimental results, the prominent role of π-π stacking interactions between the substituted electron-rich phenyl groups outside of the polymeric selector and the complementary aromatic region in defining analyte retention and stereodiscrimination was identified. The importance of compound polarity in explaining the retention behaviour with the employed RP system was readily evident when a quantitative structure-property relationship study was performed on the retention factor values (k) of the 10 compounds, as computed with a 30% (v) methanol containing mobile phase. Indeed, good Pearson correlation coefficients of retention factors (r - log k1st = −0.93; r - log k2nd = −0.94) were obtained with a water solubility descriptor (Ali-logS). Interestingly, a n-hexane/chloroform/ethanol (88:10:2, v/v/v)-based non-standard mobile phase allowed the almost base-line enantioseparation (α = 1.06; RS = 1.26) of the unique compound undiscriminated under RP conditions. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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10 pages, 2701 KiB  
Article
Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions
by Serena Mostarda, Tugçe Gür Maz, Alessandro Piccinno, Bruno Cerra and Erden Banoglu
Molecules 2019, 24(13), 2447; https://doi.org/10.3390/molecules24132447 - 3 Jul 2019
Cited by 7 | Viewed by 4276
Abstract
A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1′-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised [...] Read more.
A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1′-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised by means of design of experiment (DoE). The method allowed the efficient preparation of this privileged scaffold and to set up a general protocol for the multigram-scale preparation in high yield, purity, and productivity, and was successfully applied for the multigram flow synthesis of N-(2-chlorobenzyl)-5-cyano-benzimidazol-2-one, which is a key synthon for hit-to-lead explorations in our anti-inflammatory drug discovery program. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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17 pages, 3138 KiB  
Article
Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines
by Ubaldina Galli, Rejdia Hysenlika, Fiorella Meneghetti, Erika Del Grosso, Sveva Pelliccia, Ettore Novellino, Mariateresa Giustiniano and Gian Cesare Tron
Molecules 2019, 24(10), 1959; https://doi.org/10.3390/molecules24101959 - 21 May 2019
Cited by 3 | Viewed by 3983
Abstract
A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to [...] Read more.
A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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Review

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47 pages, 10111 KiB  
Review
Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility
by Blanca Angelica Vega Alanis, Maria Teresa Iorio, Luca L. Silva, Konstantina Bampali, Margot Ernst, Michael Schnürch and Marko D. Mihovilovic
Molecules 2020, 25(4), 999; https://doi.org/10.3390/molecules25040999 - 24 Feb 2020
Cited by 24 | Viewed by 11833
Abstract
GABAA receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This [...] Read more.
GABAA receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This review focuses on the synthetic accessibility and potential for library synthesis of GABAA receptor modulators containing at least one heterocyclic scaffold, which were disclosed within the last 10 years. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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12 pages, 2180 KiB  
Review
Flow Synthesis of Biologically-Relevant Compound Libraries
by Pilar María Luque Navarro and Daniela Lanari
Molecules 2020, 25(4), 909; https://doi.org/10.3390/molecules25040909 - 18 Feb 2020
Cited by 4 | Viewed by 3178
Abstract
Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists’ approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be [...] Read more.
Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists’ approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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13 pages, 2624 KiB  
Review
Continuous Flow Photochemistry for the Preparation of Bioactive Molecules
by Mara Di Filippo, Cormac Bracken and Marcus Baumann
Molecules 2020, 25(2), 356; https://doi.org/10.3390/molecules25020356 - 15 Jan 2020
Cited by 89 | Viewed by 8111
Abstract
The last decade has witnessed a remarkable development towards improved and new photochemical transformations in response to greener and more sustainable chemical synthesis needs. Additionally, the availability of modern continuous flow reactors has enabled widespread applications in view of more streamlined and custom [...] Read more.
The last decade has witnessed a remarkable development towards improved and new photochemical transformations in response to greener and more sustainable chemical synthesis needs. Additionally, the availability of modern continuous flow reactors has enabled widespread applications in view of more streamlined and custom designed flow processes. In this focused review article, we wish to evaluate the standing of the field of continuous flow photochemistry with a specific emphasis on the generation of bioactive entities, including natural products, drugs and their precursors. To this end we highlight key developments in this field that have contributed to the progress achieved to date. Dedicated sections present the variety of suitable reactor designs and set-ups available; a short discussion on the relevance of greener and more sustainable approaches; and selected key applications in the area of bioactive structures. A final section outlines remaining challenges and areas that will benefit from further developments in this fast-moving area. It is hoped that this report provides a valuable update on this important field of synthetic chemistry which may fuel developments in the future. Full article
(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)
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