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Special Issue "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).

Special Issue Editors

Prof. Dr. Antimo Gioiello
E-Mail Website1 Website2
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 papers will be 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 2000 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

Published Papers (5 papers)

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Research

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Open AccessFeature PaperArticle
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines
Molecules 2020, 25(3), 640; https://doi.org/10.3390/molecules25030640 - 02 Feb 2020
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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Open AccessArticle
Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions
Molecules 2019, 24(13), 2447; https://doi.org/10.3390/molecules24132447 - 03 Jul 2019
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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Open AccessArticle
Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines
Molecules 2019, 24(10), 1959; https://doi.org/10.3390/molecules24101959 - 21 May 2019
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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Open AccessReview
Flow Synthesis of Biologically-Relevant Compound Libraries
Molecules 2020, 25(4), 909; https://doi.org/10.3390/molecules25040909 (registering DOI) - 18 Feb 2020
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)
Open AccessReview
Continuous Flow Photochemistry for the Preparation of Bioactive Molecules
Molecules 2020, 25(2), 356; https://doi.org/10.3390/molecules25020356 - 15 Jan 2020
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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