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New Synthetic Methodology for Drug-Like Molecules

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 19839

Special Issue Editors


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Guest Editor
Institute of Chemical Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, UK
Interests: metalation; C-H functionalisation; flow chemistry; azole modifications; cellular signalling; EPACs

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Guest Editor

Special Issue Information

Dear Colleagues,

Small-molecule drugs retain their importance in modern medicine, offering advantages in shelf life and manufacturing scalability in comparison to biologics. Attempts to define “drug-likeness,” most famously Lipinski’s rules in 1997 and their multiple variants, outline the most pressing synthetic targets for the methodologist. The synthesis of drug-like and fragment-like structures has driven the development of synthetic methodology over the past 50 years, and the advent of new synthetic strategies such as electrochemistry and photocatalysis ensures that a brisk pace of discovery has been maintained up to the present day.

This Special Issue aims to provide a broad overview of the most recent developments in synthetic methodology and chemical technologies (such as flow chemistry) which facilitate the synthesis of drug-like molecules. Contributions (including full papers, communications and reviews) which report new methodologies or techniques or provide an overview of synthetic strategies for forming drug- and fragment-like scaffolds are welcome.

Dr. Graeme Barker
Prof. Dr. Simona Rapposelli
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

  • methodology
  • drug-likeness
  • lead-likeness
  • synthesis
  • flow chemistry
  • electrochemistry
  • catalysis
  • photocatalysis
  • microwave-assisted synthesis
  • heterocyclic chemistry
  • enantioselective synthesis
  • late-stage functionalization
  • medicinal chemistry
  • mechanisms

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 197 KiB  
Editorial
New Synthetic Methodology for Drug-like Molecules
by Graeme Barker and Simona Rapposelli
Molecules 2023, 28(15), 5632; https://doi.org/10.3390/molecules28155632 - 26 Jul 2023
Viewed by 1159
Abstract
The field of synthetic methodology plays a pivotal role in the quest for safe and effective drugs [...] Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)

Research

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11 pages, 1214 KiB  
Article
Synthesis and Characterization of Dihydrouracil Analogs Utilizing Biginelli Hybrids
by Syed Nasir Abbas Bukhari, Hasan Ejaz, Mervat A. Elsherif and Nenad Janković
Molecules 2022, 27(9), 2939; https://doi.org/10.3390/molecules27092939 - 04 May 2022
Cited by 1 | Viewed by 1716
Abstract
Dihydrouracil presents a crucial intermediate in the catabolism of uracil. The vital importance of uracil and its nucleoside, uridine, encourages scientists to synthesize novel dihydrouracils. In this paper, we present an innovative, fast, and effective method for the synthesis of dihydrouracils. Hence, under [...] Read more.
Dihydrouracil presents a crucial intermediate in the catabolism of uracil. The vital importance of uracil and its nucleoside, uridine, encourages scientists to synthesize novel dihydrouracils. In this paper, we present an innovative, fast, and effective method for the synthesis of dihydrouracils. Hence, under mild conditions, 3-chloroperbenzoic acid was used to cleave the carbon–sulfur bond of the Biginelli hybrids 5,6-dihydropyrimidin-4(3H)-ones. This approach led to thirteen novel dihydrouracils synthesized in moderate-to-high yields (32–99%). Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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20 pages, 1255 KiB  
Article
An Approach toward 17-Arylsubstituted Marginatafuran-Type Isospongian Diterpenoids via a Palladium-Catalyzed Heck–Suzuki Cascade Reaction of 16-Bromolambertianic Acid
by Yurii V. Kharitonov and Elvira E. Shults
Molecules 2022, 27(9), 2643; https://doi.org/10.3390/molecules27092643 - 20 Apr 2022
Cited by 4 | Viewed by 1526
Abstract
Isospongian diterpenes are a small but growing family of natural tetracyclic secondary metabolites isolated from marine organisms, primarily sponges and nudibranchs. A palladium-catalyzed domino Heck–Suzuki reaction sequence for the synthesis of the tetracyclic skeleton of marginatafuran-type isospongian diterpenoids with a wide variety of [...] Read more.
Isospongian diterpenes are a small but growing family of natural tetracyclic secondary metabolites isolated from marine organisms, primarily sponges and nudibranchs. A palladium-catalyzed domino Heck–Suzuki reaction sequence for the synthesis of the tetracyclic skeleton of marginatafuran-type isospongian diterpenoids with a wide variety of substituents in the C-17 position is reported. The proposed approach was based on selective transformations of the accessible plant diterpenoid lambertianic acid and includes an intramolecular Heck reaction of 16-bromolambertianic and arylation of the palladium intermediate with arylboronic acid. The influence of the nature of the substituent both in arylboronic acids and in the furan ring of 16-bromolambertianic acid on the direction and chemoselectivity of the reaction has been studied. The described derivatization of natural furanolabdanoid lambertianic acid produced new functionalized molecules for biological study and gave novel insights into the reactivity of complex molecular structures. Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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12 pages, 2386 KiB  
Communication
Catalyst-Free Site Selective Hydroxyalkylation of 5-Phenylthiophen-2-amine with α-Trifluoromethyl Ketones through Electrophilic Aromatic Substitution
by Valentin Duvauchelle, David Bénimélis, Patrick Meffre and Zohra Benfodda
Molecules 2022, 27(3), 925; https://doi.org/10.3390/molecules27030925 - 29 Jan 2022
Cited by 2 | Viewed by 1912
Abstract
An original and effective approach for achieving trifluoromethyl hydroxyalkylation of 5-phenylthiophen-2-amine using α-trifluoromethyl ketones is described. In the last few years, reaction of Friedel-Crafts had been widely used to realize hydroxyalkylation on heterocycles such as indoles or thiophenes by means of Lewis acid [...] Read more.
An original and effective approach for achieving trifluoromethyl hydroxyalkylation of 5-phenylthiophen-2-amine using α-trifluoromethyl ketones is described. In the last few years, reaction of Friedel-Crafts had been widely used to realize hydroxyalkylation on heterocycles such as indoles or thiophenes by means of Lewis acid as catalyst. Additionally, amine functions are rarely free when carbonyl reagents are used because of their tendency to form imines. This is the first time that a site-selective electrophilic aromatic substitution on C3 atom of an unprotected 5-phenylthiophen-2-amine moiety is reported. The liberty to allow reaction in neutral conditions between free amine is valuable in a synthesis pathway. The reaction proceeds smoothly using an atom-economical metal-and catalyst-free methodology in good to excellent yields. A mechanism similar to an electrophilic aromatic substitution has been proposed. Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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13 pages, 2639 KiB  
Communication
A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds
by Xiao-Tong Sun, Zhi-Gang Hu, Zhen Huang, Ling-Li Zhou and Jian-Quan Weng
Molecules 2022, 27(3), 726; https://doi.org/10.3390/molecules27030726 - 22 Jan 2022
Cited by 3 | Viewed by 2495
Abstract
To discover an efficient and convenient method to synthesize C2-arylacylated benzothiazoles as potential drug scaffolds, a novel [bis(trifluoroacetoxy)iodo]benzene(PIFA)/KOH synergistically promoted direct ring-opening C2-arylacylation reaction of 2H-benzothiazoles with aryl methyl ketones has been developed. Various substrates were tolerated under optimized conditions affording the [...] Read more.
To discover an efficient and convenient method to synthesize C2-arylacylated benzothiazoles as potential drug scaffolds, a novel [bis(trifluoroacetoxy)iodo]benzene(PIFA)/KOH synergistically promoted direct ring-opening C2-arylacylation reaction of 2H-benzothiazoles with aryl methyl ketones has been developed. Various substrates were tolerated under optimized conditions affording the C2-arylacylation products in 70–95% yields for 38 examples. A plausible mechanism was also proposed based on a series of controlled experiments. Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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16 pages, 18096 KiB  
Communication
New Methods for the Synthesis of Spirocyclic Cephalosporin Analogues
by Alan X. Zhao, Louise E. Horsfall and Alison N. Hulme
Molecules 2021, 26(19), 6035; https://doi.org/10.3390/molecules26196035 - 05 Oct 2021
Cited by 2 | Viewed by 2339
Abstract
Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We [...] Read more.
Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%). Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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12 pages, 2747 KiB  
Article
Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74
by Stuart Ruddell, Elena Sugrue, Sarah Memarzadeh, Lorna Mae Hellam, Sam J. Wilson and David J. France
Molecules 2021, 26(13), 3919; https://doi.org/10.3390/molecules26133919 - 26 Jun 2021
Cited by 1 | Viewed by 2819
Abstract
PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of [...] Read more.
PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) to be significantly more active than (R)-PF74 (IC50 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = −73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = −55.8 kcal/mol) in agreement with experimental observations. Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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6 pages, 499 KiB  
Article
Ultrasound-Assisted Synthesis of 4-Alkoxy-2-methylquinolines: An Efficient Method toward Antitubercular Drug Candidates
by Ana Flávia Borsoi, Josiane Delgado Paz, Kenia Pissinate, Raoní Scheibler Rambo, Víctor Zajaczkowski Pestana, Cristiano Valim Bizarro, Luiz Augusto Basso and Pablo Machado
Molecules 2021, 26(5), 1215; https://doi.org/10.3390/molecules26051215 - 24 Feb 2021
Cited by 9 | Viewed by 2014
Abstract
Tuberculosis (TB) has been described as a global health crisis since the second half of the 1990s. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB in humans, is a very successful pathogen, being the main cause of death in the population among infectious [...] Read more.
Tuberculosis (TB) has been described as a global health crisis since the second half of the 1990s. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB in humans, is a very successful pathogen, being the main cause of death in the population among infectious agents. In 2019, it was estimated that around 10 million individuals were contaminated by this bacillus and about 1.2 million succumbed to the disease. In recent years, our research group has reported the design and synthesis of quinoline derivatives as drug candidates for the treatment of TB. These compounds have demonstrated potent and selective growth inhibition of drug-susceptible and drug-resistant Mtb strains. Herein, a new synthetic approach was established providing efficient and rapid access (15 min) to a series of 4-alkoxy-6-methoxy-2-methylquinolines using ultrasound energy. The new synthetic protocol provides a simple procedure utilizing an open vessel system that affords the target products at satisfactory yields (45–84%) and elevated purities (≥95%). The methodology allows the evaluation of a larger number of molecules in assays against the bacillus, facilitating the determination of the structure–activity relationship with a reduced environmental cost. Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)

Review

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21 pages, 11557 KiB  
Review
Synthetic Methods of Phosphonopeptides
by Jiaxi Xu
Molecules 2020, 25(24), 5894; https://doi.org/10.3390/molecules25245894 - 12 Dec 2020
Cited by 7 | Viewed by 2532
Abstract
Phosphonopeptides are phosphorus analogues of peptides and have been widely applied as enzyme inhibitors and antigens to induce catalytic antibodies. Phosphonopeptides generally contain one aminoalkylphosphonic acid residue and include phosphonopeptides with C-terminal aminoalkylphosphonic acids and phosphonopeptides with a phosphonamidate bond. The phosphonamidate bond [...] Read more.
Phosphonopeptides are phosphorus analogues of peptides and have been widely applied as enzyme inhibitors and antigens to induce catalytic antibodies. Phosphonopeptides generally contain one aminoalkylphosphonic acid residue and include phosphonopeptides with C-terminal aminoalkylphosphonic acids and phosphonopeptides with a phosphonamidate bond. The phosphonamidate bond in the phosphonopeptides is generally formed via phosphonylation with phosphonochloridates, condensation with coupling reagents and enzymes, and phosphinylation followed by oxidation. Pseudo four-component condensation reaction of amides, aldehydes, alkyl dichlorophosphites, and amino/peptide esters is an alternative, convergent, and efficient strategy for synthesis of phosphonopeptides through simultaneous construction of aminoalkylphosphonic acids and formation of the phosphonamidate bond. This review focuses on the synthetic methods of phosphonopeptides containing a phosphonamidate bond. Full article
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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