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Molecules
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Multicomponent Reaction-Based Synthesis of Bioactive Molecules
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Multicomponent Reaction-Based Synthesis of Bioactive Molecules

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

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 43813

Special Issue Editors

Prof. Dr. Diego Muñoz-Torrero

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Guest Editor
Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Avenue Joan XXIII, 27-31, E-08028 Barcelona, Spain
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Rodolfo Lavilla

E-Mail Website
Guest Editor
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
Interests: multicomponent reactions; heterocyclic chemistry; scaffolds for medicinal chemistry; functional fluorophores; chemical biology
Prof. Dr. Christopher Hulme

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, and Department of Chemistry and Biochemistry, College of Pharmacy, The University of Arizona, Biological Sciences West Room 351, 1041 East Lowell Street, Tucson, AZ 85721, USA
Interests: multicomponent reactions; medicinal chemistry; diversity oriented synthesis; neurodegeneration

Special Issue Information

Dear Colleagues,

Multicomponent reactions (MCRs) involve the one-pot combination of three or more reactants to afford single products that feature structural elements of all the starting materials, thereby displaying a high degree of synthetic efficiency and atom economy. Because of their modular features, MCRs generate complex products, ideally in one step, amenable to a broad range of substitution patterns. This strategy represents a powerful tool for combinatorial and diversity-oriented synthesis, and hence, a compelling approach for new hit discovery and hit-to-lead optimization campaigns. As a consequence, MCRs are having a tremendous impact in drug discovery both in the pharmaceutical industry and in academia.

In this Special Issue, we intend to collect original research articles and short communications about medicinal chemistry projects where MCRs have played an important role in the synthesis of the target biologically active compounds or their advanced precursors. Review articles that address the role of known MCRs and the design of novel MCRs for drug discovery will be also welcome.

Prof. Dr. Diego Muñoz-Torrero
Prof. Dr. Rodolfo Lavilla
Prof. Dr. Christopher Hulme
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

  • multicomponent reactions
  • drug discovery
  • hit-to-lead optimization
  • diversity-oriented synthesis
  • structural complexity
  • exploratory power
  • iterative efficiency

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Published Papers (7 papers)

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Research

8 pages, 813 KiB  
Communication
Tetrasubstituted Imidazolium Salts as Potent Antiparasitic Agents against African and American Trypanosomiases
by Ouldouz Ghashghaei, Nicola Kielland, Marc Revés, Martin C. Taylor, John M. Kelly, Ornella Di Pietro, Diego Muñoz-Torrero, Belén Pérez and Rodolfo Lavilla
Molecules 2018, 23(1), 177; https://doi.org/10.3390/molecules23010177 - 16 Jan 2018
Cited by 6 | Viewed by 4770
Abstract
Imidazolium salts are privileged compounds in organic chemistry, and have valuable biological properties. Recent studies show that symmetric imidazolium salts with bulky moieties can display antiparasitic activity against T. cruzi. After developing a facile methodology for the synthesis of tetrasubstituted imidazolium salts [...] Read more.
Imidazolium salts are privileged compounds in organic chemistry, and have valuable biological properties. Recent studies show that symmetric imidazolium salts with bulky moieties can display antiparasitic activity against T. cruzi. After developing a facile methodology for the synthesis of tetrasubstituted imidazolium salts from propargylamines and isocyanides, we screened a small library of these adducts against the causative agents of African and American trypanosomiases. These compounds display nanomolar activity against T. brucei and low (or sub) micromolar activity against T. cruzi, with excellent selectivity indexes and favorable molecular properties, thereby emerging as promising hits for the treatment of Chagas disease and sleeping sickness. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
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2463 KiB  
Article
Multienzyme Biosynthesis of Dihydroartemisinic Acid
by Xixian Chen, Congqiang Zhang and Heng-Phon Too
Molecules 2017, 22(9), 1422; https://doi.org/10.3390/molecules22091422 - 28 Aug 2017
Cited by 21 | Viewed by 6234
Abstract
One-pot multienzyme biosynthesis is an attractive method for producing complex, chiral bioactive compounds. It is advantageous over step-by-step synthesis, as it simplifies the process, reduces costs and often leads to higher yield due to the synergistic effects of enzymatic reactions. In this study, [...] Read more.
One-pot multienzyme biosynthesis is an attractive method for producing complex, chiral bioactive compounds. It is advantageous over step-by-step synthesis, as it simplifies the process, reduces costs and often leads to higher yield due to the synergistic effects of enzymatic reactions. In this study, dihydroartemisinic acid (DHAA) pathway enzymes were overexpressed in Saccharomyces cerevisiae, and whole-cell biotransformation of amorpha-4,11-diene (AD) to DHAA was demonstrated. The first oxidation step by cytochrome P450 (CYP71AV1) is the main rate-limiting step, and a series of N-terminal truncation and transcriptional tuning improved the enzymatic activity. With the co-expression of artemisinic aldehyde dehydrogenase (ALDH1), which recycles NADPH, a significant 8-fold enhancement of DHAA production was observed. Subsequently, abiotic conditions were optimized to further enhance the productivity of the whole-cell biocatalysts. Collectively, approximately 230 mg/L DHAA was produced by the multi-step whole-cell reaction, a ~50% conversion from AD. This study illustrates the feasibility of producing bioactive compounds by in vitro one-pot multienzyme reactions. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
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722 KiB  
Article
A New Approach to Synthesize of 4-Phenacylideneflavene Derivatives and to Evaluate Their Cytotoxic Effects on HepG2 Cell Line
by Hongbin Chen, Yang Xu, Yinan Zhang and Zongping Zheng
Molecules 2017, 22(8), 1296; https://doi.org/10.3390/molecules22081296 - 9 Aug 2017
Cited by 2 | Viewed by 4251
Abstract
In this study, a convenient approach and green procedure for the synthesis of 4-phenacylideneflavenes has been developed from the reaction between 2,4-dihydroxybenzaldehyde and substituted acetophenones using boric acid as a catalyst in polyethylene glycol 400. Seven 4-phenacylideneflavenes were synthetized and their structures were [...] Read more.
In this study, a convenient approach and green procedure for the synthesis of 4-phenacylideneflavenes has been developed from the reaction between 2,4-dihydroxybenzaldehyde and substituted acetophenones using boric acid as a catalyst in polyethylene glycol 400. Seven 4-phenacylideneflavenes were synthetized and their structures were confirmed by NMR and mass spectral analyses. Meanwhile, their possible mechanism of formation was also discussed. These products were found to have potential cytotoxic effect on HepG2 cell line with IC50 values from 12.5 to 50 µM. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
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Graphical abstract

1922 KiB  
Article
An Efficient One-Pot Catalyzed Synthesis of 2,4-Disubstituted 5-Nitroimidazoles Displaying Antiparasitic and Antibacterial Activities
by Fanny Mathias, Youssef Kabri, Liliane Okdah, Carole Di Giorgio, Jean-Marc Rolain, Cédric Spitz, Maxime D. Crozet and Patrice Vanelle
Molecules 2017, 22(8), 1278; https://doi.org/10.3390/molecules22081278 - 3 Aug 2017
Cited by 9 | Viewed by 5170
Abstract
A one-pot regioselective bis-Suzuki-Miyaura or Suzuki-Miyaura/Sonogashira reaction on 2,4-dibromo-1-methyl-5-nitro-1H-imidazole under microwave heating was developed. This method is applicable to a wide range of (hetero)arylboronic acids and terminal alkynes. Additionally, this approach provides a simple and efficient way to synthesize 2,4-disubstituted 5-nitroimidazole [...] Read more.
A one-pot regioselective bis-Suzuki-Miyaura or Suzuki-Miyaura/Sonogashira reaction on 2,4-dibromo-1-methyl-5-nitro-1H-imidazole under microwave heating was developed. This method is applicable to a wide range of (hetero)arylboronic acids and terminal alkynes. Additionally, this approach provides a simple and efficient way to synthesize 2,4-disubstituted 5-nitroimidazole derivatives with antibacterial and antiparasitic properties. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
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930 KiB  
Article
Synthesis and Biological Evaluation of New Substituted Hantzsch Thiazole Derivatives from Environmentally Benign One-Pot Synthesis Using Silica Supported Tungstosilisic Acid as Reusable Catalyst
by Houria Bouherrou, Aicha Saidoun, Ahmed Abderrahmani, Lamia Abdellaziz, Yahia Rachedi, Françoise Dumas and Albert Demenceau
Molecules 2017, 22(5), 757; https://doi.org/10.3390/molecules22050757 - 7 May 2017
Cited by 24 | Viewed by 7224
Abstract
An efficient and green method has been developed for the synthesis of new substituted Hantzsch thiazole derivatives in 79%–90% yield, via the one-pot multi-component procedure, by the reaction of 3-(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, thiourea and substituted benzaldehydes in the presence of silica supported tungstosilisic [...] Read more.
An efficient and green method has been developed for the synthesis of new substituted Hantzsch thiazole derivatives in 79%–90% yield, via the one-pot multi-component procedure, by the reaction of 3-(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, thiourea and substituted benzaldehydes in the presence of silica supported tungstosilisic acid, as a reusable catalyst, under conventional heating or under ultrasonic irradiation. The catalyst is recoverable by a simple filtration and can be reused in the subsequent reactions. Most of the thiazoles exhibited significant antibacterial activity compared toamoxicillin and ciprofloxacin as positive controls. In addition, the new compounds showed moderate to good antioxidant (DPPH) radical scavenging activity. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
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2289 KiB  
Article
An Efficient One-Pot Protocol for the Synthesis of Substituted 3,4-Dihydropyrimidin-2(1H)-ones Using Metallophthalocyanines (MPcs) as Potent Heterogeneous Catalysts: Synthesis, Characterization, Aggregation and Antimicrobial Activity
by Naceur Hamdi, Rawdha Medyouni, Hallouma Bilel, Lamjed Mansour and Antonio Romerosa
Molecules 2017, 22(4), 605; https://doi.org/10.3390/molecules22040605 - 9 Apr 2017
Cited by 10 | Viewed by 5696
Abstract
In this study, novel phthalonitrile 3 and their corresponding metal-free 4 and metallophthalocyanine derivatives 5–7 bearing 2-isopropenyl-4-methoxy-1-methylbenzene groups were synthesized and characterized. 3,4-Dihydropyrimidinones have been synthesized by a modified Biginelli-type reaction with various metallophthalocyanines 5–7 as catalysts. Compared to [...] Read more.
In this study, novel phthalonitrile 3 and their corresponding metal-free 4 and metallophthalocyanine derivatives 5–7 bearing 2-isopropenyl-4-methoxy-1-methylbenzene groups were synthesized and characterized. 3,4-Dihydropyrimidinones have been synthesized by a modified Biginelli-type reaction with various metallophthalocyanines 5–7 as catalysts. Compared to the classical Biginielli reaction, the new method has the advantages of good yield and short reaction time. Among the various metallophthalocyanines studied, cobalt (II)-phthalocyanine was found to be most active for this transformation. The newly prepared compounds were characterized using elemental analyses, MS, IR, 1H/13C-NMR and UV-Vis spectroscopy. In addition; the 3,4-dihydropyrimidinones (DHPMs) 8–12 were investigated for antimicrobial activities and revealed good activity. The minimum inhibitory concentration (MIC) was determined by the microdilution technique in Mueller-Hinton broth. The MICs were recorded after 24 hours of incubation at 37 °C. These results are promising, showing these compounds are biologically active. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
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2134 KiB  
Communication
Reaction of 3-Amino-1,2,4-Triazole with Diethyl Phosphite and Triethyl Orthoformate: Acid-Base Properties and Antiosteoporotic Activities of the Products
by Patrycja Miszczyk, Dorota Wieczorek, Joanna Gałęzowska, Błażej Dziuk, Joanna Wietrzyk and Ewa Chmielewska
Molecules 2017, 22(2), 254; https://doi.org/10.3390/molecules22020254 - 8 Feb 2017
Cited by 8 | Viewed by 9008
Abstract
The reaction of diethyl phosphite with triethyl orthoformate and a primary amine followed by hydrolysis is presented, and the reaction was suitable for the preparation of (aminomethylene)bisphosphonates. 3-Amino-1,2,4-triazole was chosen as an interesting substrate for this reaction because it possesses multiple groups that [...] Read more.
The reaction of diethyl phosphite with triethyl orthoformate and a primary amine followed by hydrolysis is presented, and the reaction was suitable for the preparation of (aminomethylene)bisphosphonates. 3-Amino-1,2,4-triazole was chosen as an interesting substrate for this reaction because it possesses multiple groups that can serve as the amino component in the reaction—namely, the side-chain and triazole amines. This substrate readily forms 1,2,4-triazolyl-3-yl-aminomethylenebisphosphonic acid (compound 1) as a major product, along with N-ethylated bisphosphonates as side products. The in vitro antiproliferative effects of the synthesized aminomethylenebisphosphonic acids against J774E macrophages were determined. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
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