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Application of Organic Synthesis to Bioactive Compounds
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Application of Organic Synthesis to Bioactive Compounds

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

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 93751

Special Issue Editors

Prof. Dr. David Díez

E-Mail Website
Guest Editor
Department of Organic Chemistry, Faculty of Chemical Sciences, University of Salamanca, Castilla y León, 37008 Salamanca, Spain
Interests: natural product transformations; organocatalysis; organic synthesis
Special Issues, Collections and Topics in MDPI journals
Dr. Mª Ángeles Castro

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences: Pharmaceutical Chemistry, Faculty of Pharmacy, University of Salamanca, CIETUS, IBSAL, 37007 Salamanca, Spain
Interests: medicinal chemistry; organic synthesis; drug development; natural products; hybridization; antitumoral; antiparasitics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

After a billion of years of evolution, nature has achieved an enormous variety of chemical compounds that have extraordinary structural diversity and functional value. Many of these compounds have been used for plants and animals, for communication, relationships, etc. Humans have also realized that some of these compounds could be useful for the treatment of illnesses that affect their health. In many cases, the quantities available in nature are not enough for the treatment of affected people or even for appropriate biological testing. This makes it necessary to obtain them by other procedures. In this case, it is necessary to establish adequate starting materials for the synthesis not only of those biologically active compounds but also of their analogues. An easy approach is the structural manipulation of other abundant natural products to produce a similar functionalization to the bioactive compounds, which is known as hemi- or semi-synthesis. Other approaches include total synthesis. Recently there has been a large variety of methodologies directed at achieving bioactive compounds, such as diversity-oriented synthesis, target-oriented synthesis, biologically-oriented synthesis, and function-oriented synthesis, among others.

The Special Issue “Application of Organic Synthesis to Bioactive Compounds” aims to present the most recent achievements in the organic synthesis not only of natural products, but also the synthesis of active compounds not present in nature. The manuscripts together with review papers will summarize the “state of the art” of the synthesis of bioactive compounds.

Prof. David Díez
Prof. María Ángeles Castro
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

  • Natural products
  • Organic synthesis
  • Bioactive compounds

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Published Papers (23 papers)

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17 pages, 1672 KiB  
Article
Design, Synthesis, and Antimicrobial Evaluation of New Annelated Pyrimido[2,1-c][1,2,4]triazolo[3,4-f][1,2,4]triazines
by Islam H. El Azab and Nadia A.A. Elkanzi
Molecules 2020, 25(6), 1339; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25061339 - 15 Mar 2020
Cited by 15 | Viewed by 2769
Abstract
A series of 34 new pyrimido[2,1-c][1,2,4]triazine-3,4-diones were synthesized and fully characterized using IR, NMR, MS, and microanalytical analysis. In vitro investigation of 12 compounds of this series revealed promising antimicrobial activity of the conjugates 15a and 15f–j that were [...] Read more.
A series of 34 new pyrimido[2,1-c][1,2,4]triazine-3,4-diones were synthesized and fully characterized using IR, NMR, MS, and microanalytical analysis. In vitro investigation of 12 compounds of this series revealed promising antimicrobial activity of the conjugates 15a and 15f–j that were tagged with electron-withdrawing groups, with sensitivities ranging from 77% to as high as 100% of the positive control. The investigation of antimicrobial activity included Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6535, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 8739 (EC), and fungal strains Candida albicans ATCC 10231 and Aspergillus brasiliensis ATCC 16404. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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23 pages, 5422 KiB  
Article
Multicomponent Domino Reaction in the Asymmetric Synthesis of Cyclopentan[c]pyran Core of Iridoid Natural Products
by Alejandro Manchado, Victoria Elena Ramos, David Díez and Narciso M. Garrido
Molecules 2020, 25(6), 1308; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25061308 - 13 Mar 2020
Cited by 3 | Viewed by 3373
Abstract
The asymmetric synthesis of a compound with the cyclopentan[c]pyran core of iridoid natural products in four steps and 40% overall yield is reported. Our methodology includes a one-pot tandem domino reaction which provides a trisubstituted cyclopentane with five new completely determined stereocenters, which [...] Read more.
The asymmetric synthesis of a compound with the cyclopentan[c]pyran core of iridoid natural products in four steps and 40% overall yield is reported. Our methodology includes a one-pot tandem domino reaction which provides a trisubstituted cyclopentane with five new completely determined stereocenters, which were determined through 2D homo and heteronuclear NMR and n.O.e. experiments on different compounds specially designed for this purpose, such as a dioxane obtained from a diol. Due to their pharmaceutical properties, including sedative, analgesic, anti-inflammatory, CNS depressor or anti-conceptive effects, this methodology to produce the abovementioned iridoid derivatives, is an interesting strategy in terms of new drug discovery as well as pharmaceutical development. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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17 pages, 3594 KiB  
Article
Synthetic Approaches to a Challenging and Unusual Structure—An Amino-Pyrrolidine Guanine Core
by Rafael Rippel, Luís Pinheiro, Mónica Lopes, Ana Lourenço, Luísa M. Ferreira and Paula S. Branco
Molecules 2020, 25(4), 797; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25040797 - 12 Feb 2020
Cited by 2 | Viewed by 3725
Abstract
The synthesis of an unreported 2-aminopyrrolidine-1-carboxamidine unit is here described for the first time. This unusual and promising structure was attained through the oxidative decarboxylation of amino acids using the pair of reagents, silver(I)/peroxydisulfate (Ag(I)/S2O82−) followed by intermolecular [...] Read more.
The synthesis of an unreported 2-aminopyrrolidine-1-carboxamidine unit is here described for the first time. This unusual and promising structure was attained through the oxidative decarboxylation of amino acids using the pair of reagents, silver(I)/peroxydisulfate (Ag(I)/S2O82−) followed by intermolecular (in the case of l-proline derivative) and intramolecular trapping (in the case of acyl l-arginine) by N-nucleophiles. The l-proline approach has a broader scope for the synthesis of 2-aminopyrrolidine-1-carboxamidine derivatives, whereas the intramolecular cyclization afforded by the l-acylarginines, when applied, results in higher yields. The former allowed the first synthesis of cernumidine, a natural alkaloid isolated in 2011 from Solanum cernuum Vell, as its racemic form. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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12 pages, 1836 KiB  
Article
One-Pot Multicomponent Synthesis and Cytotoxic Evaluation of Novel 7-Substituted-5-(1H-Indol-3-yl)Tetrazolo[1,5-a] Pyrimidine-6-Carbonitrile
by Mohamed A. A. Radwan, Fahad M. Alminderej and Hanem M. Awad
Molecules 2020, 25(2), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020255 - 08 Jan 2020
Cited by 24 | Viewed by 12079
Abstract
A series of novel 7-substituted-5-(1H-indol-3-yl)tetrazolo[1,5-a]pyrimidine-6-carbonitrile was synthesized via a one-pot, three-multicomponent reaction of appropriate aldehydes, 1H-tetrazole-5-amine and 3-cyanoacetyl indole in catalytic triethylamine. The cytotoxic activity of the new synthesized tetrazolopyrimidine-6-carbonitrile compounds was investigated against HCT-116, MCF-7, MDA-MB-231, [...] Read more.
A series of novel 7-substituted-5-(1H-indol-3-yl)tetrazolo[1,5-a]pyrimidine-6-carbonitrile was synthesized via a one-pot, three-multicomponent reaction of appropriate aldehydes, 1H-tetrazole-5-amine and 3-cyanoacetyl indole in catalytic triethylamine. The cytotoxic activity of the new synthesized tetrazolopyrimidine-6-carbonitrile compounds was investigated against HCT-116, MCF-7, MDA-MB-231, A549 human cancer cell lines and one human healthy normal cell line (RPE-1) using the MTT cytotoxicity assay. Compounds 4h, 4b, 4c, 4i and 4a showed potent anticancer activities against human colon cancer. Additionally, all the compounds showed potent anticancer activities on human lung cancer. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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11 pages, 1621 KiB  
Article
Novel Synthetic Approaches for Bisnaphthalimidopropyl (BNIP) Derivatives as Potential Anti-Parasitic Agents for the Treatment of Leishmaniasis
by Elif Keskin, Mehmet Hikmet Ucisik, Bilgesu Onur Sucu and Mustafa Guzel
Molecules 2019, 24(24), 4607; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24244607 - 16 Dec 2019
Cited by 5 | Viewed by 2847
Abstract
Leishmaniasis is a neglected parasitic disease that is widely seen in more than 60 countries worldwide, including Turkey and its subcontinental region. There are several chemotherapy agents for the treatment of leishmaniasis, including pentavalent antimonials—i.e., sodium stibogluconate (Pentostan) and meglumine antimoniate (Glucantim), pentamidine, [...] Read more.
Leishmaniasis is a neglected parasitic disease that is widely seen in more than 60 countries worldwide, including Turkey and its subcontinental region. There are several chemotherapy agents for the treatment of leishmaniasis, including pentavalent antimonials—i.e., sodium stibogluconate (Pentostan) and meglumine antimoniate (Glucantim), pentamidine, conventional amphotericin B deoxycholate, miltefosine, paramomycin (aminosidine), and liposomal amphotericin B. However, these therapies are usually unsatisfactory due to dose-limiting toxicity issues and limited efficacy. Furthermore, resistance gained by parasites endangers future success of these therapies. Addressing these issues, the development of novel drugs with high efficacy has a vital importance. Latest studies have shown that bisnaphthalimidopropyl (BNIP) derivatives display high activity against Leishmaniasis parasites by selectively targeting parasitic sirtuin proteins and interacting with DNA. Despite the promising anti-parasitic activity, the low solubility and toxicity on human macrophages are the limitations to overcome. This study describes the new synthesis strategies for existing—i.e., BNIPDaoct and BNIPDanon—and novel BNIP derivatives differing in respect of their alkyl linker chain lengths. The new synthesis approach provides certain advantages compared to its existing alternatives reported in the literature. The proposed methodology does not only decrease the number of synthesis steps and production time of BNIPDaoct and BNIPDanon, but also provides higher yields, thereby making the synthesis highly cost-effective. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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14 pages, 961 KiB  
Article
Synthesis of Amino Acid–Naphthoquinones and In Vitro Studies on Cervical and Breast Cell Lines
by Ernesto Rivera-Ávalos, Denisse de Loera, Jorge Gustavo Araujo-Huitrado, Ismailia Leilani Escalante-García, Miguel Antonio Muñoz-Sánchez, Hiram Hernández, Jesús Adrián López and Lluvia López
Molecules 2019, 24(23), 4285; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24234285 - 25 Nov 2019
Cited by 18 | Viewed by 4017
Abstract
We performed an extensive analysis about the reaction conditions of the 1,4-Michael addition of amino acids to 1,4-naphthoquinone and substitution to 2,3-dichloronaphthoquinone, and a complete evaluation of stoichiometry, use of different bases, and the pH influence was performed. We were able to show [...] Read more.
We performed an extensive analysis about the reaction conditions of the 1,4-Michael addition of amino acids to 1,4-naphthoquinone and substitution to 2,3-dichloronaphthoquinone, and a complete evaluation of stoichiometry, use of different bases, and the pH influence was performed. We were able to show that microwave-assisted synthesis is the best method for the synthesis of naphthoquinone–amino acid and chloride–naphthoquinone–amino acid derivatives with 79–91% and 78–91% yields, respectively. The cyclic voltammetry profiles showed that both series of naphthoquinone–amino acid derivatives mainly display one quasi-reversible redox reaction process. Interestingly, it was shown that naphthoquinone derivatives possess a selective antitumorigenic activity against cervix cancer cell lines and chloride–naphthoquinone–amino acid derivatives against breast cancer cell lines. Furthermore, the newly synthetized compounds with asparagine–naphthoquinones (3e and 4e) inhibited ~85% of SiHa cell proliferation. These results show promising compounds for specific cervical and breast cancer treatment. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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9 pages, 607 KiB  
Article
Antibacterial and Antifungal Activity of Three Monosaccharide Monomyristate Derivatives
by Jumina Jumina, Mutmainah Mutmainah, Bambang Purwono, Yehezkiel Steven Kurniawan and Yana Maolana Syah
Molecules 2019, 24(20), 3692; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24203692 - 14 Oct 2019
Cited by 23 | Viewed by 4045
Abstract
Microbial infections remains a serious challenge in food industries due to their resistance to some of the well-known antibacterial and antifungal agents. In this work, a novel monomyristoyl ester (fructosyl monomyristate) and two other derivatives (i.e., glucosyl and galactosyl monomyristates) were successfully synthesized [...] Read more.
Microbial infections remains a serious challenge in food industries due to their resistance to some of the well-known antibacterial and antifungal agents. In this work, a novel monomyristoyl ester (fructosyl monomyristate) and two other derivatives (i.e., glucosyl and galactosyl monomyristates) were successfully synthesized from myristic acid and monosaccharides in two-step reactions. First, the myristic acid was converted to myristoyl chloride, and then the myristoyl chloride was reacted with fructose, glucose and galactose separately to produce the corresponding monosaccharide monomyristate derivatives. The structures of the synthesized products were confirmed by Fourier transform infrared (FTIR), proton and carbon nuclear magnetic resonance (1H- and 13C-NMR), and mass spectral (MS) data. The monomyristates esters were obtained in reaction yields of 45.80%–79.49%. The esters were then evaluated for their antimicrobial activity using the disc diffusion test. It was found that the esters exhibited a medium antibacterial activity against gram-positive bacteria; however, they showed a weak antibacterial activity against gram-negative bacteria. Amongst the esters, galactosyl myristate yielded the highest antibacterial activity against Salmonella typhimurium, Staphylococcus aureus and Bacillus subtilis, while glucosyl monomyristate exhibited the highest antibacterial activity only against Escherichia coli. Additionally, all products showed remarkable antifungal activity against Candida albicans. These findings demonstrate that monosaccharide monomyristate derivatives are promising for use as biocompatible antimicrobial agents in the future. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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16 pages, 1902 KiB  
Article
Asymmetric and Reduced Xanthene Fluorophores: Synthesis, Photochemical Properties, and Application to Activatable Fluorescent Probes for Detection of Nitroreductase
by Kunal N. More, Tae-Hwan Lim, Julie Kang, Hwayoung Yun, Sung-Tae Yee and Dong-Jo Chang
Molecules 2019, 24(17), 3206; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24173206 - 03 Sep 2019
Cited by 13 | Viewed by 6162
Abstract
Xanthene fluorophores, including fluorescein, rhodol, and rhodamines, are representative classes of fluorescent probes that have been applied in the detection and visualization of biomolecules. “Turn on” activatable fluorescent probes, that can be turned on in response to enzymatic reactions, have been developed and [...] Read more.
Xanthene fluorophores, including fluorescein, rhodol, and rhodamines, are representative classes of fluorescent probes that have been applied in the detection and visualization of biomolecules. “Turn on” activatable fluorescent probes, that can be turned on in response to enzymatic reactions, have been developed and prepared to reduce the high background signal of “always-on” fluorescent probes. However, the development of activity-based fluorescent probes for biological applications, using simple xanthene dyes, is hampered by their inefficient synthetic methods and the difficulty of chemical modifications. We have, thus, developed a highly efficient, versatile synthetic route to developing chemically more stable reduced xanthene fluorophores, based on fluorescein, rhodol, and rhodamine via continuous Pd-catalyzed cross-coupling. Their fluorescent nature was evaluated by monitoring fluorescence with variation in the concentration, pH, and solvent. As an application to activatable fluorescent probe, nitroreductase (NTR)-responsive fluorescent probes were also developed using the reduced xanthene fluorophores, and their fluorogenic properties were evaluated. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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15 pages, 3027 KiB  
Article
Germacrone Derivatives as new Insecticidal and Acaricidal Compounds: A Structure-Activity Relationship
by Alberto Galisteo Pretel, Helena Pérez del Pulgar, Estela Guerrero de León, José Luis López-Pérez, A. Sonia Olmeda, Azucena Gonzalez-Coloma, Alejandro F. Barrero and José Francisco Quílez del Moral
Molecules 2019, 24(16), 2898; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24162898 - 09 Aug 2019
Cited by 5 | Viewed by 3973
Abstract
Currently, the use of synthetic pesticides is the main method of plant protection applied in agri- and horticulture. However, its excessive use leads to the development of pesticide resistance, a contamination of the environment, toxicity to non-target organisms, and risks for human health. [...] Read more.
Currently, the use of synthetic pesticides is the main method of plant protection applied in agri- and horticulture. However, its excessive use leads to the development of pesticide resistance, a contamination of the environment, toxicity to non-target organisms, and risks for human health. With the ultimate aim of contributing to the develop of a more sustainable pest management, we used the natural product germacrone (compound 1), reported to possess significant insecticidal activity, as starting material for the generation of molecular diversity (2–24). Some of the generated derivatives are natural compounds, such as 1,10-epoxygermacrone (2), 4,5-epoxygermacrone (3), gajutsulactone A (7), germacrol (11), isogermacrone (14), 9-hydroxyeudesma-3,7(11)dien-6-one (19), eudesma-4,7(11),dien-8-one (20), eudesma-3,7(11)-dien-8-one (21) and eudesma-4(15),7(11)-dien-8-one (22). Compounds, 7,11-9,10-diepoxigermacr-4,5-en-8-ol (17), 7,11-epoxieudesma-4,7(11)-dien-8-one (23) and 7,11-epoxieudesma-3,7(11)-dien-8-one (24) are described for the first time. The biocidal activity of most of these compounds was assayed against the tick Hyalomma lusitanicum. The acaricidal effects of compound 24 were four times higher than that of germacrone (1). Compound 2 is an insect antifeedant a thousand times more potent than germacrone against Rhopalosiphum padi, which makes this substance a promising selective antifeedant against this cereal pest. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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21 pages, 1434 KiB  
Article
Thiol-ene "Click" Synthesis and Pharmacological Evaluation of C-Glycoside sp2-Iminosugar Glycolipids
by Elena M. Sánchez-Fernández, M. Isabel García-Moreno, Raquel García-Hernández, José M. Padrón, José M. García Fernández, Francisco Gamarro and Carmen Ortiz Mellet
Molecules 2019, 24(16), 2882; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24162882 - 08 Aug 2019
Cited by 9 | Viewed by 3669
Abstract
The unique stereoelectronic properties of sp2-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp2-iminosugar conjugates, the sp2-iminosugar glycolipids (sp2-IGLs) have shown a variety of interesting pharmacological properties ranging [...] Read more.
The unique stereoelectronic properties of sp2-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp2-iminosugar conjugates, the sp2-iminosugar glycolipids (sp2-IGLs) have shown a variety of interesting pharmacological properties ranging from glycosidase inhibition to antiproliferative, antiparasitic, and anti-inflammatory activities. Developing strategies compatible with molecular diversity-oriented strategies for structure–activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective C-allylation followed by thiol-ene “click” coupling provides a very convenient access to α-C-glycoside sp2-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp2-iminosugar precursors with different configurational profiles (d-gluco or d-galacto in this work) and varied thiols, as well as by oxidation of the sulfide adducts (to the corresponding sulfones in this work). A series of derivatives was prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were evaluated in different settings. The results confirm that the inhibition of glycosidases, particularly α-glucosidase, and the antitumor/leishmanicidal activities are unrelated. The data are also consistent with the two later activities arising from the ability of the sp2-IGLs to interfere in the immune system response in a cell line and cell context dependent manner. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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15 pages, 4055 KiB  
Article
Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines
by Daniel Segura-Olvera, Ailyn N. García-González, Ivette Morales-Salazar, Alejandro Islas-Jácome, Yareli Rojas-Aguirre, Ilich A. Ibarra, Erik Díaz-Cervantes, Sofía Lizeth Alcaraz-Estrada and Eduardo González-Zamora
Molecules 2019, 24(14), 2648; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24142648 - 22 Jul 2019
Cited by 7 | Viewed by 3438
Abstract
A series of 12 polysubstituted pyrrolo[3,4-b]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi–3CR/aza Diels-Alder/N-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative [...] Read more.
A series of 12 polysubstituted pyrrolo[3,4-b]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi–3CR/aza Diels-Alder/N-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative cytotoxicity against the three cell lines, with HeLa being the most sensitive one. Then, based on these results, in silico studies by docking techniques were performed using Paclitaxel as a reference and αβ-tubulin as the selected biological target. Worth highlighting is that strong hydrophobic interactions were observed between the three active molecules and the reference drug Paclitaxel, to the αβ-tubulin. In consequence, it was determined that hydrophobic–aromatic moieties of bioactive compounds and Paclitaxel play a key role in making stronger interactions to the ligand–target complex. A quantitative structure activity relationship (QSAR) study revealed that the six membered rings are the most significant molecular frameworks, being present in all proposed models for the in vitro-studied cell lines. Finally, also from the docking interpretation, a ligand-based pharmacophore model is proposed in order to find further potential polyheterocyclic candidates to bind stronger to the αβ-tubulin. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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20 pages, 5249 KiB  
Article
Synthesis, Crystal Structure, and Biological Evaluation of Fused Thiazolo[3,2-a]Pyrimidines as New Acetylcholinesterase Inhibitors
by Mohamed Y. Mahgoub, Awatef M. Elmaghraby, Abd-Elfttah A. Harb, João L. Ferreira da Silva, Gonçalo C. Justino and M. Matilde Marques
Molecules 2019, 24(12), 2306; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24122306 - 21 Jun 2019
Cited by 15 | Viewed by 3536
Abstract
A new series of thiazolo[3,2-a]pyrimidine bromide salt derivatives 7a–d were synthesized from 3,4-dihydropyrimidinethione precursors. The target compounds were fully characterized by 1D- and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which confirmed a regioselective 5H [...] Read more.
A new series of thiazolo[3,2-a]pyrimidine bromide salt derivatives 7a–d were synthesized from 3,4-dihydropyrimidinethione precursors. The target compounds were fully characterized by 1D- and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which confirmed a regioselective 5H cyclization of the dihydropyrimidinethiones. All target compounds were evaluated in vitro as human acetylcholinesterase (hAChE) inhibitors via an Ellman-based colorimetric assay and showed good inhibition activities (better than 70% at 10 µM and IC50 values in the 1 µM range). Molecular docking simulations for all target products into hAChE were performed and confirmed strong binding to the enzyme. These results provide a promising and new starting point to improve acetylcholinesterase inhibitors and explore novel treatment options against Alzheimer’s disease. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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17 pages, 3683 KiB  
Article
Antiproliferative Benzoindazolequinones as Potential Cyclooxygenase-2 Inhibitors
by Aurora Molinari, Alfonso Oliva, Marlene Arismendi-Macuer, Leda Guzmán, Waldo Acevedo, Daniel Aguayo, Raúl Vinet and Arturo San Feliciano
Molecules 2019, 24(12), 2261; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24122261 - 18 Jun 2019
Cited by 7 | Viewed by 3406
Abstract
Quinones and nitrogen heterocyclic moieties have been recognized as important pharmacophores in the development of antitumor agents. This study aimed to establish whether there was any correlation between the in silico predicted parameters and the in vitro antiproliferative activity of a family of [...] Read more.
Quinones and nitrogen heterocyclic moieties have been recognized as important pharmacophores in the development of antitumor agents. This study aimed to establish whether there was any correlation between the in silico predicted parameters and the in vitro antiproliferative activity of a family of benzoindazolequinones (BIZQs), and to evaluate overexpressed proteins in human cancer cells as potential biomolecular targets of these compounds. For this purpose, this study was carried out using KATO-III and MCF-7 cell lines as in vitro models. Docking results showed that these BIZQs present better binding energies (ΔGbin) values for cyclooxygenase-2 (COX-2) than for other cancer-related proteins. The predicted ∆Gbin values of these BIZQs, classified in three series, positively correlated with IC50 measured in both cell lines (KATO-III: 0.72, 0.41, and 0.90; MCF-7: 0.79, 0.55, and 0.87 for Series I, II, and III, respectively). The results also indicated that compounds 2a, 2c, 6g, and 6k are the most prominent BIZQs, because they showed better IC50 and ∆Gbin values than the other derivatives. In silico drug absorption, distribution, metabolism, and excretion (ADME) properties of the three series were also analyzed and showed that several BIZQs could be selected as potential candidates for cancer pre-clinical assays. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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15 pages, 2654 KiB  
Article
Synthesis, X-ray Analysis, Biological Evaluation and Molecular Docking Study of New Thiazoline Derivatives
by Yahia N. Mabkhot, H. Algarni, Abdulrhman Alsayari, Abdullatif Bin Muhsinah, Nabila A. Kheder, Zainab M. Almarhoon and Faiz A. Al-aizari
Molecules 2019, 24(9), 1654; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24091654 - 26 Apr 2019
Cited by 10 | Viewed by 3350
Abstract
A series of new thiazoline derivatives were synthesized. Structure analyses were accomplished employing 1H-NMR, 13C-NMR, X-ray and MS techniques. The in vitro antitumor activities were assessed against human hepatocellular carcinoma (HepG-2) and colorectal carcinoma (HCT-116) cell lines. The results revealed that [...] Read more.
A series of new thiazoline derivatives were synthesized. Structure analyses were accomplished employing 1H-NMR, 13C-NMR, X-ray and MS techniques. The in vitro antitumor activities were assessed against human hepatocellular carcinoma (HepG-2) and colorectal carcinoma (HCT-116) cell lines. The results revealed that the thiazolines 5b and 2c exhibited significant activity against the two cell lines. The in vitro antimicrobial screening showed that the thiazolines 2c, 5b and 5d showed promising inhibition activity against Salmonella sp. Additionally, the inhibition activity of thiazolines 2e and 5b against Escherichia coli was comparable to that of the reference compound gentamycin. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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17 pages, 2282 KiB  
Article
Anti-Herpetic, Anti-Dengue and Antineoplastic Activities of Simple and Heterocycle-Fused Derivatives of Terpenyl-1,4-Naphthoquinone and 1,4-Anthraquinone
by Vicky C. Roa-Linares, Yaneth Miranda-Brand, Verónica Tangarife-Castaño, Rodrigo Ochoa, Pablo A. García, Mª Ángeles Castro, Liliana Betancur-Galvis and Arturo San Feliciano
Molecules 2019, 24(7), 1279; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24071279 - 02 Apr 2019
Cited by 29 | Viewed by 3545
Abstract
Quinones are secondary metabolites of higher plants associated with many biological activities, including antiviral effects and cytotoxicity. In this study, the anti-herpetic and anti-dengue evaluation of 27 terpenyl-1,4-naphthoquinone (NQ), 1,4-anthraquinone (AQ) and heterocycle-fused quinone (HetQ) derivatives was done in vitro against Human Herpesvirus [...] Read more.
Quinones are secondary metabolites of higher plants associated with many biological activities, including antiviral effects and cytotoxicity. In this study, the anti-herpetic and anti-dengue evaluation of 27 terpenyl-1,4-naphthoquinone (NQ), 1,4-anthraquinone (AQ) and heterocycle-fused quinone (HetQ) derivatives was done in vitro against Human Herpesvirus (HHV) type 1 and 2, and Dengue virus serotype 2 (DENV-2). The cytotoxicity on HeLa and Jurkat tumor cell lines was also tested. Using plaque forming unit assays, cell viability assays and molecular docking, we found that NQ 4 was the best antiviral compound, while AQ 11 was the most active and selective molecule on the tested tumor cells. NQ 4 showed a fair antiviral activity against Herpesviruses (EC50: <0.4 µg/mL, <1.28 µM) and DENV-2 (1.6 µg/mL, 5.1 µM) on pre-infective stages. Additionally, NQ 4 disrupted the viral attachment of HHV-1 to Vero cells (EC50: 0.12 µg/mL, 0.38 µM) with a very high selectivity index (SI = 1728). The in silico analysis predicted that this quinone could bind to the prefusion form of the E glycoprotein of DENV-2. These findings demonstrate that NQ 4 is a potent and highly selective antiviral compound, while suggesting its ability to prevent Herpes and Dengue infections. Additionally, AQ 11 can be considered of interest as a leader for the design of new anticancer agents. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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9 pages, 1714 KiB  
Article
Enantioselective Synthesis of the Ethyl Analog of the Marine Alkaloid Haliclorensin C
by Guillaume Guignard, Núria Llor, David Pubill, Joan Bosch and Mercedes Amat
Molecules 2019, 24(6), 1069; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24061069 - 18 Mar 2019
Viewed by 2665
Abstract
The enantioselective synthesis (3.7% overall yield in nine steps from 2) and biological screening of the ethyl analog of the macrocyclic marine alkaloid haliclorensin C (compound 5) are reported. Amino alcohol 3, generated by a LiNH2BH3-promoted [...] Read more.
The enantioselective synthesis (3.7% overall yield in nine steps from 2) and biological screening of the ethyl analog of the macrocyclic marine alkaloid haliclorensin C (compound 5) are reported. Amino alcohol 3, generated by a LiNH2BH3-promoted reductive ring-opening/debenzylation sequence from phenylglycinol-derived lactam 2, was used as the starting chiral linear building block. Incorporation of the undecene chain via the nosyl derivative 12, methylenation of the pentanol moiety, and a ring-closing metathesis are the key steps of the synthesis. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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11 pages, 2711 KiB  
Article
The First Total Synthesis of (±)-Methyl Salvianolate A Using a Convergent Strategy
by Bo Wang, Liping Wang, Ying Peng, Yiying Pang, Hesheng Xiao, Xiaoji Wang and Shuangping Huang
Molecules 2019, 24(5), 999; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24050999 - 12 Mar 2019
Cited by 2 | Viewed by 3548
Abstract
Herein, a convergent, practicable and first total synthesis of the natural product, (±)-methyl salvianolate A, is reported. The key features of the approach are the use of a Horner–Wadsworth–Emmons reaction and the protection of multiple hydroxyls using silyl protecting groups. The employment of [...] Read more.
Herein, a convergent, practicable and first total synthesis of the natural product, (±)-methyl salvianolate A, is reported. The key features of the approach are the use of a Horner–Wadsworth–Emmons reaction and the protection of multiple hydroxyls using silyl protecting groups. The employment of the readily removable silyl protecting groups allows the synthesis of (±)-methyl salvianolate A and its derivatives on a reasonably large scale. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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12 pages, 2408 KiB  
Article
Novel Phosphorylated Penta-1,4-dien-3-one Derivatives: Design, Synthesis, and Biological Activity
by Lijuan Chen, Tao Guo, Rongjiao Xia, Xu Tang, Ying Chen, Cheng Zhang and Wei Xue
Molecules 2019, 24(5), 925; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24050925 - 07 Mar 2019
Cited by 18 | Viewed by 2961
Abstract
A series of novel phosphorylated penta-1,4-dien-3-one derivatives were designed and synthesized. The structures of all title compounds were determined by 1H-NMR, 13C-NMR, 31P-NMR, and high-resolution mass spectrometry (HRMS). Bioassay results showed that several of the title compounds exhibited remarkable antibacterial [...] Read more.
A series of novel phosphorylated penta-1,4-dien-3-one derivatives were designed and synthesized. The structures of all title compounds were determined by 1H-NMR, 13C-NMR, 31P-NMR, and high-resolution mass spectrometry (HRMS). Bioassay results showed that several of the title compounds exhibited remarkable antibacterial and antiviral activities. Among these, compound 3g exhibited substantial antibacterial activity against Xanthomonas oryzae pv. Oryzae (Xoo), with a 50% effective concentration (EC50) value of 8.6 μg/mL, which was significantly superior to bismerthiazol (BT) (58.8 µg/mL) and thiodiazole-copper (TC) (78.7 μg/mL). In addition, compound 3h showed remarkable protective activity against tobacco mosaic virus (TMV), with an EC50 value of 104.2 μg/mL, which was superior to that of ningnanmycin (386.2 μg/mL). Furthermore, the microscale thermophoresis and molecular docking experiments on the interaction of compounds 3h and 3j with TMV coat protein (TMV CP) were also investigated. Compounds 3h and 3j bound to TMV CP with dissociation constants of 0.028 and 0.23 μmol/L, which were better than that of ningnanmycin (0.52 μmol/L). These results suggest that novel phosphorylated penta-1,4-dien-3-one derivatives may be considered as an activator for antibacterial and antiviral agents. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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14 pages, 2435 KiB  
Article
A Straightforward Synthesis of Functionalized cis-Perhydroisoquinolin-1-ones
by Federica Arioli, Maria Pérez, Celeste Are, Elies Molins, Joan Bosch and Mercedes Amat
Molecules 2019, 24(3), 557; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24030557 - 03 Feb 2019
Viewed by 2979
Abstract
Base-catalyzed annulation reactions of 5,6-dihydro-2(1H)-pyridones with Nazarov-type reagents are reported. The effect of the solvent polarity and the concentration of the reagents is studied. The process involves two successive Michael additions and stereoselectively provides functionalized cis-perhydroisoquinolin-1-ones. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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14 pages, 2830 KiB  
Article
Comparison of the Inhibitory Activities of 5,6-Dihydroergosterol Glycoside α- and β-Anomers on Skin Inflammation
by Tae Kyun Kim, Young Kyoung Cho, HoonGyu Park, Tae Hoon Lee and Hakwon Kim
Molecules 2019, 24(2), 371; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24020371 - 21 Jan 2019
Cited by 5 | Viewed by 2982
Abstract
Chronic skin inflammatory diseases, such as atopic dermatitis, are associated with a dysfunctional skin barrier due to an increase in various inflammatory stimuli, for instance inflammatory cytokines and chemokines. In particular, CCL17 and CCL22 expression is increased in patients with chronic skin inflammation. [...] Read more.
Chronic skin inflammatory diseases, such as atopic dermatitis, are associated with a dysfunctional skin barrier due to an increase in various inflammatory stimuli, for instance inflammatory cytokines and chemokines. In particular, CCL17 and CCL22 expression is increased in patients with chronic skin inflammation. In this study, we synthesized several α- and β-anomers of dihydroergosterol (DHE)-glycosides and assessed their effects on CCL17 and CCL22 expression. We confirmed that the β-anomers of DHE-glycosides were superior to α-anomers of DHE-glycosides in inhibiting CCL17 and CCL22 mRNA and protein expression. In addition, we determined that DHE-glycoside β-anomers showed strong inhibitory activity towards pro-inflammatory cytokine mRNA and protein expression, including that of TNF-α, IL-6, and IL-1β- in stimulated HaCaT cells. These results imply that DHE-glycoside α- and β-anomers should be separated during synthesis of drugs for chronic skin inflammation. Our results also suggest that β-anomers of DHE-glycosides may play an important role as new drugs for chronic skin inflammation because of their ability to inhibit the skin inflammatory biomarker proteins CCL17 and CCL22. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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10 pages, 621 KiB  
Communication
Synthesis, Anticancer Activity, and Apoptosis Induction of Novel 3,6-Diazaphenothiazines
by Beata Morak-Młodawska, Krystian Pluta, Małgorzata Latocha, Małgorzata Jeleń and Dariusz Kuśmierz
Molecules 2019, 24(2), 267; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24020267 - 12 Jan 2019
Cited by 13 | Viewed by 3403
Abstract
New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized and screened for their anticancer action. The compounds exhibited varied anticancer activities against human glioblastoma SNB-19, melanoma C-32, and breast cancer MDA-MB231 cell [...] Read more.
New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized and screened for their anticancer action. The compounds exhibited varied anticancer activities against human glioblastoma SNB-19, melanoma C-32, and breast cancer MDA-MB231 cell lines, depending on the nature of the substituents. The most active 3,6-diazaphenothiazine, 4, was the derivative with the N,N-diethylamino-2-butynyl substituent against glioblastoma SNB-19, and was ten times more potent than cisplatin. For this compound, the expression of H3, TP53, CDKN1A, BCL-2, and BAX genes was detected by the RT-qPCR method. The gene expression ratio BAX/BCL-2 indicated the induction of mitochondrial apoptosis in cancer cell lines. The transformation of the propynyl substituent into amino-2-butynyl can be a method applicable to the search for more anticancer-active azaphenothiazines. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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Review

Jump to: Research

24 pages, 1024 KiB  
Review
Biological Activities of Gedunin—A Limonoid from the Meliaceae Family
by Teresa M. Braga, Lídia Rocha, Tsz Yan Chung, Rita F. Oliveira, Cláudia Pinho, Ana I. Oliveira, Joaquim Morgado and Agostinho Cruz
Molecules 2020, 25(3), 493; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25030493 - 23 Jan 2020
Cited by 48 | Viewed by 6044
Abstract
Gedunin is an important limonoid present in several genera of the Meliaceae family, mainly in seeds. Several biological activities have been attributed to gedunin, including antibacterial, insecticidal, antimalarial, antiallergic, anti-inflammatory, anticancer, and neuroprotective effects. The discovery of gedunin as a heat shock protein [...] Read more.
Gedunin is an important limonoid present in several genera of the Meliaceae family, mainly in seeds. Several biological activities have been attributed to gedunin, including antibacterial, insecticidal, antimalarial, antiallergic, anti-inflammatory, anticancer, and neuroprotective effects. The discovery of gedunin as a heat shock protein (Hsp) inhibitor represented a very important landmark for its application as a biological therapeutic agent. The current study is a critical literature review based on the several biological activities so far described for gedunin, its therapeutic effect on some human diseases, and future directions of research for this natural compound. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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26 pages, 4580 KiB  
Review
The Methylene-Cycloalkylacetate (MCA) Scaffold in Terpenyl Compounds with Potential Pharmacological Activities
by Ignacio E. Tobal, Alejandro M. Roncero, Rosalina F. Moro, David Díez and Isidro S. Marcos
Molecules 2019, 24(11), 2120; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24112120 - 05 Jun 2019
Cited by 1 | Viewed by 3163
Abstract
Recently, the methylene-cycloakylacetate (MCA) scaffold has been reported as a potential pharmacophore for neurite outgrowth activity. In this work, natural diterpenes that embed MCA fragments are reviewed, as they are major components of Halimium viscosum: ent-halimic acid, the prototype for these [...] Read more.
Recently, the methylene-cycloakylacetate (MCA) scaffold has been reported as a potential pharmacophore for neurite outgrowth activity. In this work, natural diterpenes that embed MCA fragments are reviewed, as they are major components of Halimium viscosum: ent-halimic acid, the prototype for these bioactive compounds. Herein, structures, sources, and activities for the natural diterpenes, as well as their synthetic derivatives of interest, are reviewed. Full article
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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