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12 pages, 11546 KiB

Open AccessArticle

Nitrogen-Based Linkers with a Mesitylene Core: Synthesis and Characterization

by Lucian Gabriel Bahrin, Alina Nicolescu, Sergiu Shova, Narcisa Laura Marangoci, Lucian Mihail Birsa and Laura Gabriela Sarbu

Molecules 2021, 26(19), 5952; https://doi.org/10.3390/molecules26195952 - 30 Sep 2021

Cited by 3 | Viewed by 1854

Abstract

Mesitylene was used as a core in seven new tritopic nitrogen containing linkers. Three of the linkers, each containing three nitrile groups, were obtained through Suzuki, Sonogashira and Heck-type coupling reactions. Next, these were converted to tetrazol-5-yl moieties by the cycloaddition of [...] Read more.

Mesitylene was used as a core in seven new tritopic nitrogen containing linkers. Three of the linkers, each containing three nitrile groups, were obtained through Suzuki, Sonogashira and Heck-type coupling reactions. Next, these were converted to tetrazol-5-yl moieties by the cycloaddition of sodium azide to the nitrile functionalities. The last linker, containing three 1,2,3-triazol-4-yl moieties, was synthesized by the Huisgen cycloaddition of phenyl azide to the corresponding alkyne. The latter was obtained via a Corey–Fuchs reaction sequence from the previously reported formyl derivative. As the proof of concept for their potential in MOF design, one of the nitriles was used to build an Ag-based network. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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11 pages, 2334 KiB

Open AccessArticle

Novel Pyridyl–Oxazole Carboxamides: Toxicity Assay Determination in Fungi and Zebrafish Embryos

by Shu Chen, Dong-Lin Zhang, Chao-Li Ren, Wen-Qian Zou, Xiao-Yu Tian, Xiao-Hua Du and Cheng-Xia Tan

Molecules 2021, 26(13), 3883; https://doi.org/10.3390/molecules26133883 - 25 Jun 2021

Cited by 5 | Viewed by 1667

Abstract

Eight novel pyridyl–oxazole carboxamides were evaluated against fungi and displayed good fungicidal activities against Botrytis cinereal and Rhizoctonia solani. Preliminary bioassay results indicated that at 100 mg/L, compounds 6a–6e, 6g and 6h exhibited 100% fungicidal activities against Botrytis [...] Read more.

Eight novel pyridyl–oxazole carboxamides were evaluated against fungi and displayed good fungicidal activities against Botrytis cinereal and Rhizoctonia solani. Preliminary bioassay results indicated that at 100 mg/L, compounds 6a–6e, 6g and 6h exhibited 100% fungicidal activities against Botrytis cinerea, and the compound 6b to Rhizoctonia solani at 100%. Then, the zebrafish embryo acute toxicity test was performed to assess the toxicity of 6b and 6c. A series of malformations appeared, when the zebrafish embryos were exposed to 6b and 6c, such as delayed yolk sac resorption, significant shortening of body length, pericardial edema, bending spine, lack of melanin, heart hemorrhage, head hemorrhage, delayed swim sac development, yolk malformation and head malformation. In addition, the acute toxicity of 6b to zebrafish embryo is 4.878 mg/L, and 6c is 6.257 mg/L. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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18 pages, 2608 KiB

Open AccessArticle

Synthesis, Characterization and Biological Evaluation of New 3,5-Disubstituted-Pyrazoline Derivatives as Potential Anti-Mycobacterium tuberculosis H37Ra Compounds

by Kok Tong Wong, Hasnah Osman, Thaigarajan Parumasivam, Unang Supratman, Mohammad Tasyriq Che Omar and Mohamad Nurul Azmi

Molecules 2021, 26(7), 2081; https://doi.org/10.3390/molecules26072081 - 05 Apr 2021

Cited by 13 | Viewed by 3066

Abstract

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (¹H, ¹³C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC [...] Read more.

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (¹H, ¹³C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 μM. In addition, six other synthesized compounds, 5a and 5c–5g, exhibited moderate activity, with MIC ranges between 60 μM to 140 μM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 μM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand–receptor interactions, and to hypothesize potential refinements for the compound. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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12 pages, 3969 KiB

Open AccessArticle

Unexpectedly Long Lifetime of the Excited State of Benzothiadiazole Derivative and Its Adducts with Lewis Acids

by Taisiya S. Sukhikh, Radmir M. Khisamov and Sergey N. Konchenko

Molecules 2021, 26(7), 2030; https://doi.org/10.3390/molecules26072030 - 02 Apr 2021

Cited by 5 | Viewed by 1869

Abstract

We report a study of photoluminescent properties of 4-bromo-7-(3-pyridylamino)-2,1,3-benzothiadiazole (Py-btd) and its novel Lewis adducts: (PyH-btd)₂(ZnCl₄) and [Cu₂Cl₂(Py-btd)₂{PPO}₂]·2C₇H₈ [...] Read more.

We report a study of photoluminescent properties of 4-bromo-7-(3-pyridylamino)-2,1,3-benzothiadiazole (Py-btd) and its novel Lewis adducts: (PyH-btd)₂(ZnCl₄) and [Cu₂Cl₂(Py-btd)₂{PPO}₂]·2C₇H₈ (PPO = tetraphenyldiphosphine monoxide), whose crystal structure was determined by X-ray diffraction analysis. Py-btd exhibits a lifetime of 9 microseconds indicating its phosphorescent nature, which is rare for purely organic compounds. This phenomenon arises from the heavy atom effect: the presence of a bromine atom in Py-btd promotes mixing of the singlet and triplet states to allow efficient singlet-to-triplet intersystem crossing. The Lewis adducts also feature a microsecond lifetime while emitting in a higher energy range than free Py-btd, which opens up the possibility to color-tune luminescence of benzothiadiazole derivatives. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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21 pages, 14416 KiB

Open AccessArticle

Polymer-Supported Synthesis of Various Pteridinones and Pyrimidodiazepinones

by Jan Chasák and Lucie Brulíková

Molecules 2021, 26(6), 1603; https://doi.org/10.3390/molecules26061603 - 14 Mar 2021

Cited by 1 | Viewed by 1925

Abstract

In this report, we employed the solid-phase synthetic approach to prepare variously substituted dihydropteridinones, tetrahydropyrrolopteridinones, and pyrimidodiazepinones, using a versatile building block-4,6-dichloro-5-nitropyrimidine. All these compounds are pharmacologically significant scaffolds of the great importance of medicinal chemists. The fast and efficient synthetic methodology is [...] Read more.

In this report, we employed the solid-phase synthetic approach to prepare variously substituted dihydropteridinones, tetrahydropyrrolopteridinones, and pyrimidodiazepinones, using a versatile building block-4,6-dichloro-5-nitropyrimidine. All these compounds are pharmacologically significant scaffolds of the great importance of medicinal chemists. The fast and efficient synthetic methodology is highly desirable for defining their structure-activity relationship (SAR) and optimizing pharmacokinetic properties. Our research efforts utilize simple synthetic methods to generate a library of analogues for future SAR studies. The efficiency of our approach was exemplified in various pteridinones as well as pyrimidodiazepinones. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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13 pages, 3994 KiB

Open AccessArticle

Substituted 2-Phenacylbenzoxazole Difluoroboranes: Synthesis, Structure and Properties

by Agnieszka Skotnicka and Przemysław Czeleń

Molecules 2020, 25(22), 5420; https://doi.org/10.3390/molecules25225420 - 19 Nov 2020

Cited by 3 | Viewed by 1797

Abstract

Novel fluorescent dyes such as benzoxazole-boron complexes, bearing β-ketoiminate ligands, have been synthesized and characterized with a focus on the influence of a substituent on the basic photophysical properties. ¹H, ¹¹B, ¹³C, ¹⁵N, and ¹⁹F nuclear magnetic resonance [...] Read more.

Novel fluorescent dyes such as benzoxazole-boron complexes, bearing β-ketoiminate ligands, have been synthesized and characterized with a focus on the influence of a substituent on the basic photophysical properties. ¹H, ¹¹B, ¹³C, ¹⁵N, and ¹⁹F nuclear magnetic resonance (NMR) spectra of substituted 2-phenacylbenzoxazole difluoroboranes have been recorded and discussed. It is worth mentioning that a high correlation coefficient was found between ¹⁵N-NMR parameters and substituent constants. The photophysical properties of these new dyes have been investigated by fluorescence and ultraviolet-visible (UV-Vis) absorption spectroscopy. The geometry optimization, vibrational spectra, and the HOMO and LUMO energies were calculated based on density functional theory with the use of the B3LYP functional and 6-311++G(d,p) basis set. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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11 pages, 1319 KiB

Open AccessArticle

Practical Synthesis of Quinoline-Protected Morpholino Oligomers for Light-Triggered Regulation of Gene Function

by Davide Deodato and Timothy M. Dore

Molecules 2020, 25(9), 2078; https://doi.org/10.3390/molecules25092078 - 29 Apr 2020

Cited by 12 | Viewed by 6778

Abstract

Photoactivatable cyclic caged morpholino oligomers (ccMOs) represent a promising tool to selectively regulate gene expression with spatiotemporal control. Nevertheless, some challenges associated with the preparation of these reagents have limited their broader use in biological settings. We describe a novel ccMO design that [...] Read more.

Photoactivatable cyclic caged morpholino oligomers (ccMOs) represent a promising tool to selectively regulate gene expression with spatiotemporal control. Nevertheless, some challenges associated with the preparation of these reagents have limited their broader use in biological settings. We describe a novel ccMO design that overcomes many of the challenges and considerably expedites the synthetic preparation. The key factor is the introduction of an ethynyl function on the photocleavable linker to facilitate the use of a Huisgen 1,3-dipolar cycloaddition for the coupling reaction with the oligonucleotide. Compared to previous strategies, this modification reduces the number of synthetic steps and significantly improves the total yield and the stability of the linker. We used the alkynyl-functionalized linker for the preparation of two different ccMOs targeting the mRNA of the glutamic acid decarboxylase genes, gad1 and gad2. HPLC analysis confirms that the caging strategy successfully inhibits the DNA binding ability, and the activity can be restored by brief illumination with 405-nm light. Overall, the straightforward preparation together with the clean and fast photochemistry make these caged antisense reagents excellent tools to modulate gene function in-vivo with spatial and temporal precision. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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14 pages, 2065 KiB

Open AccessArticle

Synthesis and Biological Evaluation of a Novel C8-Pyrrolobenzodiazepine (PBD) Adenosine Conjugate. A Study on the Role of the PBD Ring in the Biological Activity of PBD-Conjugates

by Lindsay Ferguson, Sanjib Bhakta, Keith R. Fox, Geoff Wells and Federico Brucoli

Molecules 2020, 25(5), 1243; https://doi.org/10.3390/molecules25051243 - 10 Mar 2020

Cited by 7 | Viewed by 4167

Abstract

Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a [...] Read more.

Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD–ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to affect and modulate the biological and biophysical properties of PBD hybrids. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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12 pages, 1819 KiB

Open AccessArticle

Introduction of Mercaptoethyl at Sorafenib Pyridine-2-Amide Motif as a Potentially Effective Chain to Further get Sorafenib-PEG-DGL

by Ke Wang, Kudelaidi Kuerbana, Qi Wan, Zhihui Yu, Li Ye and Ying Chen

Molecules 2020, 25(3), 573; https://doi.org/10.3390/molecules25030573 - 28 Jan 2020

Cited by 1 | Viewed by 3599

Abstract

The crystal structure of the sorafenib and B-RAF complex indicates that the binding cavity occupied by the pyridine-2-carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti-cancer activity, better safety and [...] Read more.

The crystal structure of the sorafenib and B-RAF complex indicates that the binding cavity occupied by the pyridine-2-carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti-cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine-2-amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC₅₀ 58.79 and 63.67 μM, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib-PEG-DGL, which could be developed as a delivery vehicle to improve the concentration of anti-tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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13 pages, 3831 KiB

Open AccessArticle

Synthesis of a New Series of Nitrogen/Sulfur Heterocycles by Linking Four Rings: Indole; 1,2,4-Triazole; Pyridazine; and Quinoxaline

by Ahmed T. A. Boraei, Ahmed A. M. Sarhan, Sammer Yousuf and Assem Barakat

Molecules 2020, 25(3), 450; https://doi.org/10.3390/molecules25030450 - 21 Jan 2020

Cited by 23 | Viewed by 3908

Abstract

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes [...] Read more.

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2–6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7–16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7–13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K₂CO₃, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19–25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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17 pages, 3846 KiB

Open AccessReview

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

by Tehreem Tahir, Muhammad Ashfaq, Muhammad Saleem, Muhammad Rafiq, Mirza Imran Shahzad, Katarzyna Kotwica-Mojzych and Mariusz Mojzych

Molecules 2021, 26(16), 4872; https://doi.org/10.3390/molecules26164872 - 11 Aug 2021

Cited by 35 | Viewed by 4713

Abstract

Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the [...] Read more.

Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure–activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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30 pages, 9782 KiB

Open AccessReview

1,2,3-Triazoles as Biomimetics in Peptide Science

by Naima Agouram, El Mestafa El Hadrami and Abdeslem Bentama

Molecules 2021, 26(10), 2937; https://doi.org/10.3390/molecules26102937 - 14 May 2021

Cited by 35 | Viewed by 5013

Abstract

Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules [...] Read more.

Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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29 pages, 7665 KiB

Open AccessReview

Advances in the Synthesis of Ring-Fused Benzimidazoles and Imidazobenzimidazoles

by Martin Sweeney, Darren Conboy, Styliana I. Mirallai and Fawaz Aldabbagh

Molecules 2021, 26(9), 2684; https://doi.org/10.3390/molecules26092684 - 04 May 2021

Cited by 21 | Viewed by 4911

Abstract

This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is [...] Read more.

This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is categorized according to the cyclization reaction and mechanisms are detailed. Nitrobenzene reduction, cyclization of aryl amidines, lactams and isothiocyanates are described. Protocols include condensation, cross-dehydrogenative coupling with transition metal catalysis, annulation onto benzimidazole, often using CuI-catalysis, and radical cyclization with homolytic aromatic substitution. Many oxidative transformations are under metal-free conditions, including using thermal, photochemical, and electrochemical methods. Syntheses of diazole analogues of mitomycin C derivatives are described. Traditional oxidations of o-(cycloamino)anilines using peroxides in acid via the t-amino effect remain popular. Full article

(This article belongs to the Special Issue Synthetic Heterocyclic Chemistry)

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