2023

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Open AccessArticle

Synthesis of New Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via an Ugi-Zhu/Cascade/Click Strategy

by

Roberto E. Blanco-Carapia

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Enrique A. Aguilar-Rangel

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Mónica A. Rincón-Guevara

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Alejandro Islas-Jácome

and

Eduardo González-Zamora

Molecules 2023, 28(10), 4087; https://doi.org/10.3390/molecules28104087 - 14 May 2023

Viewed by 887

Abstract

A diversity-oriented synthesis (DOS) of two new polyheterocyclic compounds was performed via an Ugi-Zhu/cascade (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration)/click strategy, both step-by-step to optimize all involved experimental stages, and in one pot manner to evaluate the scope and sustainability of this polyheterocyclic-focused [...] Read more.

A diversity-oriented synthesis (DOS) of two new polyheterocyclic compounds was performed via an Ugi-Zhu/cascade (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration)/click strategy, both step-by-step to optimize all involved experimental stages, and in one pot manner to evaluate the scope and sustainability of this polyheterocyclic-focused synthetic strategy. In both ways, the yields were excellent, considering the high number of bonds formed with release of only one carbon dioxide and two molecules of water. The Ugi-Zhu reaction was carried out using the 4-formylbenzonitrile as orthogonal reagent, where the formyl group was first transformed into the pyrrolo[3,4-b]pyridin-5-one core, and then the remaining nitrile group was further converted into two different nitrogen-containing polyheterocycles, both via click-type cycloadditions. The first one used sodium azide to obtain the corresponding 5-substituted-1H-tetrazolyl-pyrrolo[3,4-b]pyridin-5-one, and the second one with dicyandiamide to synthesize the 2,4-diamino-1,3,5-triazine-pyrrolo[3,4-b]pyridin-5-one. Both synthesized compounds may be used for further in vitro and in silico studies because they contain more than two heterocyclic moieties of high interest in medicinal chemistry, as well as in optics due to their high π-conjugation. Full article

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Open AccessArticle

Macrocycle with Equatorial Coordination Sites Provides New Opportunity for Structure-Diverse Metallacages

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Molecules 2023, 28(6), 2537; https://doi.org/10.3390/molecules28062537 - 10 Mar 2023

Viewed by 1225

Abstract

Reported here is the synthesis of a macrocycle with equatorial coordination sites for the construction of self-assembled metallacages. The macrocycle is prepared via a post-modification on the equator of biphen[n]arene. Utilizing this macrocycle as a ligand, three prismatic cages and one [...] Read more.

Reported here is the synthesis of a macrocycle with equatorial coordination sites for the construction of self-assembled metallacages. The macrocycle is prepared via a post-modification on the equator of biphen[n]arene. Utilizing this macrocycle as a ligand, three prismatic cages and one octahedral cage were synthesized by regulating the geometric structures and coordination number of metal acceptors. The multi-cavity configuration of prismatic cage was revealed by single-crystal structure. We prove that a macrocycle with equatorial coordination sites can be an excellent building block for synthesizing structure-diverse metallacages. Our results provide a typical example and a general method for the design and synthesis of metallacages. Full article

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Figure 1

2022

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Open AccessArticle

Synthesis, Structure and Photochemistry of Dibenzylidenecyclobutanones

by

Marina V. Fomina

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Alexandra Y. Freidzon

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Molecules 2022, 27(21), 7602; https://doi.org/10.3390/molecules27217602 - 05 Nov 2022

Cited by 1 | Viewed by 1211

Abstract

A series of symmetrical dibenzylidene derivatives of cyclobutanone were synthesized with the goal of studying the physicochemical properties of cross-conjugated dienones (ketocyanine dyes). The structures of the products were established and studied by X-ray diffraction and by NMR and electronic spectroscopy. All the [...] Read more.

A series of symmetrical dibenzylidene derivatives of cyclobutanone were synthesized with the goal of studying the physicochemical properties of cross-conjugated dienones (ketocyanine dyes). The structures of the products were established and studied by X-ray diffraction and by NMR and electronic spectroscopy. All the products had E,E-geometry. The oxidation and reduction potentials of the dienones were determined by cyclic voltammetry. The potentials were shown to depend on the nature, position, and number of substituents in the benzene rings. A linear correlation was found between the difference of the electrochemical oxidation and reduction potentials and the energy of the long-wavelength absorption maximum. This correlation can be employed to analyze the properties of other compounds of this type. Quantum chemistry was used to explain the observed regularities in the electrochemistry, absorption, and fluorescence of the dyes. The results are in good agreement with the experimental redox potentials and spectroscopy data. Full article

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Open AccessArticle

Experimental and Computational Analysis of Newly Synthesized Benzotriazinone Sulfonamides as Alpha-Glucosidase Inhibitors

by

Zunera Khalid

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Maha Abdallah Alnuwaiser

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Muhammad Mujtaba Abbas

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M. A. Kalam

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Menna A. Ewida

Molecules 2022, 27(20), 6783; https://doi.org/10.3390/molecules27206783 - 11 Oct 2022

Cited by 2 | Viewed by 1242

Abstract

Diabetes mellitus is a chronic metabolic disorder in which the pancreas secretes insulin but the body cells do not recognize it. As a result, carbohydrate metabolism causes hyperglycemia, which may be fatal for various organs. This disease is increasing day by day and [...] Read more.

Diabetes mellitus is a chronic metabolic disorder in which the pancreas secretes insulin but the body cells do not recognize it. As a result, carbohydrate metabolism causes hyperglycemia, which may be fatal for various organs. This disease is increasing day by day and it is prevalent among people of all ages, including young adults and children. Acarbose and miglitol are famous alpha-glucosidase inhibitors but they complicate patients with the problems of flatulence, pain, bloating, diarrhea, and loss of appetite. To overcome these challenges, it is crucial to discover new anti-diabetic drugs with minimal side effects. For this purpose, benzotriazinone sulfonamides were synthesized and their structures were characterized by FT-IR, ¹H-NMR and ¹³C-NMR spectroscopy. In vitro alpha-glucosidase inhibition studies of all synthesized hybrids were conducted using the spectrophotometric method. The synthesized compounds revealed moderate-to-good inhibition activity; in particular, nitro derivatives 12e and 12f were found to be the most effective inhibitors against this enzyme, with IC₅₀ values of 32.37 ± 0.15 µM and 37.75 ± 0.11 µM. In silico studies, including molecular docking as well as DFT analysis, also strengthened the experimental findings. Both leading compounds 12e and 12f showed strong hydrogen bonding interactions within the enzyme cavity. DFT studies also reinforced the strong binding interactions of these derivatives with biological molecules due to their lowest chemical hardness values and lowest orbital energy gap values. Full article

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Open AccessArticle

Synthesis, Experimental and Theoretical Study of Azidochromones

by

Ena G. Narváez-Ordoñez

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Kevin A. Pabón-Carcelén

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Daniel A. Zurita-Saltos

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Pablo M. Bonilla-Valladares

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Trosky G. Yánez-Darquea

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Luis A. Ramos-Guerrero

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Sonia E. Ulic

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Jorge L. Jios

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Gustavo A. Echeverría

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Oscar E. Piro

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Peter Langer

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Christian D. Alcívar-León

and

Jorge Heredia-Moya

Molecules 2022, 27(9), 2636; https://doi.org/10.3390/molecules27092636 - 20 Apr 2022

Cited by 1 | Viewed by 1613

Abstract

A series of 2-(haloalkyl)-3-azidomethyl and 6-azido chromones has been synthetized, characterized and studied by theoretical (DFT calculations) and spectroscopic methods (UV-Vis, NMR). The crystal structure of 3-azidomethyl-2-difluoromethyl chromone, determined by X-ray diffraction methods, shows a planar framework due to extended π-bond delocalization. Its [...] Read more.

A series of 2-(haloalkyl)-3-azidomethyl and 6-azido chromones has been synthetized, characterized and studied by theoretical (DFT calculations) and spectroscopic methods (UV-Vis, NMR). The crystal structure of 3-azidomethyl-2-difluoromethyl chromone, determined by X-ray diffraction methods, shows a planar framework due to extended π-bond delocalization. Its molecular packing is stabilized by F···H, N···H and O···H hydrogen bonds, π···π stacking and C–O···π intermolecular interactions. Moreover, AIM, NCI and Hirshfeld analysis evidenced that azido moiety has a significant role in the stabilization of crystal packing through weak intermolecular interactions, where analysis of electronic density suggested closed-shell (CS) interatomic interactions. Full article

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Open AccessArticle

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

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Molecules 2022, 27(8), 2603; https://doi.org/10.3390/molecules27082603 - 18 Apr 2022

Cited by 2 | Viewed by 2055

Abstract

Eliglustat (Cerdelga^®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral [...] Read more.

Eliglustat (Cerdelga^®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the S_Ni and the S_N1 mechanisms, leading to the retention of stereochemistry. Full article

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Figure 1

Open AccessArticle

3,4-Unsubstituted 2-tert-Butyl-pyrrolidine-1-oxyls with Hydrophilic Functional Groups in the Side Chains

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Molecules 2022, 27(6), 1922; https://doi.org/10.3390/molecules27061922 - 16 Mar 2022

Cited by 3 | Viewed by 1455

Abstract

Pyrrolidine nitroxides with four bulky alkyl substituents adjacent to N–O group are known for their high resistance to bioreduction. The 3,4-unsubstituted 2-tert-butyl-2-ethylpyrrolidine-1-oxyls were prepared from the corresponding 2-tert-butyl-1-pyrroline-1-oxides via either the addition of ethinylmagnesium bromide with subsequent hydrogenation or [...] Read more.

Pyrrolidine nitroxides with four bulky alkyl substituents adjacent to N–O group are known for their high resistance to bioreduction. The 3,4-unsubstituted 2-tert-butyl-2-ethylpyrrolidine-1-oxyls were prepared from the corresponding 2-tert-butyl-1-pyrroline-1-oxides via either the addition of ethinylmagnesium bromide with subsequent hydrogenation or via treatment with ethyllithium. The new nitroxides showed excellent stability to reduction with ascorbate with no evidence for additional large hyperfine couplings in the EPR spectra. Full article

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Open AccessArticle

Synthesis and Fluorescent Properties of Aminopyridines and the Application in “Click and Probing”

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Molecules 2022, 27(5), 1596; https://doi.org/10.3390/molecules27051596 - 28 Feb 2022

Cited by 1 | Viewed by 1396

Abstract

Unsubstituted pyridin-2-amine has a high quantum yield and is a potential scaffold for a fluorescent probe. However, the facile access to conjugated highly substituted aminopyridines and the study of their fluorescent properties is scarce. In this paper, synthesis and fluorescent properties of multisubstituted [...] Read more.

Unsubstituted pyridin-2-amine has a high quantum yield and is a potential scaffold for a fluorescent probe. However, the facile access to conjugated highly substituted aminopyridines and the study of their fluorescent properties is scarce. In this paper, synthesis and fluorescent properties of multisubstituted aminopyridines were studied based on a recently developed Rh-catalyzed coupling of vinyl azide with isonitrile to form a vinyl carbodiimide intermediate, following tandem cyclization with an alkyne. An aminopyridine substituted with an azide group as a potential probe was further designed, synthesized, and evaluated. The “clicking-and-probing” experiment of it on BSA protein showed the potential of aminopyridine as a scaffold of a biological probe. Full article

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Scheme 1

2021

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Open AccessCommunication

BN-Embedded Perylenes

by

Xiangdong Fang

Molecules 2021, 26(23), 7148; https://doi.org/10.3390/molecules26237148 - 25 Nov 2021

Cited by 3 | Viewed by 2549

Abstract

Transition metal catalyzed coupling reaction strategy has been utilized in the synthesis of two novel BN-perylenes starting from halogenated BN-naphthalene derivatives. The molecular structures and packing modes of BN-perylenes were confirmed by NMR spectroscopy and X-ray single-crystal diffraction experiments. Their photophysical properties were [...] Read more.

Transition metal catalyzed coupling reaction strategy has been utilized in the synthesis of two novel BN-perylenes starting from halogenated BN-naphthalene derivatives. The molecular structures and packing modes of BN-perylenes were confirmed by NMR spectroscopy and X-ray single-crystal diffraction experiments. Their photophysical properties were further investigated using UV-vis and fluorescence spectroscopy and DFT calculations. Interestingly, the isosteric BN-insertion in perylene system resulted in stronger π-π stacking interaction both in solid and solution phases. The synthesized BN-perylenes are proved to be highly stable and thus provide a new valuable platform for novel organic materials applications which is otherwise inaccessible to date. Full article

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Figure 1

Open AccessArticle

Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1H-imidazole-4-carboxylic Acids and 1,5-Diaryl-1H-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors

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Molecules 2021, 26(20), 6203; https://doi.org/10.3390/molecules26206203 - 14 Oct 2021

Cited by 6 | Viewed by 1628

Abstract

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target [...] Read more.

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreen^TM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 μM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33–45% with cytotoxicity (CC₅₀) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN. Full article

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Open AccessArticle

Synthesis of 6-Membered-Ring Fused Thiazine-Dicarboxylates and Thiazole-Pyrimidines via One-Pot Three-Component Reactions

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Molecules 2021, 26(18), 5493; https://doi.org/10.3390/molecules26185493 - 10 Sep 2021

Cited by 3 | Viewed by 1862

Abstract

A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of [...] Read more.

A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of 76–85%. The reactivity of dialkyl acetylenedicarboxylates was further tested in the synthesis of thiazole-pyrimidines where a two-component reaction of 2-aminothiazole with dialkyl acetylenedicarboxylates was successfully converted to a more efficient three-component reaction of a thiourea, α-haloketone and dialkyl acetylenedicarboxylate (DMAD/DEtAD) to give thiazole-pyrimidines in good yields of 70–91%. Full article

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Open AccessReview

4,5,6,7-Tetrahydroindol-4-Ones as a Valuable Starting Point for the Synthesis of Polyheterocyclic Structures

by

Tomas Horsten

and

Wim Dehaen

Molecules 2021, 26(15), 4596; https://doi.org/10.3390/molecules26154596 - 29 Jul 2021

Cited by 1 | Viewed by 2286

Abstract

This review focuses on the synthesis of polyheterocyclic structures with a variety of medicinal and optoelectronic applications, starting from readily available 4,5,6,7-tetrahydroindol-4-one analogs. First, routes toward the 4,5,6,7-tetrahydroindol-4-one starting materials are summarized, followed by synthetic pathways towards polyheterocyclic structures which are categorized based [...] Read more.

This review focuses on the synthesis of polyheterocyclic structures with a variety of medicinal and optoelectronic applications, starting from readily available 4,5,6,7-tetrahydroindol-4-one analogs. First, routes toward the 4,5,6,7-tetrahydroindol-4-one starting materials are summarized, followed by synthetic pathways towards polyheterocyclic structures which are categorized based on the size and attachment point of the newly formed (hetero)cyclic ring. Full article

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Open AccessArticle

3-Benzoylisoxazolines by 1,3-Dipolar Cycloaddition: Chloramine-T-Catalyzed Condensation of α-Nitroketones with Dipolarophiles

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Molecules 2021, 26(12), 3491; https://doi.org/10.3390/molecules26123491 - 08 Jun 2021

Cited by 4 | Viewed by 1921

Abstract

In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various α-nitroketones using chloramine-T as the base. The scope of α-nitroketones and alkenes is extensive, including different alkenes and alkynes to form various isoxazolines and isoxazoles. The use of chloramine-T, as the low-cost, [...] Read more.

In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various α-nitroketones using chloramine-T as the base. The scope of α-nitroketones and alkenes is extensive, including different alkenes and alkynes to form various isoxazolines and isoxazoles. The use of chloramine-T, as the low-cost, easily handled, moderate base for 1,3-dipolar cycloaddition is attractive. Full article

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Figure 1

Open AccessArticle

Synthesis and Rational Design of New Appended 1,2,3-Triazole-uracil Ensembles as Promising Anti-Tumor Agents via In Silico VEGFR-2 Transferase Inhibition

by

Nadipolla Naresh Reddy

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Sung-Jen Hung

,

Merugu Kumara Swamy

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Ananthula Sanjeev

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Vankadari Srinivasa Rao

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Puchakayala Muralidhar Reddy

Molecules 2021, 26(7), 1952; https://doi.org/10.3390/molecules26071952 - 30 Mar 2021

Cited by 4 | Viewed by 2010

Abstract

Angiogenesis inhibition is a key step towards the designing of new chemotherapeutic agents. In a view to preparing new molecular entities for cancer treatment, eighteen 1,2,3-triazole-uracil ensembles 5a–r were designed and synthesized via the click reaction. The ligands were well characterized [...] Read more.

Angiogenesis inhibition is a key step towards the designing of new chemotherapeutic agents. In a view to preparing new molecular entities for cancer treatment, eighteen 1,2,3-triazole-uracil ensembles 5a–r were designed and synthesized via the click reaction. The ligands were well characterized using ¹H-, ¹³C-NMR, elemental analysis and ESI-mass spectrometry. The in silico binding propinquities of the ligands were studied sequentially in the active region of VEGFR-2 using the Molegro virtual docker. All the compounds produced remarkable interactions and potentially inhibitory ligands against VEGFR-2 were obtained with high negative binding energies. Drug-likeness was assessed from the ADME properties. Cytotoxicity of the test compounds was measured against HeLa and HUH-7 tumor cells and NIH/3T3 normal cells by MTT assay. Compound 5h showed higher growth inhibition activity than the positive control, 5-fluorouracil (5-FU), against both HeLa and HUH-7 cells with IC₅₀ values of 4.5 and 7.7 μM respectively. Interestingly, the compounds 5a–r did not show any cytotoxicity towards the normal cell lines. The results advance the position of substituted triazoles in the area of drug design with no ambiguity. Full article

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Open AccessArticle

Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates

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Molecules 2021, 26(4), 890; https://doi.org/10.3390/molecules26040890 - 08 Feb 2021

Cited by 3 | Viewed by 1916

Abstract

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to [...] Read more.

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward S_NAr ring closure. A control experiment established that the initial reaction was an S_N2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the S_NAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O₂, the expected dihydroquinolines were formed, while in the presence of O₂, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed. Full article

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Graphical abstract

2020

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Open AccessArticle

A General and Scalable Synthesis of Polysubstituted Indoles

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David Tejedor

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Raquel Diana-Rivero

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Fernando García-Tellado

Molecules 2020, 25(23), 5595; https://doi.org/10.3390/molecules25235595 - 28 Nov 2020

Cited by 3 | Viewed by 2562

Abstract

A consecutive 2-step synthesis of N-unprotected polysubstituted indoles bearing an electron-withdrawing group at the C-3 position from readily available nitroarenes is reported. The protocol is based on the [3,3]-sigmatropic rearrangement of N-oxyenamines generated by the DABCO-catalyzed reaction of N-arylhydroxylamines and [...] Read more.

A consecutive 2-step synthesis of N-unprotected polysubstituted indoles bearing an electron-withdrawing group at the C-3 position from readily available nitroarenes is reported. The protocol is based on the [3,3]-sigmatropic rearrangement of N-oxyenamines generated by the DABCO-catalyzed reaction of N-arylhydroxylamines and conjugated terminal alkynes, and delivers indoles endowed with a wide array of substitution patterns and topologies. Full article

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Open AccessReview

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines

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Maria Fuertes

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Carme Masdeu

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Endika Martin-Encinas

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Molecules 2020, 25(14), 3252; https://doi.org/10.3390/molecules25143252 - 16 Jul 2020

Cited by 3 | Viewed by 3988

Abstract

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies [...] Read more.

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes. Finally, some properties and applications of these heterocycles studied during this period are examined. Full article

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Figure 1

Open AccessCommunication

Two Annulated Azaheterocyclic Cores Readily Available from a Single Tetrahydroisoquinolonic Castagnoli–Cushman Precursor

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Elizaveta Karchuganova

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Olga Bakulina

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Dmitry Dar’in

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Mikhail Krasavin

Molecules 2020, 25(9), 2049; https://doi.org/10.3390/molecules25092049 - 28 Apr 2020

Cited by 1 | Viewed by 2291

Abstract

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus [...] Read more.

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus providing access to substituted dibenzo[c,h][1,6]naphthyridine via cyclization and dehydrogenation). However, attempted reduction with sodium sulfide initiated a previously unknown reaction cascade including double reduction, cyclization, and decarboxylation, leading to formation of indolo[3,2-c]isoquinoline polyheterocycle in one synthetic step. Full article

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Open AccessArticle

Synthesis and Antibacterial Evaluation of Novel 1,3,4-Oxadiazole Derivatives Containing Sulfonate/Carboxylate Moiety

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Molecules 2020, 25(7), 1488; https://doi.org/10.3390/molecules25071488 - 25 Mar 2020

Cited by 5 | Viewed by 2493

Abstract

In order to discover new lead compounds with high antibacterial activity, a series of new derivatives were designed and synthesized by introducing a sulfonate or carboxylate moiety into the 1,3,4-oxadiazole structure. Antibacterial activity against two phytopathogens, Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas [...] Read more.

In order to discover new lead compounds with high antibacterial activity, a series of new derivatives were designed and synthesized by introducing a sulfonate or carboxylate moiety into the 1,3,4-oxadiazole structure. Antibacterial activity against two phytopathogens, Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac), was assayed in vitro. The preliminary results indicated that ten compounds including 4a-1-4a-4 and 4a-11-4a-16 had good antibacterial activity against Xoo, with EC₅₀ values ranging from 50.1-112.5 µM, which was better than those of Bismerthiazol (253.5 µM) and Thiodiazole copper (467.4 µM). Meanwhile, 4a-1, 4a-2, 4a-3 and 4a-4 demonstrated good inhibitory effect against Xanthomonas axonopodis pv. citri with EC₅₀ values around 95.8-155.2 µM which were better than those of bismerthiazol (274.3 µM) and thiodiazole copper (406.3 µM). In addition, in vivo protection activity of compound 4a-2 and 4a-3 against rice bacterial leaf blight was 68.6% and 62.3%, respectively, which were better than bismerthiazol (49.6%) and thiodiazole copper (42.2%). Curative activity of compound 4a-2 and 4a-3 against rice bacterial leaf blight was 62.3% and 56.0%, which were better than bismerthiazol (42.9%) and thiodiazole copper (36.1%). Through scanning electron microscopy (SEM) analysis, it was observed that compound 4a-2 caused the cell membrane of Xanthomonas oryzae pv. oryzae ruptured or deformed. The present results indicated novel derivatives of 5-phenyl sulfonate methyl 1,3,4-oxadiazole might be potential antibacterial agents. Full article

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Open AccessArticle

Formal [3+2] Cycloaddition Reactions of Electron-Rich Aryl Epoxides with Alkenes under Lewis Acid Catalysis Affording Tetrasubstituted Tetrahydrofurans

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Víctor E. Macías-Villamizar

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Luís Cuca-Suárez

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Santiago Rodríguez

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Florenci V. González

Molecules 2020, 25(3), 692; https://doi.org/10.3390/molecules25030692 - 06 Feb 2020

Viewed by 3362

Abstract

We report on the regio- and stereoselective synthesis of tetrahydrofurans by reaction between epoxides and alkenes in the presence of a Lewis acid. This is an unprecedented formal [3+2] cycloaddition reaction between an epoxide and an alkene. The chemical reaction represents a very [...] Read more.

We report on the regio- and stereoselective synthesis of tetrahydrofurans by reaction between epoxides and alkenes in the presence of a Lewis acid. This is an unprecedented formal [3+2] cycloaddition reaction between an epoxide and an alkene. The chemical reaction represents a very concise synthesis of tetrahydrofurans from accessible starting compounds. Full article

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2019

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Open AccessArticle

A Suitable Functionalization of Nitroindazoles with Triazolyl and Pyrazolyl Moieties via Cycloaddition Reactions

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M. Amparo F. Faustino

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José A. S. Cavaleiro

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Ricardo F. Mendes

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Filipe A. A. Paz

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Maria G. P. M. S. Neves

and

El Mostapha Rakib

Molecules 2020, 25(1), 126; https://doi.org/10.3390/molecules25010126 - 28 Dec 2019

Cited by 2 | Viewed by 2700

Abstract

The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N [...] Read more.

The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N-(2-bromoethyl)nitroindazoles into the corresponding azide. The reactivity in 1,3-dipolar cycloaddition reactions with nitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates was studied with nitroindazoles bearing a vinyl unit. The corresponding nitroindazole-pyrazoline derivatives were obtained in good to excellent yields. Full article

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Open AccessArticle

Synthesis and Antimicrobial Activity of a New Series of Thiazolidine-2,4-diones Carboxamide and Amino Acid Derivatives

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Beatriz G. de la Torre

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Fernando Albericio

Molecules 2020, 25(1), 105; https://doi.org/10.3390/molecules25010105 - 27 Dec 2019

Cited by 13 | Viewed by 3057

Abstract

Novel thiazolidine-2,4-dione carboxamide and amino acid derivatives were synthesized in excellent yield using OxymaPure/N,N′-diisopropylcarbodimide coupling methodology and were characterized by chromatographic and spectrometric methods, and elemental analysis. The antimicrobial and antifungal activity of these derivatives was evaluated against two Gram-positive bacteria [...] Read more.

Novel thiazolidine-2,4-dione carboxamide and amino acid derivatives were synthesized in excellent yield using OxymaPure/N,N′-diisopropylcarbodimide coupling methodology and were characterized by chromatographic and spectrometric methods, and elemental analysis. The antimicrobial and antifungal activity of these derivatives was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), two-Gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and one fungal isolate (Candida albicans). Interestingly, several samples demonstrated weak to moderate antibacterial activity against Gram-negative bacteria, as well as antifungal activity. However, only one compound namely, 2-(5-(3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid, showed antibacterial activity against Gram-positive bacteria, particularly S. aureus. Full article

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Open AccessArticle

Synthesis and Antimicrobial Activity of Some New Substituted Quinoxalines

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Molecules 2019, 24(22), 4198; https://doi.org/10.3390/molecules24224198 - 19 Nov 2019

Cited by 21 | Viewed by 4317

Abstract

A number of new symmetrically and asymmetrically 2,3-disubstituted quinoxalines were synthesized through functionalization of 2,3-dichloroquinoxaline (2,3-DCQ) with a variety of sulfur and/or nitrogen nucleophiles. The structures of the obtained compounds were established based on their spectral data and elemental analysis. The antimicrobial activity [...] Read more.

A number of new symmetrically and asymmetrically 2,3-disubstituted quinoxalines were synthesized through functionalization of 2,3-dichloroquinoxaline (2,3-DCQ) with a variety of sulfur and/or nitrogen nucleophiles. The structures of the obtained compounds were established based on their spectral data and elemental analysis. The antimicrobial activity for the prepared compounds was investigated against four bacterial species and two fungal strains. The symmetrically disubstituted quinoxalines 2, 3, 4, and 5 displayed the most significant antibacterial activity, while compounds 6a, 6b, and the pentacyclic compound 10 showed considerable antifungal activity. Furthermore, compounds 3f, 6b showed broad antimicrobial spectrum against most of the tested strains. Full article

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Open AccessReview

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

by

Guillem Jubete

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Raimon Puig de la Bellacasa

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Roger Estrada-Tejedor

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Jordi Teixidó

and

José I. Borrell

Molecules 2019, 24(22), 4161; https://doi.org/10.3390/molecules24224161 - 16 Nov 2019

Cited by 21 | Viewed by 5054

Abstract

Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) [...] Read more.

Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds. Full article

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Open AccessArticle

A Simple, Efficient, and Eco-Friendly Method for the Preparation of 3-Substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives

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Molecules 2019, 24(22), 4052; https://doi.org/10.3390/molecules24224052 - 09 Nov 2019

Cited by 2 | Viewed by 3338

Abstract

A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The [...] Read more.

A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The novel feature of this protocol is the use of 2-methyl tetrahydrofuran (2-MeTHF) as an eco-friendly alternative solvent to tetrahydrofuran (THF) in the first step. In the second step, methanol in the presence of potassium carbonate as a catalyst was used under conventional heating or microwave irradiation, which provided an eco-friendly method to afford the target products in excellent yields and purities. NMR (¹H and ¹³C), elemental analysis, and LC-MS confirmed the structures of all compounds. X-ray crystallography further confirmed the structure of the intermediate 2-amino-N-(2-substituted-ethyl)benzamide 3a. The molecular structure of 3a was monoclinic crystal, with P21/c, a = 13.6879 (11) Å, b = 10.2118 (9) Å, c = 9.7884 (9) Å, β = 105.068 (7)°, V = 1321.2 (2) Å3, and Z = 4. Full article

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Open AccessArticle

One Pot and Metal-Free Approach to 3-(2-Hydroxybenzoyl)-1-aza-anthraquinones

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Molecules 2019, 24(16), 3017; https://doi.org/10.3390/molecules24163017 - 20 Aug 2019

Cited by 3 | Viewed by 2980

Abstract

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert [...] Read more.

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert gas and expensive transition metal catalysts. Some compounds displayed good anti-proliferative activities. Full article

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Open AccessArticle

Intramolecular Carbene C-H Insertion Reactions of 2-Diazo-2-sulfamoylacetamides

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Molecules 2019, 24(14), 2628; https://doi.org/10.3390/molecules24142628 - 19 Jul 2019

Cited by 2 | Viewed by 3995

Abstract

The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo- [...] Read more.

The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide can take the formal aromatic 1,5-C-H insertion in its N-phenylsulfonamide moiety to afford the corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide derivative; (2) no aliphatic C-H insertions occur for 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides; and (3) for 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides, the formal aromatic 1,5-C-H insertion in the N-phenylacetamide moiety is favorable to afford the corresponding 3-sulfamoylindolin-2-one derivatives as sole or major products. The intramolecular competitive aromatic 1,5-C-H insertion reactions of 2-diazo-2-sulfamoylacetamides with aryl groups on both amide and sulfonamide groups reveal that the N-aryl substituents on acetamide are more active than those on sulfonamide. The chemoselectivity is controlled by electronic effect of the aryl group. Full article

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Open AccessArticle

Novel Synthesis of Substituted 2-Trifluoromethyl and 2-Perfluoroalkyl N-Arylpyridinium Compounds—Mechanistic Insights

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Molecules 2019, 24(12), 2328; https://doi.org/10.3390/molecules24122328 - 25 Jun 2019

Cited by 3 | Viewed by 3674

Abstract

We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated β-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of [...] Read more.

We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated β-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of this multicomponent reaction, involves the formation of a 3-perfluoroalkyl-N,N’-diaryl-1,5-diazapentadiene intermediate, various examples of which were isolated and characterized for the first time, together with investigation of their reactivity. We propose a mechanism involving a concurrent inverse electron demand Diels-Alder or Aza-Robinson cascade cyclisation, followed by a bis-de-anilino-elimination. Noteworthy, a meta-methoxy substituent on the aniline directs the reaction towards a 2-perfluoroalkyl-7-methoxyquinoline, resulting from the direct cyclization of the diazapentadiene intermediate, instead of pyridinium formation. This is the first evidence of synthesis of pyridinium derivatives from activated β-dicarbonyls, ketones, and an aromatic amine, the structures of which (both reactants and products) being analogous to species involved in biological systems, especially upon neurodegenerative diseases such as Parkinson’s. Beyond suggesting chemical/biochemical analogies, we thus hope to outline new research directions for understanding the mechanism of in vivo formation of pyridiniums, hence possible pharmaceutical strategies to better monitor, control or prevent it. Full article

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Open AccessArticle

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

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Molecules 2019, 24(6), 1110; https://doi.org/10.3390/molecules24061110 - 20 Mar 2019

Cited by 3 | Viewed by 2406

Abstract

Reactions of a series of 3-oxo-2-arylhydrazonopropanal derivatives with two molar ratio of ammonium acetate afforded a library of tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona- 3,7-diene derivatives in good to excellent isolated yields. The reaction was activated with triethylamine catalyst under three different heating modes: thermal, ultrasonic and [...] Read more.

Reactions of a series of 3-oxo-2-arylhydrazonopropanal derivatives with two molar ratio of ammonium acetate afforded a library of tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona- 3,7-diene derivatives in good to excellent isolated yields. The reaction was activated with triethylamine catalyst under three different heating modes: thermal, ultrasonic and microwave irradiating conditions in ethanol solvent. The structures of the isolated products were fully characterized by spectral and analytical data as well as X-ray single crystal of selected examples. Full article

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Open AccessArticle

Synthesis, In Vitro Antimicrobial and Cytotoxic Activities of Some New Pyrazolo[1,5-a]pyrimidine Derivatives

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Serag Eldin I. Elbehairi

Molecules 2019, 24(6), 1080; https://doi.org/10.3390/molecules24061080 - 19 Mar 2019

Cited by 36 | Viewed by 3533

Abstract

A new series of pyrazole 4–7 and pyrazolo[1,5-a]pyrimidine 8–13 were synthesized by using a simple, efficient procedure, and screened for their in-vitro antimicrobial and antitumor activities. Symmetrical and asymmetrical 3,6-diarylazo-2,5,7-triaminopyrazolo[1,5-a]pyrimidine were synthesized by the conventional [...] Read more.

A new series of pyrazole 4–7 and pyrazolo[1,5-a]pyrimidine 8–13 were synthesized by using a simple, efficient procedure, and screened for their in-vitro antimicrobial and antitumor activities. Symmetrical and asymmetrical 3,6-diarylazo-2,5,7-triaminopyrazolo[1,5-a]pyrimidine were synthesized by the conventional method and also subjected to microwave irradiation and under ultrasound conditions. The biological results revealed that most of the tested compounds proved to be active as antibacterial and antifungal agents. The antitumor activity of the synthesized compounds was evaluated against human cancer cell lines, MCF-7, HCT-116, and HepG-2, as compared with Doxorubicin as a control. Full article

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Figure 1

Open AccessArticle

Convenient Synthesis of 6,7,12,13-Tetrahydro-5H-Cyclohepta[2,1-b:3,4-b’]diindole Derivatives Mediated by Hypervalent Iodine (III) Reagent

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Lei Peng

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Xiaofei Zhang

and

Chunhao Yang

Molecules 2019, 24(5), 960; https://doi.org/10.3390/molecules24050960 - 08 Mar 2019

Cited by 7 | Viewed by 3014

Abstract

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5 [...] Read more.

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindole scaffold thus far, including the classical Fischer indole synthesis conducted by reacting indole-fused cycloheptanone and hydrazines, and the condensation reaction to build the seven-membered ring. Here, we report for the first time a new route to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles through intramolecular oxidative coupling of 1,3-di(1H-indol-3-yl)propanes in the presence of PIFA, DDQ and TMSCl with moderate to excellent yields. Full article

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Open AccessArticle

Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format

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Molecules 2019, 24(5), 864; https://doi.org/10.3390/molecules24050864 - 28 Feb 2019

Cited by 7 | Viewed by 3044

Abstract

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic [...] Read more.

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe³⁺, which makes them suitable candidates for the above-mentioned applications. Full article

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Open AccessArticle

Synthesis of 4-Alkyl-4H-1,2,4-triazole Derivatives by Suzuki Cross-Coupling Reactions and Their Luminescence Properties

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Molecules 2019, 24(3), 652; https://doi.org/10.3390/molecules24030652 - 12 Feb 2019

Cited by 7 | Viewed by 3627

Abstract

New derivatives of 4-alkyl-3,5-diaryl-4H-1,2,4-triazole were synthesized utilizing the Suzuki cross-coupling reaction. The presented methodology comprises of the preparation of bromine-containing 4-alkyl-4H-1,2,4-triazoles and their coupling with different commercially available boronic acids in the presence of ionic liquids or in conventional [...] Read more.

New derivatives of 4-alkyl-3,5-diaryl-4H-1,2,4-triazole were synthesized utilizing the Suzuki cross-coupling reaction. The presented methodology comprises of the preparation of bromine-containing 4-alkyl-4H-1,2,4-triazoles and their coupling with different commercially available boronic acids in the presence of ionic liquids or in conventional solvents. The obtained compounds were tested for their luminescence properties. Full article

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2018

Jump to: 2023, 2022, 2021, 2020, 2019, 2017, 2016, 2015

Open AccessArticle

HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation

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Molecules 2018, 23(12), 3317; https://doi.org/10.3390/molecules23123317 - 14 Dec 2018

Cited by 4 | Viewed by 4106

Abstract

1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) was found to be effective for the Bischler indole synthesis under microwave irradiation in the absence of a metal catalyst. Under the catalysis of HFIP, a wide range of α-amino arylacetones were successfully transformed into indole derivatives with moderate to good [...] Read more.

1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) was found to be effective for the Bischler indole synthesis under microwave irradiation in the absence of a metal catalyst. Under the catalysis of HFIP, a wide range of α-amino arylacetones were successfully transformed into indole derivatives with moderate to good yields. Full article

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Open AccessArticle

Synthesis, Antibacterial, and Anti HepG2 Cell Line Human Hepatocyte Carcinoma Activity of Some New Potentially Benzimidazole-5-(Aryldiazenyl)Thiazole Derivatives

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Abdulraheem S. A. Almalki

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Mahmoud A. Mohamed

Molecules 2018, 23(12), 3285; https://doi.org/10.3390/molecules23123285 - 11 Dec 2018

Cited by 16 | Viewed by 3666

Abstract

The paper describes the synthesis and biological evaluation of some new benzimidazole derivatives as potent clinical drugs that are useful in the treatment of some microbial infections and tumor inhibition. The starting compound 2-(bromomethyl)-1H-benzimidazole (1) was prepared, and hence [...] Read more.

The paper describes the synthesis and biological evaluation of some new benzimidazole derivatives as potent clinical drugs that are useful in the treatment of some microbial infections and tumor inhibition. The starting compound 2-(bromomethyl)-1H-benzimidazole (1) was prepared, and hence underwent interesting functionalization reactions to afford several series of benzimidazole-5-(aryldiazenyl)thiazole derivatives: 3a–c, 7a–c, and 8a–c. The antibacterial activities of the synthesized compounds were evaluated by calculation of the inhibition zone diameter (mm) and the determination of minimum inhibitory concentration (µg/mL) against selected pathogenic bacteria Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria).Noticeable efficiency was found based on in vitro screening for their antioxidant activity and cytotoxicity effect against the human liver cancer cell line (HepG2) and human hepatocyte carcinoma cells at relatively high concentrations. Full article

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Open AccessArticle

Conversion of Medium-Sized Lactams to α-Vinyl or α-Acetylenyl Azacycles via N,O-Acetal TMS Ethers

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Minjun Kim

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Jaebong Jang

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Goyoung Choi

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Molecules 2018, 23(11), 3023; https://doi.org/10.3390/molecules23113023 - 19 Nov 2018

Cited by 5 | Viewed by 3245

Abstract

α-Vinyl or α-acetylenyl azacycles were easily synthesized from 7- to 9-membered lactams and 6- to 9-membered lactams via N,O-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane reagents afforded reasonable yields for the respective N-acyliminium ion vinylation and acetylenylation intermediates generated [...] Read more.

α-Vinyl or α-acetylenyl azacycles were easily synthesized from 7- to 9-membered lactams and 6- to 9-membered lactams via N,O-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane reagents afforded reasonable yields for the respective N-acyliminium ion vinylation and acetylenylation intermediates generated from N,O-acetal TMS ethers in the presence of a Lewis acid. Full article

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Open AccessFeature PaperArticle

Eco-Friendly Synthesis, Characterization and Biological Evaluation of Some Novel Pyrazolines Containing Thiazole Moiety as Potential Anticancer and Antimicrobial Agents

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Molecules 2018, 23(11), 2970; https://doi.org/10.3390/molecules23112970 - 14 Nov 2018

Cited by 31 | Viewed by 3192

Abstract

The one-pot synthesis of a series of pyrazoline derivatives containing the bioactive thiazole ring has been performed through a 1,3-dipolar cycloaddition reaction of N-thiocarbamoylpyrazoline and different hydrazonoyl halides or α-haloketones in the presence of DABCO (1,4-diazabicyclo[2.2.2] octane) as an eco-friendly catalyst using [...] Read more.

The one-pot synthesis of a series of pyrazoline derivatives containing the bioactive thiazole ring has been performed through a 1,3-dipolar cycloaddition reaction of N-thiocarbamoylpyrazoline and different hydrazonoyl halides or α-haloketones in the presence of DABCO (1,4-diazabicyclo[2.2.2] octane) as an eco-friendly catalyst using the solvent-drop grinding method. The structure of the synthesized compounds was elucidated using elemental and spectroscopic analyses (IR, NMR, and Mass). The activity of these compounds against human hepatocellular carcinoma cell line (HepG2) was tested and the results showed that the pyrazoline 11f, which has a fluorine substituent, is the most active. The antimicrobial activities of the newly synthesized compounds were determined against two fungi and four bacterial strains, and the results indicated that some of the newly synthesized pyrazolines are more potent than the standard drugs against test organisms. Full article

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Open AccessFeature PaperArticle

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

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Molecules 2018, 23(11), 2961; https://doi.org/10.3390/molecules23112961 - 13 Nov 2018

Cited by 5 | Viewed by 4590

Abstract

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids [...] Read more.

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2′,3′:5,6] pyrido[4,3-b]indole and pyrazino[2′,3′:4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition). Full article

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Open AccessArticle

Quinazolin-4(3H)-ones and 5,6-Dihydropyrimidin-4(3H)-ones from β-Aminoamides and Orthoesters

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Joshua T. Gavin

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Joel K. Annor-Gyamfi

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Richard A. Bunce

Molecules 2018, 23(11), 2925; https://doi.org/10.3390/molecules23112925 - 09 Nov 2018

Cited by 12 | Viewed by 3720

Abstract

Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic [...] Read more.

Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic acid for 12–24 h. Ring-substituted and hindered 2-aminobenzamides as well as cases incorporating an additional basic nitrogen required pressure tube conditions with 3 equivalents each of the orthoester and acetic acid in ethanol at 110 °C for 12–72 h. The reaction was tolerant towards functionality on the benzamide and a range of structures was accessible. Workup involved removal of the solvent under vacuum and either recrystallization from ethanol or trituration with ether-pentane. Several 5,6-dihydropyrimidin-4(3H)-ones were also prepared from 3-amino-2,2-dimethylpropionamide. All products were characterized by melting point, FT-IR, ¹H-NMR, ¹³C-NMR, and HRMS. Full article

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Open AccessFeature PaperArticle

Regioselective Synthesis of New 2,4-(Het)aryl-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidines Involving Palladium-Catalyzed Cross-Coupling Reactions

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Molecules 2018, 23(11), 2740; https://doi.org/10.3390/molecules23112740 - 23 Oct 2018

Cited by 5 | Viewed by 2627

Abstract

The design of some novel di-(het)arylated-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidine derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium catalyzed cross coupling reactions by alkyl [...] Read more.

The design of some novel di-(het)arylated-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidine derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium catalyzed cross coupling reactions by alkyl sulfur release and C-O activation, respectively. The two regioselective and successive cross-coupling reactions were first carried out in C-4 by in situ C-O activation and next in C-2 by a methylsulfur release. Process optimization furnished conditions leading to products in high yields. The scope and limitations of the methodologies were evaluated and the final compounds characterized. Full article

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Open AccessReview

Synthesis of Multi-Substituted Pyrrole Derivatives Through [3+2] Cycloaddition with Tosylmethyl Isocyanides (TosMICs) and Electron-Deficient Compounds

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Zhengning Ma

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Zicheng Ma

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Dawei Zhang

Molecules 2018, 23(10), 2666; https://doi.org/10.3390/molecules23102666 - 17 Oct 2018

Cited by 41 | Viewed by 12279

Abstract

Pyrrole and its polysubstituted derivatives are important five-membered heterocyclic compounds, which exist alone or as a core framework in many pharmaceutical and natural product structures, some of which have good biological activities. The Van Leusen [3+2] cycloaddition reaction based on tosylmethyl isocyanides (TosMICs) [...] Read more.

Pyrrole and its polysubstituted derivatives are important five-membered heterocyclic compounds, which exist alone or as a core framework in many pharmaceutical and natural product structures, some of which have good biological activities. The Van Leusen [3+2] cycloaddition reaction based on tosylmethyl isocyanides (TosMICs) and electron-deficient compounds as a substrate, which has been continuously developed due to its advantages such as operationally simple, easily available starting materials, and broadly range of substrates, is one of the most convenient methods to synthetize pyrrole heterocycles. In this review, we discuss the different types of two carbon synthons in the Van Leusen pyrrole reaction and give a summary of the progress of these synthesis methods in the past two decades. Full article

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Scheme 1

Open AccessArticle

Synthesis, Spectroscopic Characterization, and In Vitro Antibacterial Evaluation of Novel Functionalized Sulfamidocarbonyloxyphosphonates

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Molecules 2018, 23(7), 1682; https://doi.org/10.3390/molecules23071682 - 10 Jul 2018

Cited by 12 | Viewed by 3792

Abstract

Several new sulfamidocarbonyloxyphosphonates were prepared in two steps, namely carbamoylation and sulfamoylation, by using chlorosulfonyl isocyanate (CSI), α-hydroxyphosphonates, and various amino derivatives and related (primary or secondary amines, β-amino esters, and oxazolidin-2-ones). All structures were confirmed by ¹H, ¹³C, and ³¹ [...] Read more.

Several new sulfamidocarbonyloxyphosphonates were prepared in two steps, namely carbamoylation and sulfamoylation, by using chlorosulfonyl isocyanate (CSI), α-hydroxyphosphonates, and various amino derivatives and related (primary or secondary amines, β-amino esters, and oxazolidin-2-ones). All structures were confirmed by ¹H, ¹³C, and ³¹P NMR spectroscopy, IR spectroscopy, and mass spectroscopy, as well as elemental analysis. Eight compounds were evaluated for their in vitro antibacterial activity against four reference bacteria including Gram-positive Staphylococcus aureus (ATCC 25923), and Gram-negative Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Pseudomonas aeruginosa (ATCC 27853), in addition to three clinical strains of each studied bacterial species. Compounds 1a–7a and 1b showed significant antibacterial activity compared to sulfamethoxazole/trimethoprim, the reference drug used in this study. Full article

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Open AccessCorrection

Correction: El-kalyoubi, S.; et al. Novel 2-Thioxanthine and Dipyrimidopyridine Derivatives: Synthesis and Antimicrobial Activity. Molecules, 2015, 20, 19263–19276

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Samar El-kalyoubi

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Fatmah Agili

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Shaker Youssif

Molecules 2018, 23(7), 1592; https://doi.org/10.3390/molecules23071592 - 29 Jun 2018

Viewed by 2475

Abstract

The authors wish to make the following changes to their paper [1].[...] Full article

Open AccessArticle

Synthesis of 8-Fluoro-3,4-dihydroisoquinoline and Its Transformation to 1,8-Disubstituted Tetrahydroisoquinolines

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Molecules 2018, 23(6), 1280; https://doi.org/10.3390/molecules23061280 - 26 May 2018

Cited by 3 | Viewed by 3786

Abstract

A simple procedure for the synthesis of 8-fluoro-3,4-dihydroisoquinoline is described below, based on a directed ortho-lithiation reaction. This key intermediate was then applied in various transformations. Fluorine–amine exchange afforded the corresponding 8-amino-3,4-dihydroisoquinolines, suitable starting compounds for the synthesis of 1-substituted 8-amino-tetrahydroisoquinolines. On [...] Read more.

A simple procedure for the synthesis of 8-fluoro-3,4-dihydroisoquinoline is described below, based on a directed ortho-lithiation reaction. This key intermediate was then applied in various transformations. Fluorine–amine exchange afforded the corresponding 8-amino-3,4-dihydroisoquinolines, suitable starting compounds for the synthesis of 1-substituted 8-amino-tetrahydroisoquinolines. On the other hand, reduction and alkylation reactions of 8-fluoro-3,4-dihydroisoquinoline led to novel 1,2,3,4-tetrahydroisoquinoline derivatives that can be used as building blocks in the synthesis of potential central nervous system drug candidates. Full article

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Open AccessArticle

Synthesis and Pharmacological Studies of Unprecedented Fused Pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine Derivatives

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Rania S. Ali

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Hosam A. Saad

Molecules 2018, 23(5), 1024; https://doi.org/10.3390/molecules23051024 - 27 Apr 2018

Cited by 5 | Viewed by 3634

Abstract

A novel fused system with three or four fused rings—pyridazino[3′,4′:5,6][1,2,4]triazino[4,3-b][1,2,4,5]tetrazine and pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b]pyrimido[4,5-e][1,3,4]thiadiazine was obtained from the starting materials 4(6H)-amino-3-hydrazino-7-(2-thienyl)pyridazino[3,4-e][1,2,4]-triazine 2 and 9-amino-3-(2-thienyl)-2H,8H-pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine-8-carbonitrile 12. Each of the [...] Read more.

A novel fused system with three or four fused rings—pyridazino[3′,4′:5,6][1,2,4]triazino[4,3-b][1,2,4,5]tetrazine and pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b]pyrimido[4,5-e][1,3,4]thiadiazine was obtained from the starting materials 4(6H)-amino-3-hydrazino-7-(2-thienyl)pyridazino[3,4-e][1,2,4]-triazine 2 and 9-amino-3-(2-thienyl)-2H,8H-pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine-8-carbonitrile 12. Each of the starting compounds was subjected to a number of cyclization reactions to obtain a series of new heterocyclic fused systems, 3–10 and 13–23, via bifunctional reagents. Some of the synthesized compounds were screened against three cell lines including HepG2, HCT-116 and MCF-7 to discover their anticancer activity. The synthesized compounds were characterized depending on their elemental analyses and spectral data. Full article

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Open AccessArticle

Synthesis of Some Novel Fused Pyrimido[4″,5″:5′,6′]-[1,2,4]triazino[3′,4′:3,4] [1,2,4]triazino[5,6-b]indoles with Expected Anticancer Activity

by

Rania S. Ali

and

Hosam A. Saad

Molecules 2018, 23(3), 693; https://doi.org/10.3390/molecules23030693 - 19 Mar 2018

Cited by 9 | Viewed by 4229

Abstract

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was [...] Read more.

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was prepared by the diazotization of 3-amino[1,2,4]-triazino[5,6-b]indole 1 followed by coupling with malononitrile in basic medium then cyclization under reflux to get 4. Also, new fused pyrimido[4″,5″:5′,6′][1,2,4]triazino-[3′,4′:3,4][1,2,4]triazino[5,6-b]indole derivative 6 was prepared and used to obtain polycyclic heterocyclic systems. Confirmation of the synthesized compounds’ structures was carried out using elemental analyses and spectral data (IR, ¹H-NMR and ¹³C-NMR and mass spectra). The anticancer activity of some of the synthesized compounds was tested against HepG2, HCT-116 and MCF-7 cell lines. The anticancer screening results showed that some derivatives display good activity which was more potent than that of the reference drug used. Molecular docking was used to predict the binding between some of the synthesized compounds and the prostate cancer 2q7k hormone and breast ‎cancer 3hb5 receptors. Full article

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Open AccessFeature PaperArticle

Syntheses of 1-Aryl-5-nitro-1H-indazoles and a General One-Pot Route to 1-Aryl-1H-indazoles

by

Joel K. Annor-Gyamfi

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Krishna Kumar Gnanasekaran

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Richard A. Bunce

Molecules 2018, 23(3), 674; https://doi.org/10.3390/molecules23030674 - 16 Mar 2018

Cited by 4 | Viewed by 4917

Abstract

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) [...] Read more.

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) ring closure in 45–90%. Modification of this procedure to a one-pot domino process was successful in the acetophenone series (73–96%), while the benzaldehyde series (63–73%) required a step-wise addition of reagents. A general one-pot protocol for 1-aryl-1H-indazole formation without the limiting substitution patterns required for the S_NAr cyclization has also been achieved in 62–78% yields. A selection of 1-aryl-1H-indazoles was prepared in high yield by a procedure that requires only a single laboratory operation. Full article

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Open AccessArticle

Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring-Closing Metathesis from 4-Allyloxy-1H-pyrazoles

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Molecules 2018, 23(3), 592; https://doi.org/10.3390/molecules23030592 - 06 Mar 2018

Cited by 8 | Viewed by 3215

Abstract

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for [...] Read more.

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for the RCM of 5-allyl-4-allyloxy-1H-pyrazoles (4) was proved to be the Grubbs second generation catalyst (Grubbs^2nd) to give the predicted RCM product at room temperature in three hours. The same reactions of the regioisomer, 3-allyl-4-allyloxy-1H-pyrazoles (5), also proceeded to give the corresponding RCM products. On the other hand, microwave aided RCM at 140 °C on both of 4 and 5 afforded mixtures of isomeric products with double bond rearrangement from normal RCM products in spite of remarkable reduction of the reaction time to 10 min. Full article

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Open AccessArticle

Synthesis and Optical Properties of Near-Infrared meso-Phenyl-Substituted Symmetric Heptamethine Cyanine Dyes

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Andrew Levitz

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Fahad Marmarchi

and

Maged Henary

Molecules 2018, 23(2), 226; https://doi.org/10.3390/molecules23020226 - 24 Jan 2018

Cited by 25 | Viewed by 6831

Abstract

Heptamethine cyanine dyes are a class of near infrared fluorescence (NIRF) probes of great interest in bioanalytical and imaging applications due to their modifiability, allowing them to be tailored for particular applications. Generally, modifications at the meso-position of these dyes are achieved [...] Read more.

Heptamethine cyanine dyes are a class of near infrared fluorescence (NIRF) probes of great interest in bioanalytical and imaging applications due to their modifiability, allowing them to be tailored for particular applications. Generally, modifications at the meso-position of these dyes are achieved through Suzuki-Miyaura C-C coupling and S_RN1 nucleophilic substitution of the chlorine atom at the meso-position of the dye. Herein, a series of 15 meso phenyl-substituted heptamethine cyanines was synthesized utilizing a modified dianil linker. Their optical properties, including molar absorptivity, fluorescence, Stokes shift, and quantum yield were measured. The HSA binding affinities of two representative compounds were measured and compared to that of a series of trimethine cyanines previously synthesized by our lab. The results indicate that the binding of these compounds to HSA is not only dependent on hydrophobicity, but may also be dependent on steric interferences in the binding site and structural dynamics of the NIRF compounds. Full article

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Open AccessArticle

Regioselectivity in Reactions between Bis(2-benzothiazolyl)ketone and Vinyl Grignard Reagents: C- versus O-alkylation—Part III

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Molecules 2018, 23(1), 171; https://doi.org/10.3390/molecules23010171 - 15 Jan 2018

Cited by 3 | Viewed by 4310

Abstract

The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave the product derived from attack on the carbonylic carbon- and/or oxygen-atom. The regioselectivity of the attack depends on the kind of substituents bound to the vinylic carbon [...] Read more.

The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave the product derived from attack on the carbonylic carbon- and/or oxygen-atom. The regioselectivity of the attack depends on the kind of substituents bound to the vinylic carbon atoms and on their relative position. The reaction between vinylmagnesium bromide and 2-methyl-1-propenylmagnesium bromide was carried out under different experimental conditions and in the presence of radical scavengers. The results indicate a plausible mechanistic pathway involving radical intermediates in the case of O-alkylation, but a polar ones in the case of classic C-alkylation. This agrees with our previous reports indicating a key role played by the delocalization ability of the substituents bound to the carbonyl group in driving the regioselectivity of the vinylmagnesium bromide attack towards O-alkylation. Further support of this was obtained by diffractometric analysis of four distinct bis(heteroaryl)ketones. Full article

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