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17 pages, 3627 KiB

Open AccessArticle

BF₃-OEt₂ Catalyzed C3-Alkylation of Indole: Synthesis of Indolylsuccinimidesand Their Cytotoxicity Studies

by Iqbal N. Shaikh, Abdul Rahim, Shaikh Faazil, Syed Farooq Adil, Mohamed E. Assal and Mohammad Rafe Hatshan

Molecules 2021, 26(8), 2202; https://doi.org/10.3390/molecules26082202 - 11 Apr 2021

Cited by 6 | Viewed by 5453

Abstract

A simple and efficient BF₃-OEt₂ promoted C3-alkylation of indole has been developed to obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent yields under mild reaction conditions. Furthermore, anti-proliferative activity of these conjugates was evaluated against HT-29 (Colorectal), Hepg2 (Liver) and [...] Read more.

A simple and efficient BF₃-OEt₂ promoted C3-alkylation of indole has been developed to obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent yields under mild reaction conditions. Furthermore, anti-proliferative activity of these conjugates was evaluated against HT-29 (Colorectal), Hepg2 (Liver) and A549 (Lung) human cancer cell lines. One of the compounds, 3w, having N,N-Dimethylatedindolylsuccinimide is a potent congener amongst the series with IC₅₀ value 0.02 µM and 0.8 µM against HT-29 and Hepg2 cell lines, respectively, and compound 3i was most active amongst the series with IC₅₀ value 1.5 µM against A549 cells. Molecular docking study and mechanism of reaction have briefly beendiscussed. This method is better than previous reports in view of yield and substrate scope including electron deficient indoles. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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13 pages, 3344 KiB

Open AccessCommunication

Triazolopyridopyrimidine: A New Scaffold for Dual-Target Small Molecules for Alzheimer’s Disease Therapy

by Lazhar Zribi, Irene Pachòn-Angona, Òscar M. Bautista-Aguilera, Daniel Diez-Iriepa, José Marco-Contelles, Lhassane Ismaili, Isabel Iriepa and Fakher Chabchoub

Molecules 2020, 25(14), 3190; https://doi.org/10.3390/molecules25143190 - 13 Jul 2020

Cited by 10 | Viewed by 2867

Abstract

Alzheimer’s disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aβ) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it [...] Read more.

Alzheimer’s disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aβ) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it is urgent to explore all the opportunities available to combat this illness. Among them, the discovery of new heterocyclic scaffolds binding different receptors involved in AD should offer structural diversity and new therapeutic solutions. In this context, this work describes new triazolopyridopyrimidine easily prepared in good yields showing anticholinesterase inhibition and strong antioxidant power, particularly the most balanced: 6-amino-5-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1′,5′:1,6] pyrido[2,3-d]pyrimidine-4-carbonitrile(3c) with IC₅₀ equal to 1.32 μM against AChE and oxygen radical absorbance capacity (ORAC) value equal to 4.01 Trolox equivalents (TE); thus representing a new and very promising hit-triazolopyridopyrimidine for AD therapy. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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14 pages, 1708 KiB

Open AccessFeature PaperArticle

Deep Eutectic Solvents as Effective Reaction Media for the Synthesis of 2-Hydroxyphenylbenzimidazole-Based Scaffolds en Route to Donepezil-Like Compounds

by Luca Piemontese, Roberta Sergio, Federica Rinaldo, Leonardo Brunetti, Filippo M. Perna, M. Amélia Santos and Vito Capriati

Molecules 2020, 25(3), 574; https://doi.org/10.3390/molecules25030574 - 28 Jan 2020

Cited by 25 | Viewed by 3948

Abstract

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer’s disease (AD) treatment. Building [...] Read more.

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer’s disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs). Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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15 pages, 7215 KiB

Open AccessArticle

Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines

by Tamie Suzuki, Nilamber A. Mate, Arijit A. Adhikari and John D. Chisholm

Molecules 2019, 24(22), 4143; https://doi.org/10.3390/molecules24224143 - 15 Nov 2019

Cited by 3 | Viewed by 3801

Abstract

2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method [...] Read more.

2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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10 pages, 2197 KiB

Open AccessCommunication

Synthesis, Physicochemical Properties, and Biological Activities of 4-(S-Methyl-N-(2,2,2-Trifluoroacetyl)Sulfilimidoyl) Anthranilic Diamide

by Hwan Jung Lim, Won Hyung Lee and Seong Jun Park

Molecules 2019, 24(19), 3451; https://doi.org/10.3390/molecules24193451 - 23 Sep 2019

Cited by 8 | Viewed by 4383

Abstract

Novel anthranilic diamides with sulfilimidoyl and sulfoximidoyl functionalities were successfully prepared. Among newly-prepared organosulfur compounds, 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)phenyl)-1H-pyrazole-5-carboxamide and (S,E)-3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl)-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide showed good levels of efficacy and a strong correlation between insecticidal [...] Read more.

Novel anthranilic diamides with sulfilimidoyl and sulfoximidoyl functionalities were successfully prepared. Among newly-prepared organosulfur compounds, 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)phenyl)-1H-pyrazole-5-carboxamide and (S,E)-3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl)-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide showed good levels of efficacy and a strong correlation between insecticidal activities and physical properties, respectively. In particular, available data indicated that the N-trifluoroacetyl sulfilimine moiety could be an appealing structural scaffold for the discovery of a new crop-protecting agent. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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11 pages, 1287 KiB

Open AccessArticle

Synthesis of 6,12-Disubstituted Methanodibenzo[b,f][1,5]dioxocins: Pyrrolidine Catalyzed Self-Condensation of 2′-Hydroxyacetophenones

by Benedicta Assoah, Vesa Riihonen, João R. Vale, Arto Valkonen and Nuno R. Candeias

Molecules 2019, 24(13), 2405; https://doi.org/10.3390/molecules24132405 - 29 Jun 2019

Cited by 3 | Viewed by 3261

Abstract

The preparation of unprecedented 6,12-disubstituted methanodibenzo[b,f][1,5]dioxocins from pyrrolidine catalyzed self-condensation of 2′-hydroxyacetophenones is herein described. This method provides easy access to this highly bridged complex core, resulting in construction of two C–O and two C–C bonds, a methylene bridge [...] Read more.

The preparation of unprecedented 6,12-disubstituted methanodibenzo[b,f][1,5]dioxocins from pyrrolidine catalyzed self-condensation of 2′-hydroxyacetophenones is herein described. This method provides easy access to this highly bridged complex core, resulting in construction of two C–O and two C–C bonds, a methylene bridge and two quaternary centers in a single step. The intricate methanodibenzo[b,f][1,5]dioxocin compounds were obtained in up to moderate yields after optimization of the reaction conditions concerning solvent, reaction times and the use of additives. Several halide substituted methanodibenzo[b,f][1,5]dioxocins could be prepared from correspondent 2′-hydroxyacetophenones. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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Review

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26 pages, 4889 KiB

Open AccessReview

Laccases: Versatile Biocatalysts for the Synthesis of Heterocyclic Cores

by Ana Catarina Sousa, Lígia O. Martins and M. Paula Robalo

Molecules 2021, 26(12), 3719; https://doi.org/10.3390/molecules26123719 - 18 Jun 2021

Cited by 32 | Viewed by 4513

Abstract

Laccases are multicopper oxidases that have shown a great potential in various biotechnological and green chemistry processes mainly due to their high relative non-specific oxidation of phenols, arylamines and some inorganic metals, and their high redox potentials that can span from 500 to [...] Read more.

Laccases are multicopper oxidases that have shown a great potential in various biotechnological and green chemistry processes mainly due to their high relative non-specific oxidation of phenols, arylamines and some inorganic metals, and their high redox potentials that can span from 500 to 800 mV vs. SHE. Other advantages of laccases include the use of readily available oxygen as a second substrate, the formation of water as a side-product and no requirement for cofactors. Importantly, addition of low-molecular-weight redox mediators that act as electron shuttles, promoting the oxidation of complex bulky substrates and/or of higher redox potential than the enzymes themselves, can further expand their substrate scope, in the so-called laccase-mediated systems (LMS). Laccase bioprocesses can be designed for efficiency at both acidic and basic conditions since it is known that fungal and bacterial laccases exhibit distinct optimal pH values for the similar phenolic and aromatic amines. This review covers studies on the synthesis of five- and six-membered ring heterocyclic cores, such as benzimidazoles, benzofurans, benzothiazoles, quinazoline and quinazolinone, phenazine, phenoxazine, phenoxazinone and phenothiazine derivatives. The enzymes used and the reaction protocols are briefly outlined, and the mechanistic pathways described. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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24 pages, 15017 KiB

Open AccessReview

Advances in Synthesis of π-Extended Benzosilole Derivatives and Their Analogs

by Tuan Thanh Dang, Hue Minh Thi Nguyen, Hien Nguyen, Tran Ngoc Dung, Minh Tho Nguyen and Wim Dehaen

Molecules 2020, 25(3), 548; https://doi.org/10.3390/molecules25030548 - 27 Jan 2020

Cited by 18 | Viewed by 4529

Abstract

Benzosiloles and their π-extended derivatives are present in many important advanced materials due to their excellent physical properties. Especially, they have found many potential applications in the development of novel electronic materials such as OLEDs, semiconductors and solar cells. In this review, we [...] Read more.

Benzosiloles and their π-extended derivatives are present in many important advanced materials due to their excellent physical properties. Especially, they have found many potential applications in the development of novel electronic materials such as OLEDs, semiconductors and solar cells. In this review, we have summarized several main approaches to construct (di)benzosilole derivatives and (benzo)siloles fused to aromatic five- and six-membered heterocycles. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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28 pages, 3180 KiB

Open AccessReview

Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles

by Alina Secrieru, Paul Michael O’Neill and Maria Lurdes Santos Cristiano

Molecules 2020, 25(1), 42; https://doi.org/10.3390/molecules25010042 - 20 Dec 2019

Cited by 44 | Viewed by 13629

Abstract

Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they [...] Read more.

Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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27 pages, 8248 KiB

Open AccessReview

Current Advances in the Synthesis of Valuable Dipyrromethane Scaffolds: Classic and New Methods

by Bruno F. O. Nascimento, Susana M. M. Lopes, Marta Pineiro and Teresa M. V. D. Pinho e Melo

Molecules 2019, 24(23), 4348; https://doi.org/10.3390/molecules24234348 - 28 Nov 2019

Cited by 24 | Viewed by 6893

Abstract

This review presents the most recent developments on the synthesis of dipyrromethanes, covering classical synthetic strategies, using acid catalyzed condensation of pyrroles and aldehydes or ketones, and recent breakthroughs which allow the synthesis of these type of heterocycles with new substitution patterns. Full article

(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)

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