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Non-Natural Multi-Heteroatom Heterocycles: New Chemical Space

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 18009

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Special Issue Editors

Prof. Dr. Panayiotis A. Koutentis

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Department of Chemistry, University of Cyprus, P. O. Box 20537, Nicosia 1678, Cyprus
Interests: heterocyclic chemistry; sulfur-nitrogen heterocycles; synthetic methods; azaacenes; zwitterionic acenes; stable organic radicals; biologically active heterocycles; isothiazoles; 1,2,3-dithiazoles; 1,2,6-thiadiazines; 1,2,4-benzotriazines
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Dr. Andreas S. Kalogirou

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Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P.O. Box 22006, 1516 Nicosia, Cyprus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Owing to the ever-increasing competitiveness within the chemical industries, there is a need to discover and develop new chemical space. New chemical structures offer competitive advantages for securing intellectual property (IP) rights. Many new and potentially useful chemicals are regularly discovered from natural sources, which is a rich pool of unusual chemical structures. Nevertheless, chemical structures that arise from nature can lead to difficulties in securing and upholding IP as these can be the subject of counter claims of ‘bio-piracy’.

A complementary source of new chemical space comes from the exploration of unusual heterocyclic systems that are rich in heteroatoms. Many such systems are not available from natural sources but are man-made. Often, chemical techniques that are alien to nature’s own synthetic tool box are needed to create and develop these heterocycles.

This Special Issue focuses on the synthesis, chemistry, applications and theoretical studies of such multi-heteroatom heterocycles whose core heterocyclic structure has not yet been reported in any structure derived from natural sources.

Prof. Dr. Panayiotis A. Koutentis
Dr. Andreas S. Kalogirou
Guest Editors

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Keywords

heterocycle
heteroarene
hetarene
synthesis
medicinal, agrochemical, materials
computational
theoretical
crystallography
chemical space

Published Papers (6 papers)

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Research

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10 pages, 3260 KiB

Open AccessArticle

Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors

by Liang Xia, Yan Zhang, Jingbo Zhang, Songwen Lin, Kehui Zhang, Hua Tian, Yi Dong and Heng Xu

Molecules 2020, 25(20), 4630; https://doi.org/10.3390/molecules25204630 - 12 Oct 2020

Cited by 9 | Viewed by 2070

Abstract

A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC₅₀ of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC₅₀ value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC₅₀ value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction. Full article

(This article belongs to the Special Issue Non-Natural Multi-Heteroatom Heterocycles: New Chemical Space)

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13 pages, 10573 KiB

Open AccessArticle

A New Method for the Synthesis of 3-Thiocyanatopyrazolo[1,5-a]pyrimidines

by Vladimir A. Kokorekin, Sergey V. Neverov, Vera N. Kuzina and Vladimir A. Petrosyan

Molecules 2020, 25(18), 4169; https://doi.org/10.3390/molecules25184169 - 11 Sep 2020

Cited by 12 | Viewed by 2272

Abstract

In this article, we demonstrate how an original effective “metal-free” and “chromatography-free” route for the synthesis of 3-thiocyanatopyrazolo[1,5-a]pyrimidines has been developed. It is based on electrooxidative (anodic) C–H thiocyanation of 5-aminopyrazoles by thiocyanate ion leading to 4-thiocyanato-5-aminopyrazoles (stage 1, yields up to 87%) following by their chemical condensation with 1,3-dicarbonyl compounds or their derivatives (stage 2, yields up to 96%). This method is equally effective for the synthesis of 3-thiocyanatopyrazolo[1,5-a]pyrimidines, both without substituents and with various donor (acceptor) substituents in the pyrimidine ring. Full article

(This article belongs to the Special Issue Non-Natural Multi-Heteroatom Heterocycles: New Chemical Space)

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18 pages, 3809 KiB

Open AccessArticle

Synthesis, Structure, and Reactivity of Binaphthyl Supported Dihydro[1,6]diazecines

by Miran Lemmerer, Michael Abraham, Bogdan R. Brutiu, Alexander Roller and Michael Widhalm

Molecules 2019, 24(17), 3098; https://doi.org/10.3390/molecules24173098 - 26 Aug 2019

Viewed by 2944

Abstract

A short approach to chiral diaza-olefines from protected 2,2′-diamino-1,1′-binaphthyl is presented. Cis- and trans-olefines can be selectively obtained by twofold N-allylation followed by RCM or by bridging a 2,2′-diamino-1,1′-binaphthyl precursor with trans-1,4-dibromo-2-butene. Deprotection afforded cis- and trans-dihydro[1,6]diazecines 1 in 58 and 64% overall yield. The reactivity of the but-2-ene-1,4-diyl fragment was investigated yielding corresponding epoxides, diols, and mono- and dibromo products. In several cases rearrangements and participation of the proximate N-Boc group was observed. In no case could allylic substitution be accomplished. From 13 compounds X-ray structure analyses could be obtained. Full article

(This article belongs to the Special Issue Non-Natural Multi-Heteroatom Heterocycles: New Chemical Space)

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17 pages, 4114 KiB

Open AccessFeature PaperArticle

[1,2,5]Thiadiazolo[3,4-d]Pyridazine as an Internal Acceptor in the D-A-π-A Organic Sensitizers for Dye-Sensitized Solar Cells

by Timofey N. Chmovzh, Ekaterina A. Knyazeva, Ellie Tanaka, Vadim V. Popov, Ludmila V. Mikhalchenko, Neil Robertson and Oleg A. Rakitin

Molecules 2019, 24(8), 1588; https://doi.org/10.3390/molecules24081588 - 22 Apr 2019

Cited by 21 | Viewed by 3760

Abstract

Four new D-A-π-A metal-free organic sensitizers for dye-sensitized solar cells (DSSCs), with [1,2,5]thiadiazolo[3,4-d]pyridazine as internal acceptor, thiophene unit as π-spacer and cyanoacrylate as anchoring electron acceptor, have been synthesized. The donor moiety was introduced into [1,2,5]thiadiazolo[3,4-d]pyridazine by nucleophilic aromatic substitution and Suzuki cross-coupling reactions, allowing design of D-A-π-A sensitizers with the donor attached to the internal heterocyclic acceptor not only by the carbon atom, as it is in a majority of DSSCs, but by the nitrogen atom also. Although low values of power conversion efficiency (PCE) were found, a few important consequences were identified: (i) poor PCE data can be attributed to high electron deficiency of the internal [1,2,5]thiadiazolo[3,4-d]pyridazine acceptor due to lower light harvesting by the dye; (ii) the manner in which the donor was attached to the internal acceptor (by carbon or nitrogen) did not play an essential role in the photovoltaic properties of the dyes; (iii) dyes based on the novel donor 2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazolyl and 9-(p-tolyl)-2,3,4,4a,9,9a-hexahydro-1H- carbazole moieties showed similar photovoltaic properties to dyes based on the well-known 4-(p-tolyl)-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indolyl building block, which opens the door for further optimization potential of new dye families. Full article

(This article belongs to the Special Issue Non-Natural Multi-Heteroatom Heterocycles: New Chemical Space)

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13 pages, 983 KiB

Open AccessArticle

Fused Heterocyclic Systems with an s-Triazine Ring. 34. Development of a Practical Approach for the Synthesis of 5-Aza-isoguanines

by Ahmad Junaid, Felicia Phei Lin Lim, Yvonne Peijun Zhou, Wai Keung Chui and Anton V. Dolzhenko

Molecules 2019, 24(8), 1453; https://doi.org/10.3390/molecules24081453 - 12 Apr 2019

Cited by 3 | Viewed by 3087

Abstract

Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents. Full article

(This article belongs to the Special Issue Non-Natural Multi-Heteroatom Heterocycles: New Chemical Space)

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Review

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21 pages, 7840 KiB

Open AccessReview

Recent Advances in Catalytic Synthesis of Benzosultams

by Quan-Qing Zhao and Xiao-Qiang Hu

Molecules 2020, 25(19), 4367; https://doi.org/10.3390/molecules25194367 - 23 Sep 2020

Cited by 25 | Viewed by 3002

Abstract

Benzosultams represent one category of multi-heteroatom heterocyclic scaffolds, which have been frequently found in pharmaceuticals, agricultural agents, and chiral catalysts. Given the diversely significant functions of these compounds in organic and medicinal chemistry, great efforts have been made to develop novel catalytic systems for the efficient construction of benzosultam motifs over the past decades. Herein, in this review, we mainly summarize the recent advances in the field of catalytic synthesis of benzosultams from 2017 to August of 2020, with an emphasis on the scopes and mechanisms of representative reactions. Full article

(This article belongs to the Special Issue Non-Natural Multi-Heteroatom Heterocycles: New Chemical Space)

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