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Open AccessFeature PaperReview

The Synthesis and Biological Applications of the 1,2,3-Dithiazole Scaffold

by Andreas S. Kalogirou, Hans J. Oh and Christopher R. M. Asquith

Molecules 2023, 28(7), 3193; https://doi.org/10.3390/molecules28073193 - 3 Apr 2023

Cited by 9 | Viewed by 4421

The 1,2,3-dithiazole is an underappreciated scaffold in medicinal chemistry despite possessing a wide variety of nascent pharmacological activities. The scaffold has a potential wealth of opportunities within these activities and further afield. The 1,2,3-dithiazole scaffold has already been reported as an antifungal, herbicide, [...] Read more.

The 1,2,3-dithiazole is an underappreciated scaffold in medicinal chemistry despite possessing a wide variety of nascent pharmacological activities. The scaffold has a potential wealth of opportunities within these activities and further afield. The 1,2,3-dithiazole scaffold has already been reported as an antifungal, herbicide, antibacterial, anticancer agent, antiviral, antifibrotic, and is a melanin and Arabidopsis gibberellin 2-oxidase inhibitor. These structure activity relationships are discussed in detail, along with insights and future directions. The review also highlights selected synthetic strategies developed towards the 1,2,3-dithiazole scaffold, how these are integrated to accessibility of chemical space, and to the prism of current and future biological activities. Full article

(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)

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6 pages, 812 KB

Open AccessShort Note

5-Chloro-6-oxo-6H-xantheno[4,3-d]thiazole-2-carbonitrile

by Konstantinos Paraskevas, Christos Iliopoulos-Tsoutsouvas, Eleftheria A. Georgiou and Ioannis K. Kostakis

Molbank 2022, 2022(4), M1489; https://doi.org/10.3390/M1489 - 10 Nov 2022

Viewed by 2517

Abstract

Xanthones and benzothiazoles are important classes of heterocyclic compounds with versatile biological activities. Herein, we describe a straightforward and scalable synthesis of 5-chloro-6-oxo-6H-xantheno[4,3-d]thiazole-2-carbonitrile, a thiazole-fused xanthone, via a six-step approach, using Appel’s salt for the synthesis of the thiazole [...] Read more.

Xanthones and benzothiazoles are important classes of heterocyclic compounds with versatile biological activities. Herein, we describe a straightforward and scalable synthesis of 5-chloro-6-oxo-6H-xantheno[4,3-d]thiazole-2-carbonitrile, a thiazole-fused xanthone, via a six-step approach, using Appel’s salt for the synthesis of the thiazole ring. The thiazole-fused xanthone was fully characterized employing ¹H and ¹³C NMR spectra, using direct and long-range heteronuclear correlation experiments (HMBC and HMQC). Full article

(This article belongs to the Collection Heterocycle Reactions)

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18 pages, 5941 KB

Open AccessArticle

Crystal Structure and Solid-State Packing of 4-Chloro-5H-1,2,3-dithiazol-5-one and 4-Chloro-5H-1,2,3-dithiazole-5-thione

by Christos P. Constantinides, Maria Koyioni, Fadwat Bazzi, Maria Manoli, Daniel B. Lawson and Panayiotis A. Koutentis

Molecules 2021, 26(19), 5875; https://doi.org/10.3390/molecules26195875 - 28 Sep 2021

Cited by 4 | Viewed by 2815

Abstract

The crystal structure and solid-state packing of 4-chloro-5H-1,2,3-dithiazol-5-one and two polymorphs of 4-chloro-5H-1,2,3-dithiazole-5-thione were analyzed and compared to structural data of similar systems. These five-membered S,N-rich heterocycles are planar with considerable bond localization. All three structures demonstrate tight solid-state [...] Read more.

The crystal structure and solid-state packing of 4-chloro-5H-1,2,3-dithiazol-5-one and two polymorphs of 4-chloro-5H-1,2,3-dithiazole-5-thione were analyzed and compared to structural data of similar systems. These five-membered S,N-rich heterocycles are planar with considerable bond localization. All three structures demonstrate tight solid-state packing without voids which is attributed to a rich network of short intermolecular electrostatic contacts. These include S^δ+…N^δ−, S^δ+…O^δ−, S^δ+…Cl^δ− and S^δ+…S^δ− interactions that are well within the sum of their van der Waals radii (∑_VDW). B3LYP, BLYP, M06, mPW1PW, PBE and MP2 were employed to calculate their intramolecular geometrical parameters, the Fukui condensed functions to probe their reactivity, the bond order, Bird Index and NICS(1) to establish their aromaticity. Full article

(This article belongs to the Special Issue Polysulfur- and Sulfur-Nitrogen Heterocycles)

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13 pages, 2829 KB

Open AccessFeature PaperArticle

Synthesis of 2-Mercapto-(2-Oxoindolin-3-Ylidene)Acetonitriles from 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-ones

by Boris Letribot, Régis Delatouche, Hervé Rouillard, Antoine Bonnet, Jean-René Chérouvrier, Lisianne Domon, Thierry Besson and Valérie Thiéry

Molecules 2018, 23(6), 1390; https://doi.org/10.3390/molecules23061390 - 8 Jun 2018

Cited by 5 | Viewed by 6774

Abstract

Alkylidene oxindoles are important functional moieties and building blocks in pharmaceutical and synthetic chemistry. Our interest in biologically active compounds focused our studies on the synthesis of novel oxindoles, bearing on the exocyclic double bond at the C8, CN, and S groups. Extending [...] Read more.

Alkylidene oxindoles are important functional moieties and building blocks in pharmaceutical and synthetic chemistry. Our interest in biologically active compounds focused our studies on the synthesis of novel oxindoles, bearing on the exocyclic double bond at the C8, CN, and S groups. Extending the potential applications of Appel’s salt, we developed a new synthetic approach by investigating the reactions of C5-substituted 2-oxindoles with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) to give original (Z)-3-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)indolin-2-one derivatives, and new 2-mercapto-(2-oxoindolin-3-ylidene)acetonitriles via a dithiazole ring-opening reaction. The work described in this article represents further applications of Appel’s salt in the conception of novel heterocyclic rings, in an effort to access original bioactive compounds. Fifteen new compounds were prepared and fully characterized. Full article

(This article belongs to the Special Issue Focusing on Sulfur in Medicinal Chemistry)

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19 pages, 780 KB

Open AccessArticle

A Qualitative Comparison of the Reactivities of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine and 4,5-Dichloro-1,2,3-dithiazolium Chloride

by Andreas S. Kalogirou and Panayiotis A. Koutentis

Molecules 2015, 20(8), 14576-14594; https://doi.org/10.3390/molecules200814576 - 12 Aug 2015

Cited by 25 | Viewed by 6241

Abstract

The high yielding transformations of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine into 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (up to 85%) and 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (up to 83%) have been investigated and compared to the analogous transformations of the closely-related 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) into 4-chloro-5H-1,2,3-dithiazol-5-one and [...] Read more.

The high yielding transformations of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine into 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (up to 85%) and 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (up to 83%) have been investigated and compared to the analogous transformations of the closely-related 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) into 4-chloro-5H-1,2,3-dithiazol-5-one and 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile. Furthermore, cyclocondensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with 2-aminophenol and 1,2-benzenediamines gave fused 4H-1,2,6-thiadiazines in 68%–85% yields. Full article

(This article belongs to the Special Issue Design and Synthesis of Novel Conjugated and Non Conjugated Small Molecules)

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26 pages, 960 KB

Open AccessArticle

Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I

by Alicia Foucourt, Damien Hédou, Carole Dubouilh-Benard, Laurent Désiré, Anne-Sophie Casagrande, Bertrand Leblond, Nadège Loäec, Laurent Meijer and Thierry Besson

Molecules 2014, 19(10), 15546-15571; https://doi.org/10.3390/molecules191015546 - 29 Sep 2014

Cited by 49 | Viewed by 9648

Abstract

The convenient synthesis of a library of novel 6,6,5-tricyclic thiazolo[5,4-f] quinazolines (forty molecules) was achieved mainly under microwave irradiation. Dimroth rearrangement and 4,5-dichloro-1,2,3,-dithiazolium chloride (Appel salt) chemistry were associated for the synthesis of a novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (16) [...] Read more.

The convenient synthesis of a library of novel 6,6,5-tricyclic thiazolo[5,4-f] quinazolines (forty molecules) was achieved mainly under microwave irradiation. Dimroth rearrangement and 4,5-dichloro-1,2,3,-dithiazolium chloride (Appel salt) chemistry were associated for the synthesis of a novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (16) a versatile molecular platform for the synthesis of various bioactive derivatives. Kinase inhibition of the final compounds was evaluated on a panel of four Ser/Thr kinases (DYRK1A, CDK5, CK1 and GSK3) chosen for their strong implications in various regulation processes, especially Alzheimer’s disease (AD). In view of the results of this preliminary screening, thiazolo[5,4-f]quinazoline scaffolds constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. Among the compounds of this novel chemolibrary, 7i, 8i and 9i inhibited DYRK1A with IC₅₀ values ranging in the double-digit nanomolar range (40, 47 and 50 nM, respectively). Full article

(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)

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11 pages, 238 KB

Open AccessArticle

Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines

by Panayiotis A. Koutentis, Maria Koyioni and Sophia S. Michaelidou

Molecules 2011, 16(11), 8992-9002; https://doi.org/10.3390/molecules16118992 - 25 Oct 2011

Cited by 19 | Viewed by 6954

Abstract

The reactions of 2-, 3- and 4-aminopyridines with 4,5-dichloro-1,2,3-dithiazol-ium chloride (Appel salt) 4 to give N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-X-amines 1a (X = 2), 1g (X = 3) and 1k (X = 4) were optimized with respect to base, temperature and reaction time. [...] Read more.

The reactions of 2-, 3- and 4-aminopyridines with 4,5-dichloro-1,2,3-dithiazol-ium chloride (Appel salt) 4 to give N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-X-amines 1a (X = 2), 1g (X = 3) and 1k (X = 4) were optimized with respect to base, temperature and reaction time. Based on these conditions a total of thirteen [(dithiazol-ylidene)amino]azines 1a-m were prepared and fully characterized. Full article

(This article belongs to the Special Issue Heterocycles)

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4 pages, 167 KB

Open AccessShort Note

(Z)-2-(4-Chloro-5H-1,2,3-dithiazol-5-ylideneamino)-6-ethoxy-4-phenylpyridine-3,5-dicarbonitrile

by Panayiotis A. Koutentis and Sophia S. Michaelidou

Molbank 2010, 2010(3), M690; https://doi.org/10.3390/M690 - 3 Aug 2010

Cited by 1 | Viewed by 5213

Abstract

2-Amino-6-ethoxy-4-phenylpyridine-3,5-dicarbonitrile 1 reacts with 4,5-dichloro-1,2,3-dithiazolium chloride 2 in the presence of pyridine (2 equiv.) to afford (Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-6-ethoxy-4-phenylpyridine-3,5- dicarbonitrile 3 in 88% yield. Full article

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7 pages, 138 KB

Open AccessArticle

The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines

by Andreas S. Kalogirou and Panayiotis A. Koutentis

Molecules 2009, 14(7), 2356-2362; https://doi.org/10.3390/molecules14072356 - 2 Jul 2009

Cited by 6 | Viewed by 12382

Abstract

N-Aryl-S,S-dimethylsulfimides 3(Ar = 4-NO₂C₆H₄), 4 (Ar = Ph) and 5 (Ar = 4-Tol)react with Appel salt 1 to give the corresponding N-aryl-(4-chloro-5H-1,2,3-dithiazolylidene)benzenamines 8 (Ar = 4-NO₂C₆ [...] Read more.

N-Aryl-S,S-dimethylsulfimides 3(Ar = 4-NO₂C₆H₄), 4 (Ar = Ph) and 5 (Ar = 4-Tol)react with Appel salt 1 to give the corresponding N-aryl-(4-chloro-5H-1,2,3-dithiazolylidene)benzenamines 8 (Ar = 4-NO₂C₆H₄), 9 (Ar = Ph) and 10 (Ar = 4-Tol) in 84, 94 and 87% yields, respectively. The reaction proceeds in the absence of base and a proposed reaction mechanism is given. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Chemistry)

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