Diastereoselective Synthesis of 2,6‐Diaryltetrahydrothiopyran‐4‐ones by Phase‐Transfer Catalysis

Gendron, Thibault; Kessedjian, Hripsimee; Davioud‐Charvet, Elisabeth; Lanfranchi, Don Antoine

doi:10.1002/ejoc.201403516

Cited by 8 publications

(10 citation statements)

References 23 publications

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“…The cyclohexyl ring is almost perpendicular to the 1,3-benzothiazin-4-one and piperazine core. In the 1,3-benzothiazin-4-one fragment, the C1-S1 bond length is 1.776 (2) Å , which is very close to the reported literature values (Narasimhamurthy et al, 2003;Duvvuru et al, 2012;Gendron et al, 2015;Rosiak et al, 2006;Schmidt et al, 2005;Ramalingam et al, 1979;Xu et al, 2015;Wang et al, 2011;Mojtahedi et al, 2011;Karisalmi et al, 2003). Similarly, the C4-S1 bond length of 1.739 (2) Å and the C1-S1-C4 bond angle of 100.61 (10) are comparable to the control crystal structures (Table S4 in the supporting information).…”

Section: Crystal Datasupporting

confidence: 88%

“…A search of the Cambridge Structural Database (CSD, Version 5.37; Groom et al, 2016) for the thiopyran-4-one fragment resulted in 42 hits, of which 10 possessing the most similar structures were compared with those of the title compound (Table S5 in the supporting information) (Narasimhamurthy et al, 2003;Duvvuru et al, 2012;Gendron et al, 2015;Rosiak et al, 2006;Schmidt et al, 2005;Ramalingam et al, 1979;Xu et al, 2015;Wang et al, 2011;Mojtahedi et al, 2011;Karisalmi et al, 2003). This is the first small-molecule crystal structure reported for macozinone or any BTZ analogue.…”

Section: Crystal Datamentioning

confidence: 99%

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Macozinone: revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis

Zhang

Aldrich

2019

Acta Crystallogr C

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Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-quarter of humanity and is now the leading cause of infectious disease mortality by a single pathogen. Macozinone {2-[4-(cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, C20H23F3N4O3S} is a promising new drug for treating drug-sensitive and drug-resistant TB that has successfully completed phase I clinical trials. We report the complete spectroscopic and structural characterization by 1H NMR, 13C NMR, HRMS, IR, and X-ray crystallography. The cyclohexyl moiety is observed to be nearly perpendicular to the core formed by the 1,3-benzothiazin-4-one and piperazine groups. The central piperazine ring adopts a slightly distorted chair conformation caused by sp 2-hybridization of the nitro N atom, which donates into the electron-deficient 1,3-benzothiazin-4-one group.

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Section: Crystal Datasupporting

confidence: 88%

Section: Crystal Datamentioning

confidence: 99%

Macozinone: revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis

Zhang

Aldrich

2019

Acta Crystallogr C

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“…As second category composed of 2,6-DATHP derivatives was also selected, as these may be seen as a prodrug of DAA and therefore of great interest as antimalarial candidates. Both series were recently synthesized in-house as previously described [27,28,29,30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Candidate molecules were previously designed and synthetized by chemists for other applications [27,28,29,30,31]. These were both symmetrical and dissymmetrical diarylideneacetone (DAA) derivatives with variously-substituted aryl or heteroaryl rings, as well as symmetrical 2,6-diaryltetrahydrothiopyran-4-ones (2,6-DATHTPs).…”

Section: Introductionmentioning

confidence: 99%

In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids

et al. 2016

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Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

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“…It is well documented that S-oxides can undergo β-elimination, resulting in the formation of a double bond through pericyclic [25,26], ionic, photolytic, or radical mechanisms [27][28][29][30][31] (Scheme 3). To temporarily mask both Michael addition sites of DAAs 1, we designed a series of 2,6-diaryl-4H-tetrahydrothiopyran-4-ones (2,6-DA-4-THTPs) 2-2′ (Scheme 2 and Supplementary Materials, Figure S3) as prodrugs of DAAs and developed a diastereoselective synthesis of this scaffold [18,19]. Interestingly, 2,6-DA-4-THTPs were also considered as potential antimalarial agents [20,21].…”

Section: Introductionmentioning

confidence: 99%

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones

Gendron,

Lanfranchi,

Wenzel

et al. 2024

Molecules

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2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter—upon S-oxidation, followed by syn-eliminations—fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes.

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Diastereoselective Synthesis of 2,6‐Diaryltetrahydrothiopyran‐4‐ones by Phase‐Transfer Catalysis

Abstract: Two efficient phase-transfer-catalyzed protocols for the diastereoselective synthesis of cis and trans isomers of 2,6-diaryltetrahydrothiopyran-4-ones (2,6-DATHTPs) have been developed. In a study of the scope of the reactions, differently

Cited by 8 publications

References 23 publications

Macozinone: revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis

Macozinone: revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis

In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones

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