Biological activities of 4H-thiochromen-4-one 1,1-dioxide derivatives against tropical disease parasites: A target-based drug design approach

Ortiz, Cristian; Breuning, Matthias; Robledo, Sara M.; Echeverri, Fernándo; Vargas, Esteban; Quiñones, Winston

doi:10.1016/j.heliyon.2023.e17801

Cited by 2 publications

(2 citation statements)

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“…Sulfide oxidation into sulfoxides or sulfones has been extensively studied in polymer chemistry and medicinal chemistry [57][58][59][60]. In the case of unsaturated Mannich bases [3,25], S-oxidation of the dithiol:(bis)Michael adducts can facilitate a β-elimination which reinstates the unsaturated β-ketothioethers (polymer fragmentation) and yields to the release of sulfenic acids (Figure 22.21 in [3]).…”

Section: Putative Mode-of-action Through a Cascade Of Redox Reactionsmentioning

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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Section: Putative Mode-of-action Through a Cascade Of Redox Reactionsmentioning

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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show abstract

“…In the same context, Ortiz et al (2023) proposed three novel methodologies for the synthesis of thiochromenes from thiophenol ( 143 ) and bromopropionic acid ( 144 ) or crotonic acid ( 145 ). 67 The reaction with bromopropionic acid was catalyzed by the use of a basic buffer solution. In contrast, the reaction with crotonic acid was facilitated by a phase transfer catalyst, tetra- n -butylammonium fluoride (TBAF) (Scheme 37).…”

Section: Introductionmentioning

confidence: 99%