Elucidation of the atroposelectivity in the synthesis of axially chiral thiohydantoin derivatives

Haşlak, Zeynep Pınar; Çınar, Sesil Agopcan; Ozbek, Sevgi Sarigul; Monard, Gérald; Doğan, İlknur; Avi̇yente, Vi̇ktorya

doi:10.1039/c9ob02556a

Cited by 6 publications

(4 citation statements)

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“…The 2-thiohydantoin ring has been also incorporated into the structures of several natural products such as Enzalutamide, which has been FDA-approved as a drug for castration-resistant prostate cancer ( Figure 1 ) [ 25 , 26 , 27 ]. Based on the high therapeutical significance of the 2-thiohydantoin-based compounds, the synthesis of a novel class of substituted-2-thiohydantoins has attracted great attention in recent decades [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

et al. 2022

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Inflammation is the main cause of several autoimmune diseases, including type I diabetes, rheumatoid arthritis, bullous pemphigoid, paraneoplastic pemphigoid, and multiple sclerosis. Currently, there is an urgent demand for the discovery of novel anti-inflammatory drugs with potent activity but also safe for long-term application. Toward this aim, the present study reported the design, synthesis, and characterization of a set of novel 1,3-disubstituted-2-thiohydantoins derivatives. The anti-inflammatory activity of synthesized compounds was assessed against murine leukemia cell line (RAW264.7) by evaluating the cytotoxicity activity and their potency to prevent nitric oxide (NO) production. The results revealed that the synthesized compounds possess a considerable cytotoxic activity together with the ability to reduce the NO production in murine leukemia cell line (RAW264.7). Among synthesized compounds, compound 7 exhibited the most potent cytotoxic activity with IC50 of 197.68 μg/mL, compared to celecoxib drug (IC50 value 251.2 μg/mL), and demonstrated a significant ability to diminish the NO production (six-fold reduction). Exploring the mode of action responsible for the anti-inflammatory activity revealed that compound 7 displays a significant and dose-dependent inhibitory effect on the expression of pro-inflammatory cytokines IL-1β. Furthermore, compound 7 demonstrated the ability to significantly reduce the expression of the inflammatory cytokines IL-6 and TNF-α at 50 μg/mL, as compared to Celecoxib. Finally, detailed molecular modelling studies indicated that compound 7 exhibits a substantial binding affinity toward the binding pocket of the cyclooxygenase 2 enzyme. Taken together, our study reveals that 1,3-disubstituted-2-thiohydantoin could be considered as a promising scaffold for the development of potent anti-inflammatory agents.

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Section: Introductionmentioning

confidence: 99%

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

et al. 2022

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“…The ( S )-5-methyl-3- o -trifluoromethylphenylthiohydantoin ( 7 ), on the other hand, yielded RM / SP / SM / RP 1.4:52.4:0:46.2 at first, and after recrystallization, the P isomers this time were obtained as a 54.2:45.8 ( SP / RP ) mixture (Figure b,b′). Apparently, racemization has taken place at C5 of 6 and 7 . When the RM isomer was resolved micropreparatively by HPLC on a chiral column and the collected isomer was reinjected into HPLC for analysis, it was found that it converted to SM to give a 59:41 mixture of RM and SM isomers.…”

Section: Resultsmentioning

confidence: 99%

Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives

2021

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Two novel axially chiral ortho-trifluoromethylphenyl thiohydantoin derivatives have been prepared atroposelectively from the reaction of R and S alanine methyl ester HCl salts with ortho-trifluoromethylphenyl isothiocyanate in the presence of triethyl amine. It was found that after purification of the crude product by simple recrystallization, the R amino acid esters yielded thiohydantoins having solely M axial chirality whereas the S ones returned the P isomers only. This result prompted us to perform sterically controlled aldol reactions on M and P thiohydantoin atropisomers. It was found that during the aldol reaction of 3-o-trifluoromethyl-5methylthiohydantoins, the o-trifluoromethyl group of the M isomers efficiently shielded the Si face of the intermediate and in this way, enabled the selective formation of only the R configured aldol products at C5 of the heterocyclic ring. The P thiohydantoins, on the other hand, yielded only the S C5 configured aldol products as a result of the Re face shielding of the orthotrifluoromethyl group of intermediate enolates. A noteworthy face selectivity of the benzaldehyde molecule was not observed (anti/ syn only 3/2) during the aldolization of trifluoromethylphenyl derivatives of thiohydantoins. Aldol reactions were also done using the previously synthesized axially chiral thiohydantoins with ortho-Cl, Br, and I phenyl substituents which had predominantly P conformations (P/M ratios > 95%), and the stereochemical outcomes were compared with those of the ortho-trifluoromethyl substituted ones. 80−90% face selectivity of the benzaldehyde molecule was observed for the axially chiral o-halophenyl substituted thiohydantoins. The syntheses done with axially chiral 3-ortho-trifluoromethylphenyl-and 3-ortho-iodophenyl-5-methyl thiohydantoins enabled stereoselective formation of quaternized chiral carbon centers at C5 of the thiohydantoin ring.

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“…Several facile and efficient synthetic approaches have been developed for the synthesis of 2-thiohydantoins which allowed different structural variations at different positions [43,[52][53][54].…”

Section: Resultsmentioning

confidence: 99%

Antidiabetic Potential of Novel 1,3,5-Trisubstituted-2-Thioxoimidazloidin-4-One Analogues: Insights into α-Glucosidase, α-Amylase, and Antioxidant Activities

et al. 2022

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As the ninth leading cause of death globally, diabetes mellitus (DM) is considered to be the worst chronic metabolic disease requiring an enormous need for healthcare with over 578 million expected cases by 2023. Several recent findings have demonstrated that mediating the activity of carbohydrate-hydrolyzing enzymes, including α-amylase and α-glucosidase, could be a potential strategy for managing the development of DM. In the presented study, a novel set of 1,3,5-trisubstituted-2-thioxoimidazolidin-4-ones was designed, synthesized, and characterized. The antidiabetic activity of the synthesized compounds was explored by assessing their inhibitory activity toward α-amylase and α-glucosidase enzymes. The results demonstrated that this class of compounds exhibits considerable inhibitory activity toward both α-amylase and α-glucosidase enzymes. Among the synthesized compounds, compound 5a demonstrated the most inhibitory activity with IC50 of 5.08 and µg/mL and 0.21 µg/mL toward α-glucosidase and α-amylase activities, respectively, as compared to the drug Acarbose (IC50 =5.76 µg/mL and 0.39 µg/mL, respectively). To gain insights into the antidiabetic potential of compound 5a, we assessed the cytotoxic and antioxidant activities. Our findings indicated that compound 5a displays considerable cytotoxicity toward WI-38 cells with an IC50 of 88.54 µg/mL, as compared to the drug Celecoxib (IC50 =93.05 µg/mL). Further, compound 5a exhibited a high scavenging activity toward 2,2-Diphenyl1-picrylhydrazyl (DPPH) free radicals (IC50 = 51.75 µg/mL) and showed a low potential to produce ROS as indicated by the monitoring of the generated H2O2 (132.4 pg/mL), as compared to Trolox (IC50 =58.09 µg/mL) and Celecoxib (171.6 pg/mL). Finally, we performed extensive molecular modeling studies to affirm the binding affinity of this class of compounds to the binding pocket of α-amylase and α-glucosidase enzymes. Collectively, our findings indicate that this class of compounds, particularly compound 5a, could be utilized as a lead structure for the development of novel compounds with potential antidiabetic and antioxidant activities.

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Elucidation of the atroposelectivity in the synthesis of axially chiral thiohydantoin derivatives

Abstract: A DFT study is carried out in order to elucidate the racemization and cyclization mechanism as well as the atroposelectivity during the synthesis of 2-thiohydantoins. Computational data shows that the racemization occurs after cyclization with the assistance of triethyl amine.

Cited by 6 publications

References 46 publications

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives

Antidiabetic Potential of Novel 1,3,5-Trisubstituted-2-Thioxoimidazloidin-4-One Analogues: Insights into α-Glucosidase, α-Amylase, and Antioxidant Activities

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