79183-44-1Relevant articles and documents
Microwave-assisted synthesis and antimicrobial activity of novel spiro 1,3,4-thiadiazolines from isatin derivatives
da Costa, Daniel Pereira,de Castro, Aleff Cruz,da Silva, Girlyanderson Araújo,Lima-Junior, Claudio Gabriel,de Andrade Júnior, Francisco Patricio,de Oliveira Lima, Edeltrudes,Vaz, Boniek Gontijo,da Silva, Lidya Cardoso
, p. 766 - 776 (2020/12/31)
This work describes the synthesis of spiro 1,3,4-thiadiazolines from isatin-β-thiosemicarbazone acetylation, using microwave irradiation as a source of heating the reaction medium. N-substituted isatin derivatives were used as substrates to obtain thiosemicarbazones by adding thiosemicarbazide to the isatin ketone carbonyl. The final synthetic step was the reaction of thiosemicarbazones with acetic anhydride under microwave irradiation to get the spiro compounds. Reaction times ranged from 6 to 18 minutes resulting in yields of up to 90%. Biological assays have shown promising antibacterial and antifungal activity, especially spiro thiadiazolines derived from allylated isatins. All the proposed molecules proved to be potential drug candidates based on the results of the in silico investigation, with satisfactory drug-likeness and drug-score, respecting Lipinski's rule. The use of the microwave reactor was efficient for the synthesis of thiosemicarbazones and spiro compounds, resulting in a significant reduction in reaction times with conventional heating. Taking into account the threat of antimicrobial resistance, this work presents a series of bioactive molecules that are easily obtained via microwave reaction.
Development of isatin-thiazolo[3,2-a]benzimidazole hybrids as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological and molecular dynamics investigations
Eldehna, Wagdy M.,El Hassab, Mahmoud A.,Abo-Ashour, Mahmoud F.,Al-Warhi, Tarfah,Elaasser, Mahmoud M.,Safwat, Nesreen A.,Suliman, Howayda,Ahmed, Marwa F.,Al-Rashood, Sara T.,Abdel-Aziz, Hatem A.,El-Haggar, Radwan
supporting information, (2021/03/15)
In the current medical era, human health is experiencing numerous challenges, particularly the human malignancies. Therefore, the therapeutic arsenal for these malignancies is to be inexorably enhanced with new treatments that target tumor cells in a selective manner. In this regard, the present work aims at developing a new set of small molecules featuring the privileged isatin scaffold conjugated with a thiazolo[3,2-a]benzimidazole (TBI) motif through a cleavable hydrazide linker (7a-e and 10a-i) as potential anticancer CDK2 inhibitors. The large tricyclic TBI motif is anticipated to achieve a plethora of hydrophobic interactions within the CDK2 binding site. The growth of the two examined cell lines was significantly inhibited by most the prepared hybrids with IC50 ranges; (2.60 ± 1.47–20.90 ± 1.17 μM, against MDA-MB-231) and (1.27 ± 0.06–16.83 ± 0.95 μM, against MCF-7). In particular, hybrids 7a, 7d and 10a displayed potent dual activity against the examined cell lines, and thus selected for further investigations. They exerted a significance alteration in the cell cycle progression, in addition to an apoptosis induction within both MDA-MB-231 and MCF-7 cells. Furthermore, 7a, 7d and 10a displayed potent CDK2 inhibitory action (IC50 = 96.46 ± 5.3, 26.24 ± 1.4 and 42.95 ± 2.3 nM, respectively). The docking simulations unveiled, as expected, the ability of the TBI ring to well-accommodate and establish several hydrophobic interactions within a hydrophobic pocket in the CDK2 binding site. Also, the docking simulations highlighted the significance of incorporation of the hydrazide linker and isatin unsubstituted (NH) functionality in the H-bonding interactions. Interestingly, the most potent CDK2 inhibitor 7d achieved the best binding score (-11.2 Kcal/mole) and formed the most stable complex with CDK2 enzyme (RMSD = 1.24 ?) in a 100 ns MD simulation. In addition, the MM-PBSA calculations ascribed the lowest binding free energy to the 7d–CDK2 complex (?323.69 ± 15.17 kJ/mol). This could be attributed to an incorporation of the 5-OCH3 group that was engaged in an extra hydrogen bonding with key THR14 amino acid residue. Finally, these results suggested hybrid 7d as a good candidate for further optimization as promising breast cancer antitumor agent and CDK2 inhibitor.
Applications of Ytterbium(II) Reagent as Grignard Reagent and Single-Electron Transfer Reagent in the Synthesis of 3-Substituted 2-Oxindoles
Wang, Pengkai,Cao, Xuyan,Zhang, Songlin
supporting information, p. 3836 - 3846 (2021/07/02)
The use of ytterbium(II) reagent as both nucleophilic reagent and single-electron transfer reagent in the reaction of isatin derivatives with ytterbium(II) reagent is reported. From a synthetic point of view, a general, efficient, and experimentally simple one-pot method for the preparation of 3-substituted 2-oxindoles was developed.
Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies
Eldehna, Wagdy M.,Al-Rashood, Sara T.,Al-Warhi, Tarfah,Eskandrani, Razan O.,Alharbi, Amal,El Kerdawy, Ahmed M.
, p. 270 - 285 (2020/12/18)
The serine/threonine protein kinases CDK2 and GSK-3β are key oncotargets in breast cancer cell lines, therefore, in the present study three series of oxindole-benzofuran hybrids were designed and synthesised as dual CDK2/GSK-3β inhibitors targeting breast cancer (5a–g, 7a–h, and 13a–b). The N1 -unsubstituted oxindole derivatives, series 5, showed moderate to potent activity on both MCF-7 and T-47D breast cancer cell lines. Compounds 5d–f showed the most potent cytotoxic activity with IC50 of 3.41, 3.45 and 2.27 μM, respectively, on MCF-7 and of 3.82, 4.53 and 7.80 μM, respectively, on T-47D cell lines, in comparison to the used reference standard (staurosporine) IC50 of 4.81 and 4.34 μM, respectively. On the other hand, the N1 -substituted oxindole derivatives, series 7 and 13, showed moderate to weak cytotoxic activity on both breast cancer cell lines. CDK2 and GSK-3β enzyme inhibition assay of series 5 revealed that compounds 5d and 5f are showing potent dual CDK2/GSK-3β inhibitory activity with IC50 of 37.77 and 52.75 nM, respectively, on CDK2 and 32.09 and 40.13 nM, respectively, on GSK-3β. The most potent compounds 5d–f caused cell cycle arrest in the G2/M phase in MCF-7 cells inducing cell apoptosis because of the CDK2/GSK-3β inhibition. Molecular docking studies showed that the newly synthesised N1 -unsubstituted oxindole hybrids have comparable binding patterns in both CDK2 and GSK-3β. The oxindole ring is accommodated in the hinge region interacting through hydrogen bonding with the backbone CO and NH of the key amino acids Glu81 and Leu83, respectively, in CDK2 and Asp133 and Val135, respectively, in GSK-3β. Whereas, in series 7 and 13, the N1 -substitutions on the oxindole nucleus hinder the compounds from achieving these key interactions with hinge region amino acids what rationalises their moderate to low anti-proliferative activity.
Organocatalytic Enantioselective Synthesis of Tetrahydro-Furanyl Spirooxindoles via [3+2] Annulations of 3-Hydroxyoxindoles and Cyclic Ketolactams
Liu, Yue,Zhang, Ying,Huang, Qian-Wei,Gou, Chuan,Li, Qing-Zhu,Dai, Qing-Song,Leng, Hai-Jun,Li, Jun-Long
supporting information, p. 2177 - 2182 (2021/03/08)
Asymmetric construction of pharmacologically interesting tetrahydrofuranyl spirooxindole frameworks has been achieved through organocatalytic [3+2] annulations of the readily available 3-hydroxyoxindoles and pyrrolidone-derived cyclic ketolactams. A variety of chiral spiro tetrahydrofuranyl products, which contain four contiguous stereocenters including two tetrasubstituted carbon centers, have been rapidly synthesized with remarkable results (up to 99% yield, >95:5 dr, and 99:1 er). Synthetic derivatization of the hemiketal moiety enables the installation of various halogen atoms into the structurally complex molecules in a stereospecific manner. Preliminary screening of anticancer bioactivity was performed, and 4 w showed obvious inhibitory capacity to the proliferation on a panel of cancer cell lines. (Figure presented.).
Palladium catalyzed divergent cycloadditions of vinylidenecyclopropane-diesters with methyleneindolinones enabled by zwitterionic π-propargyl palladium species
Niu, Ben,Wei, Yin,Shi, Min
supporting information, p. 4783 - 4786 (2021/05/25)
A palladium-catalyzed divergent synthesis of spirooxindoles fused with a five- or a six-membered ring by a cycloaddition reaction of vinylidenecyclopropane-diesters with methyleneindolinones was disclosed. This protocol features anin situgenerated unprecedented zwitterionic π-propargyl palladium species in cycloaddition reactions and a switchable process between (3+2) and (4+2) cycloadditions by changing the phosphine ligand.
Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer
Eldehna, Wagdy M.,Salem, Rofaida,Elsayed, Zainab M.,Al-Warhi, Tarfah,Knany, Hamada R.,Ayyad, Rezk R.,Traiki, Thamer Bin,Abdulla, Maha-Hamadien,Ahmad, Rehan,Abdel-Aziz, Hatem A.,El-Haggar, Radwan
, p. 1424 - 1435 (2021/07/02)
In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a–e and 7a–i) was designed and synthesised. The anticancer activity for compounds (5b–d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a–e and 7a–i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC50 = 8.7 and 9.4 μM (5a), and 6.5 and 9.8 μM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.
Catalytic Asymmetric Halogenation/Semipinacol Rearrangement of 3-Hydroxyl-3-vinyl Oxindoles: A Stereodivergent Kinetic Resolution Process
Cao, Weidi,Dai, Li,Feng, Xiaoming,Hu, Xinyue,Liu, Wen,Zeng, Zi,Zhou, Yuqiao
supporting information, p. 26599 - 26603 (2021/11/16)
A highly enantioselective halogenation/semipinacol rearrangement of isatin-derived allylic alcohols has been developed with a chiral N,N′-dioxide/ScIII complex as catalyst. This strategy involved a pivotal stereodivergent kinetic resolution process and provided a facile and efficient entry to optically active halo-substituted quinolone derivatives and quinoline alkaloids with a quaternary stereocenter simultaneously under mild reaction conditions. Based on the control experiments together with kinetic studies and DFT calculations, a possible catalytic cycle was proposed to illustrate the reaction process and enantiocontrol.
Dynamic Kinetic Asymmetric Transformation of Racemic Diastereomers: Diastereo- and Enantioconvergent Michael–Henry Reactions to Afford Spirooxindoles Bearing Furan-Fused Rings
Sohail, Muhammad,Tanaka, Fujie
supporting information, p. 21256 - 21260 (2021/08/23)
Dynamic kinetic asymmetric transformation (DYKAT) reactions of racemic diastereomer mixtures that afford the products as essentially single diastereomers with high enantioselectivities are described. We demonstrated the DYKAT in the diastereo- and enantio
Organocatalytic Asymmetric Synthesis of Aza-Spirooxindoles via Michael/Friedel-Crafts Cascade Reaction of 1,3-Nitroenynes and 3-Pyrrolyloxindoles
Ni, Qijian,Wang, Xuyang,Zeng, Da,Wu, Qianling,Song, Xiaoxiao
supporting information, p. 2273 - 2278 (2021/04/05)
An asymmetric [3+3] cyclization of nitroenynes and 3-pyrrolyloxindoles has been realized with a chiral bifunctional squaramide catalyst. This Michael/Friedel-Crafts cascade strategy provides a facile and efficient access to enantioenriched polycyclic aza-spirooxindoles with 32-95% isolated yields and excellent stereocontrol under mild reaction conditions.
