Synthesis and characterization of a spiroindolone pyrothiazole analog via X-ray, biological, and computational studies

Altowyan, Mezna Saleh; Atef, Saleh; Al-Agamy, Mohamed H.; Soliman, Saied M.; Ali, Mushir; Shaik, Mohammed Rafi; Choudhary, M. Iqbal; Ghabbour, Hazem A.; Barakat, Assem

doi:10.1016/j.molstruc.2019.03.032

Cited by 12 publications

(7 citation statements)

References 22 publications

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“…According to the general method, the 6-chloro-isatin 2a (90.5 mg, 0.5 mmol) was utilized and the final compound 5a was obtained as a faint yellow solid compound with 85% chemical yield. 4.85 (q, J = 6.9 Hz, 1H), 4.18 (d, J = 9.4 Hz, 1H), 3.97 (q, J = 5.4 Hz, 2H), 3.82 (d, J = 6.2 Hz, 1H), 3.56 (d, J = 4.5 Hz, 4H), 3.46 (d, J = 6.0 Hz, 1H), 3.19-3.13 (m, 2H), 3.02 (q, J = 5.5 Hz, 1H), 2.77 (d, J = 7.8 Hz, 1H), 2.37-2.30 (m, 6H); 13 According to the general method, the 5-nitro-isatin 2b (96 mg, 0.5 mmol) was utilized and the final compound 5b was obtained as a faint yellow solid compound with 80% chemical yield. According to the general method, the 5-fluoro-isatin 2c (82.5 mg, 0.5 mmol) was utilized and the final compound 5c was obtained as a faint yellow solid compound with 88% chemical yield.…”

Section: General Methods For the Synthesis Of 5a-dmentioning

confidence: 99%

“…1 H-NMR (400 Hz, DMSO-d 6 ): δ 11.05 (s, 1H), 8.08 (t, J = 5.7 Hz, 1H), 7.45 (q, J = 8.5 Hz, 4H), 7.20 (td, J = 8.7, 2.8 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.89 (dd, J = 8.7, 4.5 Hz, 1H), 4.83 (q, J = 7.8 Hz, 1H), 4.15 (d, J = 9.2 Hz, 1H), 4.07-3.91 (m, 2H), 3.81 (d, J = 5.9 Hz, 1H), 3.57 (t, J = 4.6 Hz, 4H), 3.46 (d, J = 6.0 Hz, 1H), 3.17 (dq, J = 12.5, 6.7 Hz, 2H), 3.00 (dd, J = 9.9, 5.4 Hz, 1H), 2.76 (t, J = 8.6 Hz, 1H), 2.34 (dt, J = 18.2, 5.7 Hz, 6H); 13…”

Section: General Methods For the Synthesis Of 5a-dmentioning

confidence: 99%

“…According to the general method, the 5-chloro-isatin 2d (90.5 mg, 0.5 mmol) was utilized and the final compound 5d was obtained as a faint yellow solid compound with 90% chemical yield. 3 Hz, 1H), 3.17 (dt, J = 9.8, 6.5 Hz, 2H), 3.00 (dd, J = 9.6, 5.5 Hz, 1H), 2.81-2.72 (m, 1H), 2.34 (dt, J = 16.9, 5.6 Hz, 6H); 13 C-NMR (100 Hz, DMSO-d 6 ): δ 13…”

Section: General Methods For the Synthesis Of 5a-dmentioning

confidence: 99%

“…Isatin derivatives 2a-d and thioproline 1 are commercially available (Sigma-Aldrich Chemie GmbH, Riedstr, Germany; and Alfa Aesar GmbH & Co KG, Karlsruhe, Germany). 1 H-NMR and 13 C-NMR spectra were recorded in DMSO-d 6 (Jeol Spectrometer (400 MHz), (Jeol, Tokyo, Japan). X-ray diffraction data were collected on a Rigaku Oxford Diffraction Supernova diffractometer and processed with CrysAlisPro software v. 1.171.41.93a (Rigaku Oxford Diffraction, Yarnton, UK, 2020) using Cu Kα radiation.…”

Section: General Notesmentioning

confidence: 99%

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Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs

et al. 2021

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Straightforward regio- and diastereoselective synthesis of bi-spirooxindole-engrafted rhodanine analogs 5a–d were achieved by one-pot multicomponent [3 + 2] cycloaddition (32CA) reaction of stabilized azomethine ylide (AYs 3a–d) generated in situ by condensation of L-thioproline and 6-chloro-isatin with (E)-2-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-N-(2-morpholinoethyl)acetamide. The bi-spirooxindole-engrafted rhodanine analogs were constructed with excellent diastereo- and regioselectivity along with high chemical yield. X-ray crystallographic investigations for hybrid 5a revealed the presence of four contiguous stereocenters related to C11, C12, C19 and C22 of the spiro structure. Hirshfeld calculations indicated the presence of many short intermolecular contacts such as Cl...C, S...S, S...H, O...H, N...H, H...C, C...C and H...H interactions. These contacts played a very important role in the crystal stability. The polar nature of the 32CA reaction was studied by analysis of the conceptual DFT reactivity indices. Theoretical study of this 32CA reaction indicated that it takes place through a non-concerted two-stage one-step mechanism associated with the nucleophilic attack of AY 3a to the electrophilic ethylene derivative.

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Section: General Methods For the Synthesis Of 5a-dmentioning

confidence: 99%

Section: General Methods For the Synthesis Of 5a-dmentioning

confidence: 99%

Section: General Methods For the Synthesis Of 5a-dmentioning

confidence: 99%

Section: General Notesmentioning

confidence: 99%

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Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs

et al. 2021

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“…In 2019, Barakat et al reported the synthesis and cytotoxicity activities (HeLa) of the hit depicted in Figure 1 (i.e., VI ). The antiproliferative assay showed that the compound can inhibit the proliferation of HeLa cancer cell line (IC 50 = 11.2 μM), but less than the anticancer drug, doxorubicin (IC 50 = 1.2 μM) [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents

et al. 2021

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A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a–f to afford the target di-spirooxindole compounds 4a–n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC50 = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC50 = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO2 substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC50 = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.

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Anticancer potential of spirocompounds in medicinal chemistry: A pentennial expedition

Bora

Kaushal

Shankaraiah

2021

European Journal of Medicinal Chemistry

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Synthesis and characterization of a spiroindolone pyrothiazole analog via X-ray, biological, and computational studies

Cited by 12 publications

References 22 publications

Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs

Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents

Anticancer potential of spirocompounds in medicinal chemistry: A pentennial expedition

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