Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists

Abstract

Newly designed thiazolidine-2,4-diones 3–7a–c were synthesized, and their anticancer activities were screened against three cancer lines. They showed potent activities against HepG2 compared to the other HCT116 and MCF-7 tumor cell lines. Compounds 7c and 6c were detected as highly effective derivatives against MCF-7 (IC50 = 7.78 and 8.15 µM), HCT116 (IC50 = 5.77 and 7.11 µM) and HepG2 (IC50 = 8.82 and 8.99 µM). The highly effective derivatives 6a–c and 7a–c were tested against VERO normal cell lines. All derivatives were evaluated for their VEGFR-2 inhibitory actions and demonstrated high to low activities, with IC50 values varying from 0.08 to 0.93 µM. Moreover, derivatives 5a–c, 6a–c and 7a–c were assessed to verify their in vitro binding affinities to PPARγ and insulin-secreting activities. Finally, docking studies were performed to explore their affinities and binding modes toward both VEGFR-2 and PPARγ receptors.

The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

“…The characteristic proton, 10, resonated clearly as a sharp singlet signal at δ 8.62. Regarding the di para-substituted protons, protons (19,21) and (18,22) resonated at δ 7.58 (d, J = 8.2 Hz) and 7.99 (d, J = 8.2 Hz), respectively. Finally, the aromatic protons of the benzamide moiety resonated at the overlapped areas of 7.68 and 7.96.…”

“…The characteristic carbon, 10, resonated at δ 154.2. The di para-substituted carbons (19,21) and (18,22) resonated at δ 119.9 and 128.2, respectively. The aromatic carbons (26, 27, 28, 29, 30, and 31) of the benzamide moiety resonated at δ (135.1, 128.2, 128.9, 132.5, 128.9, and 128.2, respectively).…”

“…Computational chemistry is widely used in the pharmaceutical industry for investigating interactions between potential drugs and biomolecular targets [8]. Our team have synthesized and examined various compounds that were designed as anti-VEGFR-2, belonging to different classes such as quinazoline [9][10][11][12], nicotinamides [13], benzoxazole [14], pyridine [15] dihydroquinolones [16], thiourea-azetidine [17,18], and quinoxaline-2 (1H)-one [19][20][21][22][23], in addition to thieno [2,3-d]pyrimidine [24]. Furthermore, our team utilized the basics of in silico chemistry as a successful tool in molecular design and docking [25,26], structural similarity [27], toxicity [28], ADMET [29], DFT [30,31], MD [32], and pharmacophore [33] investigation.…”

Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation

“…However, the narrow therapeutic index besides the unpredictable effects were the major drawbacks of the primary introduced drugs 2 . In contrast, the recently developed targeted therapies gained the advantages of interfering with specific molecular targets almost located in the tumour cells with minimised effect on the normal cells 3 . Thus, these agents provide a high specific therapeutic window with limited non-specific toxicities.…”

Thiazolidin-2,4-Dione Scaffold: An Insight into Recent Advances as Antimicrobial, Antioxidant, and Hypoglycemic Agents

“…Substitutions of various moieties are possible only at the third and fifth positions of the Thiazolidin-2,4-dione (TZD) scaffold. The analogues of TZD offer a wide range of structural varieties [ 2 ] and also possess a proven range of diversified therapeutic potentials, such as antidiabetic [ 3 , 4 , 5 ], analgesic, anti-inflammatory [ 6 , 7 , 8 ], wound healing [ 9 ], antiproliferative [ 10 , 11 , 12 , 13 , 14 ], antimalarial [ 15 ], antitubercular [ 16 , 17 ], hypolipidemic [ 18 ], antiviral [ 19 ], antimicrobial, antifungal [ 20 , 21 , 22 , 23 ], and antioxidant properties [ 24 , 25 ], etc.…”