Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine‐2,5‐dione Hybrids as Potential Antitumor Agents

• DOI: 10.1002/cmdc.202000458
• Publication Date: 2020-07-27T05:53:50Z
• Authors: Kalpana Tilekar; Neha Upadhyay; Franz‐Josef Meyer...; Fulvio Loiodice; Natalia Y. Anisimova; Tatiana S. Spirina; Darina V. Sokolova; Galina B. Smirnova; Jun‐yong Choe; Vadim S. Pokrovsky; Antonio Lavecchia; C S Ramaa
• Keywords: Male; 0301 basic medicine; Pyrrolidines; Cytotoxicity; 610; Mice, Nude; Antineoplastic Agents; Pyrazoline; Docking; Synthesis; Mice; Structure-Activity Relationship; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Bcl-2; 5-diones; Pyrazolines; Pyrrolidine-2,5-dione; Cell Proliferation; Mice, Inbred BALB C; 0303 health sciences; Antitumor agents; Dose-Response Relationship, Drug; Molecular Structure; Antitumor agent; Pyrrolidine-2,5-diones; Neoplasms, Experimental; 540; Molecular Docking Simulation; Pyrrolidine-2; Pyrazoles; Antitumor agents; Bcl-2; Cytotoxicity; Docking; Pyrazolines; Pyrrolidine-2,5-diones; Synthesis; Drug Screening Assays, Antitumor

AbstractIn search of novel and effective antitumor agents, pyrazoline‐substituted pyrrolidine‐2,5‐dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC50=0.78±0.01 μM), HT29 (IC50=0.92±0.15 μM) and K562 (IC50=47.25±1.24 μM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 (1‐(2‐(3‐(4‐fluorophenyl)‐5‐(p‐tolyl)‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)‐2‐oxoethyl)pyrrolidine‐2,5‐dione). In cell‐cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G1/G0 phase and decreased cell population in G2/M phase. The excellent in vitro effects were also supported by inhibition of anti‐apoptotic protein Bcl‐2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66 % (i. p. route) and 60 % (oral route) at 50 mg kg−1 dose by both the routes, indicating oral bioavailability and antitumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine‐2,5‐dioes holds promise for the development of more potent and less toxic anticancer agents.