Novel α-Aminophosphonates of imatinib Intermediate: Synthesis, anticancer Activity, human Abl tyrosine kinase Inhibition, ADME and toxicity prediction

• Published in: Bioorganic chemistry Vol. 109; p. 104718
• Main Authors: Aita, Saikiran, Badavath, Vishnu Nayak, Gundluru, Mohan, Sudileti, Murali, Nemallapudi, Bakthavatchala Reddy, Gundala, Sravya, Zyryanov, Grigoriy Vasilievich, Chamarti, Naga Raju, Cirandur, Suresh Reddy
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.04.2021; Elsevier
• Subjects: Abl1 Tyrosine kinase inhibitor; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Cytotoxic agents; Docking studies; Drug-likenes prediction; Kabachnik-Fields reaction; Life Sciences & Biomedicine; NiO nanoparticles; Physical Sciences; Science & Technology; α-Aminophosphonates of Imatinib; Docking studies; NiO nanoparticles; Abl1 Tyrosine kinase inhibitor; α-Aminophosphonates of Imatinib; Kabachnik-Fields reaction; Drug-likenes prediction; Cytotoxic agents; DESIGN; STATE ANALOG INHIBITORS; DRUG DISCOVERY; BCR-ABL; PYRAZOLINE ANALOGS; alpha-Aminophosphonates of Imatinib; ANTITUMOR ACTIVITIES; POTENT; ACUTE LYMPHOBLASTIC-LEUKEMIA; SELECTIVE INHIBITORS; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104718

[Display omitted] •Synthesis of novel α-aminophosphonates of Imatinib derivatives under MWI and neat conditions.•Used NiO nanoparticles as a recyclable and heterogeneous catalyst, with 96% yield at 450 W within 15 min.•Compounds with halo and nitro (4f, 4h, 4g and 4i) substitution (were showed better anticancer activity than that of standard drug Doxorubicin.•Anticancer activity of the designed compounds by inhibiting human ABL tyrosine kinase.•A ll the designed compounds have shown significant drug-like characteristics. An efficient method for the synthesis of a new class of α-aminophosphonates of imatinib derivative has been developed in one-pot Kabachnik-Fields reaction of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidine amine with various aldehydes and diethyl phosphite under microwave irradiation and neat conditions using NiO nanoparticles as an reusable and heterogeneous catalyst, with 96% yield at 450 W within 15 min. All the compounds were evaluated for their in vitro cytotoxicity with various cancer cell lines by MTT assay method. Compounds with halo (4f, −4Br, IC50 = 1.068 ± 0.88 µM to 2.033 ± 0.97 µM), nitro substitution (4 h, –3NO2, IC50 = 1.380 ± 0.94 µM to 2.213 ± 0.64 µM), (4 g, −4NO2, IC50 = 1.402 ± 0.79 µM to 2.335 ± 0.73 µM) and (4i, 4-Cl, 3-NO2, IC50 = 1.437 ± 0.92 µM to 2.558 ± 0.76 µM) were showed better anticancer activity when compared with standard drugs Doxorubicin and Imatinib using MTT assay method. Further in silico target hunting reveals the anticancer activity of the designed compounds by inhibiting human ABL tyrosine kinase and all the designed compounds have shown significant drug-like characteristics.