title: Synthesis, biological evaluation, drug-likeness, and in silico screening of novel benzylidene-hydrazone analogues as small molecule anticancer agents.
abstract: A series of fifteen benzylidene-hydrazone analogues (3a-o), including eight new compounds, were synthesized and evaluated for their cytotoxic activities in four human cancer cell lines and for their antioxidant activities using DPPH. Of the tested compounds 3e, which possesses two methoxy substituents in its benzylidene phenyl ring, was found to be potently cytotoxic to all cancer cell lines tested with IC50 values of 0.12 (lung), 0.024 (ovarian), 0.097 (melanoma), and 0.05 μM (colon), and these IC50 values were comparable to those of the doxorubicin standard (IC50 = 0.021, 0.074, 0.001, and 0.872 μM, respectively). DPPH assay showed compounds 3f, 3i, and 3g had IC50 values of 0.60, 0.99, and 1.30 μM, respectively, which were comparable to that of ascorbic acid (IC50 = 0.87 μM). Computational parameters such as, drug-likeness, ADME properties, toxicity effects, and drug scores were evaluated, and none of the fifteen compounds violated Lipinski's rule of five or Veber's rule, and thus they demonstrated good drug-likeness properties. In addition, all fifteen compounds had a higher drug score than the doxorubicin and BIBR1532. In silico screening was also conducted by docking of the active compounds on the active site of telomerase reverse transcriptase catalytic subunit, an important therapeutic target of anticancer agents, to determine the probable binding properties. The total binding energies of docked compounds are correlated well with cytotoxic potencies (pIC50) against lung, ovarian, melanoma, and colon cancer cell lines indicating that the benzylidene-hydrazones could use for the development of new anticancer agents as a telomerase inhibitor.
authors.affiliation: Division of Bioscience, Dongguk University, Gyeongju, 780-714, Republic of Korea.|Department of Chemistry, Jagannath University, Dhaka, 1100, Bangladesh.
authors.forename: Mohammad Sayed
authors.initials: MS
authors.lastname: Alam
authors.affiliation: Division of Bioscience, Dongguk University, Gyeongju, 780-714, Republic of Korea. dulee@dongguk.ac.kr.
authors.forename: Dong-Ung
authors.initials: DU
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D006835:Hydrazones; D019098:Telomerase
keywords: Antioxidant; Antitumor agents; Benzylidene-hydrazones; Drug-likeness; In silico screening; Molecular modelling