title: Synthesis, anticancer, and docking studies of salicyl-hydrazone analogues: A novel series of small potent tropomyosin receptor kinase A inhibitors.
abstract: A series of novel salicyl-hydrazone analogues were synthesized and evaluated for their in vitro cytotoxic activities in five human cancer cell lines, namely, lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), colon cancer (HCT15) and pancreatic cancer (MIA-PaCa-2) cells, and for their in vitro tropomyosin receptor kinase A (TrkA) inhibitory activities. Each of the compounds showed significant cytotoxicity against all cancer cells. Compound 3i was found to be most potent against all cancer cell lines with IC50values of 2.46 (A549), 0.87 (SK-OV-3), 1.43 (SK-MEL-2), 0.89 (HCT15), and 0.48μM (MIA-PaCa-2), followed by compound 3l. Cytotoxicity of 3i was similar to that of doxorubicin (0.87μM) against HCT15 cells. Compounds 3i and 3l also showed highest TrkA inhibitory activities with IC50values of 0.231 and 0.380μM, respectively. A SAR study of the series revealed that compounds with hydroxyl groups showed better cytotoxicity and TrkA inhibitory potency (in the following order 2,4-OH>2,3,4-OH>3,4-OH>4-OH) than compounds possessing electron donating or withdrawing groups on the benzylidenephenyl ring. Docking studies of compounds 3i and 3l conducted on the crystal structure of TrkA receptor (a promising target for anticancer agents) showed both had a high docking score and similar order of experimental TrkA inhibitory activities. The formation of several hydrogen bonds involving N and O containing moieties contributed most significantly to ligand binding and stabilization at the active site of the receptor. In addition, ligand-receptor complexes were further stabilized by π-cation, π-anion, amide-π stacked, and van der Waal's interactions. Conformational analyses showed ligand molecules adopted similar conformations at the receptor active site during interactions, but that the low energy optimized conformations of compounds 3i and 3l differed.
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: Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, 141 Gajeongro, Daejeon 34114, Republic of Korea.
authors.forename: Sang-Un
authors.initials: SU
authors.lastname: Choi
authors.affiliation: Division of Bioscience, Dongguk University, Gyeongju 780-714, Republic of Korea. Electronic address: dulee@dongguk.ac.kr.
authors.forename: Dong-Ung
authors.initials: DU
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D012457:Salicylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; C000625538:N'-(2,4-dihydroxybenzylidene)-2-hydroxybenzohydrazide; C000611485:NTRK1 protein, human; D047428:Protein Kinase Inhibitors; D012457:Salicylamides; D004317:Doxorubicin; D020917:Receptor, trkA
keywords: Conformational analysis; Cytotoxicity; Docking study; Salicyl-hydrazones; TrkA inhibitor