Antiproliferative novel isoxazoles: modeling, virtual screening, synthesis, and bioactivity evaluation.
A series of novel isoxazole derivatives were efficiently synthesized through the adaptation/modification of an in situ synthetic procedure for pyrazoles. All novel compounds were tested against four different cell lines to evaluate their antiproliferative activity. Based on the Hela cells results of this study and previous work, a classification model to predict the anti-proliferative activity of isoxazole and pyrazole derivatives was developed. Random Forest modeling was used in view of the development of an accurate and reliable model that was subsequently validated. A virtual screening study was then proposed for the design of novel active derivatives. Compounds 9 and 11 demonstrated significant cytostatic activity; the fused isoxazole derivative 18 and the virtually proposed compound 2v, were proved at least 10 times more potent as compared to compound 9, with IC50 values near and below 1 μM. In conclusion, a new series of isoxazoles was exploited with some of them exhibiting promising cytostatic activities. Further studies on the substitution pattern of the isoxazole core can potentially provide compounds with cytostatic action at the nM scale. In this direction the in silico approach described herein can also be used to screen existing databases to identify derivatives with anticipated activity.
Agricultural University of Athens, Chemistry Laboratory, Iera Odos 75, Athens 11855, Greece.
Evangelia
E
Tzanetou
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Sandra
S
Liekens
Benaki Phytopathological Institute, Laboratory of Pesticides Toxicology, 8 St. Delta Street, Athens, Kifissia 14561, Greece.
Konstantinos M
KM
Kasiotis
Department of Chemoinformatics, NovaMechanics Ltd, John Kennedy Ave 62-64, Nicosia 1046, Cyprus.
Georgia
G
Melagraki
Department of Chemoinformatics, NovaMechanics Ltd, John Kennedy Ave 62-64, Nicosia 1046, Cyprus.
Antreas
A
Afantitis
Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis, Zografou 15771, Athens, Greece.
Nikolas
N
Fokialakis
Agricultural University of Athens, Chemistry Laboratory, Iera Odos 75, Athens 11855, Greece. Electronic address: sehar@aua.gr.
Serkos A
SA
Haroutounian
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007555:Isoxazoles
Antiproliferative activity; Chemical synthesis; Classification model; In silico; Isoxazoles; Virtual screening