Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study

• Published in: Bioorganic chemistry 2017-10, Vol.74, p.228-237
• Main Authors: Ewida, Menna A., Abou El Ella, Dalal A., Lasheen, Deena S., Ewida, Heba A., El-Gazzar, Yomna I., El-Subbagh, Hussein I.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell cycle analysis; Cell Line, Tumor; Cell Proliferation - drug effects; DHFR inhibitors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - pharmacology; Humans; Models, Molecular; Molecular modeling study; Molecular Structure; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Structure-Activity Relationship; Synthesis; Tetrahydrofolate Dehydrogenase - metabolism; Thiazolo[4,5-d]pyridazine
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2017.08.010

[Display omitted] •Synthesis of 1,3-thiazoles and thiazolo[4,5-d]pyridazine analogues.•Compound 26 proved to be the most active DHFR inhibitor (IC50 of 0.06μM).•Compound 4, 20, 21 showed in vitro antitumor activity against a collection of cancer cell lines.•Compound 26 proved lethal to HS 578T breast cancer cell line with IC50 value of 0.8μM, inducing apoptotic cell cycle arrest.•Binding with Phe 31 and Arg 22 amino acids is essential for DHFR binding. A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2-thioureido function were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC50 of 0.06μM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC50 value of 0.8μM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors.