Design, synthesis, biological evaluation, and docking studies of novel triazolo[4,3-]pyridazine derivatives as dual c-Met/Pim-1 potential inhibitors with antitumor activity

• Published in: RSC advances Vol. 14; no. 41; pp. 3346 - 3363
• Main Authors: Mahmoud, Mohamed E, Ahmed, Eman M, Ragab, Hamdy M, Eltelbany, Rania Farag A, Hassan, Rasha A
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 24.09.2024; The Royal Society of Chemistry
• Subjects: Binding sites; Biological activity; Cancer; Cell cycle; Chemistry; Cytotoxicity; Docking; Pyridazines
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d4ra04036h

Interest has been piqued in c-Met and Pim-1, potential new cancer treatment targets. A variety of triazolo[4,3- b ]pyridazine derivatives were synthesized to create powerful dual c-Met/Pim-1 inhibitors having the pharmacophoric elements of both enzyme inhibitors. All derivatives were screened for their cytotoxic effects on 60 cancer cell lines. Compounds 4g and 4a , had strong antiproliferative cytotoxic impacts on tumor cells, with mean GI% values of 55.84 and 29.08%, respectively. Research revealed that 4g has more powerful inhibitory activity against c-Met and Pim-1, with IC 50 of 0.163 ± 0.01 and 0.283 ± 0.01 μM, respectively than the reference and derivative 4a . Moreover, compound 4g was the subject of an additional investigation into biological processes. The findings showed that compound 4g caused MCF-7 cells to arrest in the S stage of the cell cycle. Also, it accelerated the progress of apoptosis 29.61-fold more than the control. Compound 4g demonstrated a significantly higher level of caspase-9 and a decreased level of p -PI3K, p -AKT, and p -mTOR compared to staurosporine. Later, analysis of 4g showed good drug-ability and pharmacokinetic properties. A similar mode of interaction at the ATP-binding site of c-Met and Pim-1 compared to the docked ligands was suggested by additional docking studies of compound 4g . New series of triazolo[4,3- b ]pyridazine derivatives were created. Compounds 4a and 4g demonstrated extensive antiproliferative activity on various cell lines. Compound 4g displayed higher dual inhibition on c-Met and Pim-1.