Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

Abstract

Two series of novel triazolo-pyridazine/-pyrimidine derivatives were designed, synthesized, and evaluated for their inhibitory activity against c-Met kinase, as well as three c-Met overexpressed cancer cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes cell line LO2 in vitro . The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound 12e exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC 50 values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 μM, respectively. Moreover, the inhibitory activity of compound 12e against c-Met kinase (IC 50 = 0.090 μM) was equal to that of Foretinib (IC 50 = 0.019 μM). The result of the acridine orange (AO) single staining test demonstrated that compound 12e could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound 12e could induce late apoptosis of A549 cells and stimulate A549 cells arresting in the G0/G1 phase. Structure–activity relationships (SARs), pharmacological results, and docking studies indicated that the introduction of 5-methylthiazole fragment to the five-atom moiety was beneficial for the activity. So far, the existing data indicated that compound 12e may become a potential class II c-Met inhibitor.

Versatile Palladium-Catalyzed Approach to Acyl Fluorides and Carbonylations by Combining Visible Light- and Ligand-Driven Operations

“…For example, alkyl bromides of androsterone ( 4f ), serine ( 4j ), and indomethacin ( 4h ) can be carbonylated to acyl fluorides. Similar results were found with the strongly coordinating imidazole pharmaceutical proxyphylline ( 4k ) or the chelating pyridinylthiazole-based orexin receptor antagonist in 4i . The ability to employ α-functionalized alkyl halides allows as well the first carbonylative synthesis of the protected α-amino acyl fluoride 4l from the corresponding alkyl bromide.…”

“…Similar results were found with the strongly coordinating imidazole pharmaceutical proxyphylline (4k) 24 or the chelating pyridinylthiazole-based orexin receptor antagonist in 4i. 25 The ability to employ αfunctionalized alkyl halides allows as well the first carbonylative synthesis of the protected α-amino acyl fluoride 4l from the corresponding alkyl bromide. Finally, coupling the catalytic formation of acyl fluorides with their subsequent reaction can open access to carbonylcontaining products with combinations of highly functionalized alkyl halide and nucleophilic components.…”

Design, Synthesis, and Biological Evaluation of [1,2,4]triazolo[4,3-a] Pyrazine Derivatives as Novel Dual c-Met/VEGFR-2 Inhibitors

“…We synthesized all the compounds and intermediates by referring to our group’s previous research methods ( Zhang B. et al, 2020 ) ( Zhang et al, 2020b ). 1 H NMR and ESI-MS were utilized to characterize all the synthesized compounds and intermediates.…”

Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC: QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach

“…The tyrosine kinase c-Met is considered a suitable pathway for targeting EGFR-TKD for many cancer therapies, including NSCLC. , We implemented a comprehensive approach to search in the PubMed database to identify current research on c-Met-targeted drugs for lung cancer. , Search results reflected the prevalence of keywords “non-small-cell lung cancer”, “tivantinib”, “crizotinib”, “carbozantinib”, “foretinib”, and “onartuzumab” . Mohareb et al examined the inhibitory effect of cyclohexane-1,3-dione derivatives in vitro against non-small-cell lung cancer cell lines (H460 and A549) using the standard drug Foretinib.…”