Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism

Abstract

Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (1) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (2) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (1 and 2) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone 1 and 2 were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound 1 exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC50 = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC50 = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC50 = 1.535 µM) tyrosine kinases. On the other hand, Compound 2 also exhibited excellent inhibitory activity against EGFR (IC50 = 0.369 µM), VEGFR-2 (IC50 = 0.266 µM) and FLT-3 (IC50 = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3.

Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia

“…Among the discovery of novel scaffolds with multiple kinase inhibitory activities versus various kinases, including FLT3 kinase, Al-Salem et al in 2021 synthesized many oxindole-based derivatives with versatile kinase inhibitory activity, specifically, compound 17 [ 87 ]. Compound 17 showed circumvention of different tyrosine kinases, including CDK-2 with IC 50 equal to 0.301 µM, which was about half the threshold lower than recognized kinase inhibitor imatinib with IC 50 equal to 0.131 µM and comparable to the primary FLT-3 hampering agent Sunitinib with IC 50 equal to 0.262, and versus EGFR, VEGFR-2 (KDR), and FLT-3 with IC 50 s equal to 0.369, 0.266, and 0.546 µM, respectively ( Table 3 ) .…”

Molecular docking and synthesis of N-alkyl-isatin-3-imino aromatic amine derivatives and their antileishmanial and cytotoxic activities

“…Literature surveys have shown isatin scaffold as an anticancer agent against various human tumor cell lines, especially the tyrosine kinase inhibitor ( 10 11 12 13 ). The analogs of isatin such as sunitinib were exposed to tyrosine kinase inhibitory properties ( 10 14 ) ( Fig.…”

“…Al-Salem et al . reported isatin-hydrazones as multiple receptor tyrosine kinase inhibitors ( 13 ) ( Fig. 1 ).…”

1-Benzyl-5-bromo-3-hydrazonoindolin-2-ones as Novel Anticancer Agents: Synthesis, Biological Evaluation and Molecular Modeling Insights

“…After the FDA’s approval of the VEGFR-2 inhibitor Sunitinib, medicinal chemists have paid special attention to the identification of new isatin-based anti-cancer candidates targeting VEGFR-2 kinase [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Our research team has recently reported several VEGFR-2 inhibitors based on the isatin scaffold [ 45 , 46 , 47 , 48 , 49 , 50 ].…”