Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with <i>in vitro</i> antitumor activity towards non-small lung cancer

Abstract

New series of thiazolyl-pyrazoline derivatives (<b>7a-7d</b>, <b>10a-10d</b> and <b>13a-13f</b>) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds <b>10b</b> and <b>10d</b> exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC₅₀ = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC₅₀ = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds <b>10b</b> and <b>10d</b> displayed pronounced efficacy against A549 (IC₅₀ = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC₅₀ = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that <b>10b</b> and <b>10d</b> were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds <b>10b</b> and <b>10d</b> induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.