Design, Synthesis, and Anti‐Glioblastoma Activity Evaluation of <i>N,N‐</i> Di(prop‐2‐yn‐1‐yl)‐4‐(trifluoromethyl)pyrimidin‐2‐amines and Their Bis‐Triazole Derivatives

Abstract The synthesis of two new series of N,N‐ di(prop‐2‐yn‐1‐yl)‐4‐(trifluoromethyl)pyrimidin‐2‐amines 4 and their bis‐triazole derivatives 6 , as well as the evaluation of their antitumoral activity, is reported. Eleven N,N‐ dipropargylated 6‐aryl‐4‐(trifluoromethyl)‐2‐aminopyrimidines 4 were synthesized (12%–82%) via the alkylation of 6‐alkyl(aryl/heteroaryl)‐4‐(trifluoromethyl)pyrimidin‐2‐amines 2 with propargyl bromide 3 . Subsequently, the corresponding bis‐1,2,3‐triazole derivatives 6 were obtained by [3 + 2] Huisgen cycloaddition in yields of 20%–90% by reacting the bis‐propargylated pyrimidines 4 with selected aryl azides 5 . Compounds from both series ( 4 and 6 ) were fully characterized by 1 H‐NMR, 13 C‐NMR, GC‐MS, and HRMS. Compounds 4 and 6 were then subjected to in vitro brain antitumor activity assays. Notably, 4b (R = Me; R 1 = H) and 4j (R = 2‐naphthyl; R 1 = H) exhibited the most favorable IC 50 values, 64.75 and 64.02 µM, respectively, against C6 rat glioblastoma cells. Among the bis‐triazoles, 6d (R = 4‐BrC 6 H 4 ; R 1 = H; Ar = Ph) demonstrated the highest cytotoxicity for the C6 cell line, with an IC 50 value of 11.72 µM. For the U251 human glioma cell line, 6b (R = Ph; R 1 = H; Ar = Ph) showed the greatest cytotoxic potential, with an IC 50 of 24.03 µM.