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In an effort to develop improved and effective targeted tyrosine kinase inhibitors (TKIs), a series of twelve novel compounds with the structural motif "(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-N′-(halogenated)benzylidenebenzohydrazide" were successfully synthesized in three steps, yielding high product yields (53–97%). Among this new class of compounds, 6c and 6h-j exhibited excellent cytotoxic effects against four different cancer cell lines, with half-maximal inhibitory concentration (IC50) values ranging from 7.82 to 21.48 μM. Notably, compounds 6h and 6i emerged as the most potent inhibitors, demonstrating significant activity against key kinases such as EGFR, HER2, and CDK2. Furthermore, compound 6h displayed potent inhibitory activity against AURKC, while 6i showed potent inhibitory effects against the mTOR enzyme, with excellent IC50 values comparable with well-established TKIs. The mechanistic study of lead compound 6i revealed its ability to induce cell cycle arrest and apoptosis in HepG2 liver cancer cells. This was accompanied by upregulation of pro-apoptotic caspase-3 and Bax and downregulation of anti-apoptotic Bcl-2. Additionally, molecular docking studies indicated that the binding interactions of compounds 6h and 6i with the target enzymes give multiple interactions. These results underscore the ability of compound 6i as a compelling lead candidate warranting further optimization and development as a potent multi-targeted kinase inhibitor, which could have significant implications for the treatment of various cancers. The detailed structural optimization, mechanism of action, and in vivo evaluation of this class of compounds warrant further investigation to assess their therapeutic potential. [ABSTRACT FROM AUTHOR]

In the title adamantyl derivative, C(21)H(27)N(3)OS, the terminal meth-oxy-ethyl unit is disordered over two orientations with a refined site-occupancy ratio of 0.846 (6):0.154 (6). The 1,2,4-triazole ring is statistically planar [r.m.s. deviation = 0.002 (2) Å] and the phenyl substituent is almost perpendicular to its mean plane [dihedral angle = 83.57 (11)°]. No directional inter-molecular inter-actions were observed in the crystal structure.

In the title compound, C(17)H(28)N(4)S, the 1,2,4-triazole ring is nearly planar [maximum deviation = 0.005 (2) Å]. There are no significant hydrogen bonds observed in the crystal structure. The crystal studied was a non-merohedral twin, the refined ratio of twin components being 0.281 (3):0.719 (3).

The title mol-ecule, C(29)H(35)N(5)S, displays a chair-shaped piperazine ring, as well as an approximately planar triazole ring (r.m.s. deviation = 0.001 Å) whose phenyl substituent is nearly perpendicular to the mean plane of the five-membered ring [dihedral angle = 88.9 (1)°]. The substituents on the piperazine ring occupy equatorial sites. In the crystal, the adamantyl cage is disordered over two sets of sites with a major component of 67.8 (5)%. Weak inter-molecular C-H⋯S hydrogen bonding is present in the crystal.

The title mol-ecule, C(30)H(37)N(5)S, displays a chair-shaped piperazine ring, as well as an approximately planar triazole ring [maximum deviation = 0.002 (2) Å] whose phenyl substituent is nearly perpendicular to the mean plane of the five-membered ring [dihedral angle = 80.4 (1)°]. The substit-uents on the piperazine ring occupy equatorial sites. Weak inter-molecular C-H⋯S hydrogen bonding is present in the crystal structure.

The title mol-ecule, C(26)H(35)N(5)O(2)S, displays a chair-shaped piperazine ring, as well as a planar triazole ring whose phenyl substituent is perpendicular to the mean plane of the five-membered ring [dihedral angle = 90.00 (13)°]. The methyl-ene substituent on the piperazine ring occupies an equatorial site. Weak inter-molecular C-H⋯O hydrogen bonding is present in the crystal structure. The crystal studied was a non-merohedral twin, with a 33.9 (3)% minor component.