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Syntheses of 6-halogen-substituted benzothiazoles were performed by condensation of 4-hydroxybenzaldehydes and 2-aminotiophenoles and subsequent <i>O</i>-alkylation with appropriate halides, whereas 6-amidino-substituted benzothiazoles were synthesized by condensation of 5-amidino-2-aminothiophenoles and corresponding benzaldehydes. While most of the compounds from non-substituted and halogen-substituted benzothiazole series showed marginal antiproliferative activity on tested tumor cell lines, amidino benzazoles exhibited stronger inhibitory activity. Generally, imidazolyl benzothiazoles showed pronounced and nonselective activity, with the exception of <b>36c</b> which had a strong inhibitory effect on HuT78 cells (IC₅₀ = 1.6 µM) without adverse cytotoxicity on normal BJ cells (IC₅₀ >100 µM). Compared to benzothiazoles, benzimidazole structural analogs <b>45a</b>–<b>45c</b> and <b>46c</b> containing the 1,2,3-triazole ring exhibited pronounced and selective antiproliferative activity against HuT78 cells with IC₅₀ < 10 µM. Moreover, compounds <b>45c</b> and <b>46c</b> containing the methoxy group at the phenoxy unit were not toxic to normal BJ cells. Of all the tested compounds, benzimidazole <b>45a</b> with the unsubstituted phenoxy central core showed the most pronounced cell growth inhibition on THP1 cells in the nanomolar range (IC₅₀ = 0.8 µM; SI = 70). QSAR models of antiproliferative activity for benzazoles on T-cell lymphoma (HuT78) and non-tumor MDCK-1 cells elucidated the effects of the substituents at position 6 of benzazoles, demonstrating their dependence on the topological and spatial distribution of atomic mass, polarizability, and van der Waals volumes. A notable cell cycle perturbation with higher accumulation of cells in the G₂/M phase, and a significant cell increase in subG0/G1 phase were found in HuT78 cells treated with <b>36c</b>, <b>42c</b>, <b>45a</b>–<b>45c</b> and <b>46c</b>. Apoptotic morphological changes, an externalization of phosphatidylserine, and changes in the mitochondrial membrane potential of treated cells were observed as well.