Bioisosteric replacement of 1H-1,2,3-triazole with 1H-tetrazole ring enhances anti-leukemic activity of (5-benzylthiazol-2-yl)benzamides

• DOI: 10.1016/j.ejmech.2023.115126
• Publication Date: 2023-01-25T10:11:37Z
• Authors: Nazariy Pokhodylo; Nataliya Finiuk; Olha Klyuchivska; Rostyslav Stoika; Vasyl Matiychuk; Mykola Obushak
• Keywords: Benzamide; Tetrazole; Sulforhodamine B; MTT assay; Triazole; Thiazole; IC50

Previously, we discovered that N-(5-benzyl-1,3-thiazol-2-yl)-4-(5-methyl-1H-1,2,3-triazol-1-yl)benzamide possessed a remarkable cytotoxic effect on 28 cancer cell lines with IC50 < 50 μM, including 9 lines, where was in the range of 2.02-4.70 μM. In present study, designed novel N-(5-benzylthiazol-2-yl)amide compound 3d synthesized using original bioisosteric replacement 1H-1,2,3-triazole ring by 1H-tetrazole ring. A significantly enhanced anticancer activity vitro an excellent anti-leukemic potency towards chronic myeloid leukemia cells K-562 line demonstrated. Two compounds - and 3l were highly at nanomolar concentrations various tumor following lines: K-562, NCI-H460, HCT-15, KM12, SW-620, LOX IMVI, M14, UACC-62, CAKI-1, T47D. As highlight, N-(5-(4-fluorobenzyl)thiazol-2-yl)-4-(1H-tetrazol-1-yl)benzamide inhibited growth melanoma UACC-62 IС50 56.4 56.9 nM (SRB test), respectively. The viability pseudo-normal HaCaT, NIH-3T3, J774.2 measured MTT assay. Together SAR analysis, it allowed selection lead 3d, which demonstrated highest selectivity (SI = 101.0) treated leukemic cells. caused DNA damage (single-strand breaks detected alkaline comet assay) morphological study revealed changes consistent apoptosis. Thus, (5-benzylthiazol-2-yl)amide scaffold proved to be perspective approach design heterocyclic potential.