Part IV. Synthesis and antitumor evaluation of s-triazolothiadiazines and pyrazolo s-triazoles derived from ciproxacin

An efficient modified route based on the targeting mechanism of antibacterial fluoroquinolones for the shift from the antibacterial activity to the antitumor one was further developed.  Using a fused heterocyclic ring, s-triazolothiadiazine as a carboxyl bioisostere of ciprofloxacin, the title compounds, 1-cyclopropyl-6-fluoro- 7-piperazin-1-yl-3-(6-substituted-phenyl-7H-1, 2, 4triazolo3, 4-b1, 3, 4thiadiazin-3-yl)-quinolin-4(1H)-ones (5a−5e) and their corresponding N-acetyl products (6a−6e), were designed and synthesized, separately.  Meaningfully, a ring-contraction of fused six-membered thiadiazine occurred by a sulfur extrusion reaction gave new tri-acetylated fused heterocycles related to pyrazolo5, 1-c1, 2, 4 triazoles (7a−7e).  The in vitro antitumor activity against L1210, CHO and HL60 cell lines was also evaluated for the synthesized fifteen heterocycles compared to parent ciprofloxacin by methylthiazole trazolium (MTT) assay.  Interestingly, the  results displayed that fifteen fused heterocyclic compounds showed more significant growth inhibitory activity (IC₅₀ < 25.0 μmol·L⁻¹) than that of parent ciprofloxacin (IC₅₀ > 150.0 μmol·L⁻¹), and the active order decreased from 7a−7e to 5a−5e to 6a−6e, respective.