N‐Aryl‐Methylimidazothiazolyl Thiazolamines: Synthesis and Evaluation for Antiproliferative Antitubulin Activity in a Sea Urchin Embryo Model and PC‐3 Cancer Cells

Abstract

AbstractA series of imidazothiazoles (ITZs) were conveniently accessed via an improved four‐step protocol in 55%–79% yields. The synthesized ITZs were tested in a combination of a phenotypic sea urchin embryo assay and PC‐3 human adenocarcinoma cytotoxicity studies. Both experimental approaches converged on compounds that showed microtubule targeting activity and cytotoxicity similar to the control compound, combretastatin CA‐4. Specifically, ITZs featuring electron‐donating pharmacophores in position 4, including 4‐Me‐, 4‐OMe‐, 3‐amino‐4‐Me‐, and 3,4‐ethylenedioxy‐substituted benzene ring (6, 7, 28, and 34) exhibited consistent antimitotic antitubulin effect along with the pronounced inhibition of PC‐3 cells growth. These compounds altered cleavage of the sea urchin eggs at 0.002–0.005 µM concentration and displayed cytotoxicity with IC50 values of 0.020–0.47 µM. Notably, the compound ITZ (25) featuring 3,4‐dimethoxybenzene fragment selectively inhibited growth of malignant PC‐3 cells (IC50 = 0.52 µM) while showing no effect on the sea urchin embryo development at up to 4 µM concentration. The sea urchin embryo screen also identified ITZs with systemic toxicity or solubility issues. The assay can be used to prioritize tubulin‐specific molecules for advanced evaluation.