Novel Cyano- and Amidinobenzothiazole Derivatives: Synthesis, Antitumor Evaluation, and X-ray and Quantitative Structure−Activity Relationship (QSAR) Analysis

Synthesis of a series of novel cyano- and amidinobenzothiazole derivatives <b>3</b>−<b>31</b> is described. All studied amidino derivatives showed noticeable antiproliferative effect on several tumor cell lines. Cyano derivatives <b>11</b>−<b>17</b> showed considerably less pronounced activity because of their poor solubility in aqueous cell culture medium, which was confirmed by the principal components (PC) analysis. Compounds <b>21</b>, <b>22</b>, <b>28</b>, and <b>29</b> were tested for their effects on the cell cycle and apoptosis, whereby <b>22</b> and <b>29</b>, having methyl group at the C-6 position in pyridine ring, showed drastic cell cycle perturbations that were both concentration- and time-dependent and induced apoptosis. The QSAR modeling, based on the physicochemical descriptors and on the measured biological activities, indicated the relevance of molecular polarizability and particular distribution of pharmacophores on the molecular surface for activity. In conclusion, benzothiazoles containing either isopropylamidino or imidazolyl groups will be considered as starting compounds for further investigation on lead identification.