Development of a Novel Series of Anticancer and Antidiabetic: Spirothiazolidines Analogs

Abstract

4-(4-Aminophenyl)-1-thia-4-azaspiro[4.5]decan-3-one <b>1</b> was prepared and allowed to react with nitrogen nucleophiles to give the corresponding hydrazones <b>2</b>-<b>4</b>. Further, compound <b>1</b> underwent diazotization and afforded the parallel hydrazono derivative <b>5</b>; moreover, compound <b>1</b> refluxed with active methylene derivatives yielded the corresponding aminospirothiazolo pyridine-carbonitrile derivative <b>6</b> and spirothiazolopyridinone-carbonitrile derivative <b>7</b>. Condensation of spirothiazolidine <b>1</b> with 4-chlorobenzaldehyde gave the corresponding spiro arylidiene derivative <b>8</b>, which was utilized as a component of Micheal addition to react with excess of nitrogen nucleophiles to yield novel ring frameworks 4-(3<i>'</i>-(4-chlorophenyl)-spiro [cyclohexane-1,5<i>'</i>-pyrazolo[3,4-<i>d</i>]thiazol]-6<i>'</i>(<i>1'H</i>)-yl)aniline (<b>9)</b> and 4-(3<i>'</i>-(4-chlorophenyl)-<i>6'H</i>- spiro[cyclohexane-1,5<i>'</i>-thiazolo[5,4-<i>d</i>]isoxazol]-6<i>'</i>-yl)aniline <b>(10)</b>. Finally, when spirothiazolo pyridinone-carbonitrile derivative <b>7</b> sodium salt generated in situ was reacted with different alkyl halides, it produced the corresponding <i>N</i>-derivatives <b>12</b>-<b>16</b>. Three compounds, <b>6</b>, <b>14</b>, and <b>16</b>, showed high significantly anticancer activities compared with Doxorubicin® (positive control) against human breast carcinoma (MCF-7) and human liver carcinoma (HepG-2) cell lines. On the other hand, compounds <b>6</b> and <b>9</b> showed higher therapeutic indices for both of alpha-amylase inhibitor and alpha-glucosidase inhibitor than the other tested compounds compared with the antidiabetic Acarbose (positive control).