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The present study provides an overview of the chemistry and biological importance of the cationic chalcophene derivatives (furans, thiophenes and selenophenes). The summarized literature survey includes synthetic methods, reactivity and biological activities of aryl/hetarylchalcophenes that have been reported mainly from 2001 to 2019 focusing on monochalcophenes. A discussion demonstrating the proposed mechanisms of some interesting synthetic routes and linking structure features to biological activities is presented. These classes of compounds including cationic chalcophenes possess antiproliferative, antimicrobial and antiprotozoal activities. This review highlights recent advances for arylchalcophene derivatives and may contribute to the design and structure optimization of new chalcophene derivatives in the future.

Three thienylpicolinamidine derivatives 4a–c were prepared from their corresponding picolinonitriles 3a–c on treatment with lithium trimethylsilylamide, LiN(TMS)2, followed by a de-protection step using ethanol/HCl (gas).

Fourteen new thienylnicotinamidines and their analogs 5a–5k, 12, 13a, and 13b were prepared and their antiproliferative potential was evaluated against the growth of 60 cancer cell lines. The tested compounds had a strong antiproliferative efficacy against almost all cancer cell lines, with the average GI50 at ~2.20 µM. The effect of the thienylnicotinamidines on the growth of normal lung fibroblast cells (WI‐38) indicated that these derivatives are safe to the normal cells. The selectivity index (SI) ranges from 5.5‐ to 42.0‐fold. The conceivable mechanisms of action of the effective compounds 5d, 5f, 5g, 5i, 5j, and 5k with high SI were investigated. Although the thienylnicotinamidines are similar in structure, they could be divided into three groups as per their effects on gene expression: The first group (5d and 5f) elevated p53 and caspase 3 expression, the second group (5g and 5i) elevated p53 expression, and the last group (5j and 5k) elevated p53 and reduced topoII expression. Many thienylnicotinamides inhibited the vascular endothelial growth factor receptor‐2 (VEGFR‐2) in cell lysates at concentrations comparable to or better than pazopanib. The data of caspase 3 expression were confirmed by measuring the protein level by Western blot and the activity of the cleaved active enzyme. The ability to arrest the cell cycle and induce apoptosis was confirmed by flow cytometry. Taken together, two derivatives, 5d and 5f, with a distinctive VEGFR‐2 inhibitory activity and a proapoptotic and cell cycle arrest profile merit further investigations.

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