Synthesis of a Series of Heterocyclic N-Substituted Derivatives of Alendronic Acid and Their Preliminary Biological Evaluation.

The aim of this work was to examine the influence of introduction of heteroaromatic motifs like pyridyl and imidazole rings into alendronic acid molecule on its biological properties. For this purpose, a series of heterocyclic N-substituted alendronate derivatives were synthesized via a two-step, one-pot procedure. This procedure involves the condensation of alendronate and heteroaromatic aldehydes in the presence of triethylamine, which leads to the formation of appropriate Schiff bases, followed by the in situ reduction of the resulting imines with sodium borohydride. The study investigated the ability of the obtained bisphosphonates to bind to hydroxyapatite (HAP), as well as their antiproliferative effect against RAW 264.7 mouse macrophages, MCF-7 human breast cancer and MCF-10A normal breast epithelial cells. Among the tested derivatives, the 2-imidazole derivative (4f) and its N-methylated analog (4g) showed the best activity against both RAW 264.7 macrophages and MCF-7 cells, with an IC50 value of 19.4 and 76.1 µM and of 26.4 and 107.9 µM, respectively. Furthermore, all synthesized derivatives were non-cytotoxic toward MCF-10A normal cells under the tested experimental conditions. The 4(5)-imidazole (4e) derivative showed the highest affinity to HAP.