Synthesis and structure–activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors

A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing a 1,2,5-triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC50 = 4.64 μM), a letrozole 1 analogue bearing para-cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen.

The design, synthesis and evaluation of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues were synthesized. Their effects on aromatase and antiproliferative activities were evaluated and compared to the corresponding 1,2,4-triazole and imidazole analogues.Figure optionsDownload as PowerPoint slideHighlights
► Over fifty 1- and 2-substituted-triazole letrozole-based analogues were synthesized.
► The two phenyl moieties with a para-cyano substitution are crucial for inhibition.
► A nitrogen atom at position 3 or 4 of the 5-membered ring is crucial for activity.