New 1,2,3-Triazole/1,2,4-triazole Hybrids as Aromatase Inhibitors: Design, Synthesis, and Apoptotic Antiproliferative Activity

Abstract

A novel series of 1,2,3-triazole/1,2,4-triazole hybrids 5a, 5b, and 6a-i was designed and synthesized as antiproliferative agents targeting aromatase enzymes. The antiproliferative activity of the new hybrids against four cancer cells was studied using Erlotinib as a control. Compounds 6a and 6b demonstrated the highest antiproliferative activity among these hybrids, with GI50 values of 40 nM and 35 nM, respectively. Compound 6b was the most potent derivative, with a GI50 of 35 nM, comparable to Erlotinib's GI50 of 33 nM. Compound 6b inhibited all cancer cell lines with comparable efficacy to Erlotinib. Compounds 5a, 5b, and 6a-i were tested for inhibitory action against aromatase as a potential target for their antiproliferative activity. Results revealed that compounds 6a and 6b were the most potent aromatase inhibitors, with IC50 values of 0.12 ± 0.01 µM and 0.09 ± 0.01 µM, respectively, being more potent than the reference Ketoconazole (IC50 = 2.6 ± 0.20 µM) but less potent than Letrozole (IC50 = 0.002 ± 0.0002). These findings indicated that compounds 6a and 6b had significant aromatase inhibitory action and are potential antiproliferative candidates. The findings were further linked to molecular docking investigations, which gave models of strong interactions with the aromatase domain for inhibitors with high binding scores.

Keywords: 1,2,3-triazole; 1,2,4-triazole; anticancer; aromatase; viability.

Figure 1

Structures of SAIs (type I) and NSAIs (type II) aromatase inhibitors.

Figure 2

Structures of compounds I–IV.

Figure 3

Structures of Schiff bases derived from 1,2,4-triazoles V–VII.

Figure 4

Structures of new hybrids 5a, 5b, and 6a–i.

Scheme 1

Synthesis of target compounds 5a, 5b, and 6a–i.

Scheme 2

Proposed mechanism for the formation of compounds 5a and 5b.

Figure 5

Antiproliferative activity of compounds 6a–i.

Figure 6

Aromatase inhibitory activity of compounds 6a–c.

Figure 7

Two- and three-dimensional representation of the interaction of co-crystallized androstenedione with aromatase CP450 domain.

Figure 8

Mode of binding of compound 6a inside aromatase CP450 domain: (a) 2D structure and (b) 3D structure.

Figure 9

Mode of binding of compound 6b inside aromatase CP450 domain: (a) 2D structure and (b) 3D structure.