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.

Malignant transformations are dependent on an aberrant increase in tubulin and microtubule activities for cancer cell growth, migration, invasion and metastasis. The present work includes design and synthesis of a new series of lipidated 1,3-diaryl propenones and their cyclized pyrimidine derivatives as tubulin polymerization inhibitors. These derivatives harness lipophilicity, ease of synthesis and antiproliferative activity of lipidated 1,3-diaryl propenones and their cyclized derivatives. New compounds were synthesized from 4′-hydroxyacetophenone via O-alkylation, condensation with different aromatic aldehydes followed by cyclization with urea, thiourea or guanidine. Cyclization of 1,3-diaryl propenones into 4,6-diaryl pyrimidines increased their antiproliferative activity with the most potent derivative 19 achieving IC₅₀ values at low micro molar concentration against two human cancer cell lines; MCF-7 (breast) and HepG-2 (liver). Compound 19 induced S-phase cell cycle arrest and apoptosis in MCF-7 with tubulin IC₅₀ = 9.7 μM. It is well accommodated at the colchicine binding site of the tubulin protein as demonstrated by molecular docking.