Design, synthesis, <i>in silico</i> and <i>in vitro</i> evaluation of pyrrole–indole hybrids as dual tubulin and aromatase inhibitors with potent anticancer activities

Twenty-four new pyrrolyl-3-phenyl-1<i>H</i>-indole-2-carbohydrazide derivatives were designed, synthesized and evaluated for their anticancer activities and dual inhibition properties against tubulin and aromatase. Their anticancer activities were highly potent against the NCI60 human cancer cell line panel. Amongst them, single chloro-substituted derivative 3h was the strongest tubulin inhibitor, disrupting the microtubule structure by inhibiting the colchicine site, while potently inhibiting aromatase (IC₅₀ = 1.8 µM) with strong activity against the estrogen receptor-positive T47D breast cancer cell line (IC₅₀ = 2.4 µM). Ester derivative 3k showed the best aromatase inhibitory activity (IC₅₀ = 18 nM) with moderate anti-T47D activity (IC₅₀ = 10.6 µM). Molecular docking predicted the derivatives inhibited the colchicine site of tubulin by forming mainly hydrophobic interactions with the surrounding amino acid residues. Moreover, heme chelation with the pyrrole ring was predicted as a key interaction, and the formation of intermolecular bonds with adjacent amino acid residues was predicted as important for inhibitory activity.