Design, synthesis, and biological evaluation of vanillin-piperidone hybrids with potent anticancer activity and a favourable genotoxic profile.

Authors

M Krishna Vamsi, Jhansi Mamilla, Ramya Bandari, A Niranjan Kumar, Afra Fatima, Nidhi Maurya, Kotesh Kumar J, K V N S Srinivas, Sunil Misra, Suaib Luqman, Amtul Zehra, B Balakishan

Published in

RSC advances. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

A new series of 1-ethoxycarbonyl-3,5-bis(benzyl/alkyl vanillin)-4-piperidone analogues were synthesized via a two-step process involving aldol condensation of vanillin with 1-ethoxycarbonyl-4-piperidone, followed by O-alkylation using diverse aromatic and aliphatic halides. Structural characterization of the resulting compounds (3 and 4a-4m) was confirmed by NMR and HR-MS analyses. Among the synthesized derivatives, compounds 3 and 4k exhibited the most potent and selective cytotoxicity. Compound 3 demonstrated IC₅₀ values of 2.97 µM (SKBR3), 4.4 µM (DU145), and 20.5 µM (HEK-293), while compound 4k showed strong activity against HepG2 (2.27 µM) and DU145 (5.01 µM). Genotoxic assessment revealed that 4k maintained a favourable safety profile, with chromosomal aberration and micronucleus frequencies remaining low or only mildly elevated at higher doses, and a moderate, dose-dependent decrease in mitotic index. Mechanistic studies indicated G0/G1 cell cycle arrest in CHO-K1, DU145, and HepG2 cells, along with significant apoptosis induction in HepG2 (Sub-G1: 13.9%). Although its antioxidant potential was moderate relative to rutin, 4k exhibited dose-dependent free radical scavenging. Antidiabetic screening identified compounds 1, 3, 4c, and 4m as effective α-glucosidase inhibitors (52.6-58.5%; IC₅₀ = 4.27-4.75 µg mL^-1), comparable to acarbose. Antimicrobial evaluation showed broad-spectrum activity for compound 1, and compound 4k displayed membrane-stabilizing effects similar to quercetin. In conclusion, these multifunctional vanillin-piperidone hybrids especially compound 4k demonstrate significant anticancer, antidiabetic, and antimicrobial potential, further strengthened by their confirmed non-genotoxic profile.

PMID:
42405051
Bibliographic data and abstract were imported from PubMed on 06 Jul 2026.

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