Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations

Ciorteanu, Roxana; Ciobanu, Catalina Ionica; Cibotariu, Narcis; Shova, Sergiu; Antoci, Vasilichia; Mangalagiu, Ionel I.; Danac, Ramona

doi:10.3390/ijms26178368

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Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations

by

Roxana Ciorteanu

^1,2,

Catalina Ionica Ciobanu

³

,

Narcis Cibotariu

⁴

,

Sergiu Shova

⁵

,

Vasilichia Antoci

²

,

Ionel I. Mangalagiu

²

and

Ramona Danac

^2,*

¹

Institute of Interdisciplinary Research—RECENT AIR Center, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania

²

Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania

³

Institute of Interdisciplinary Research—CERNESIM Centre, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania

⁴

Centre of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry of Romanian Academy, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania

⁵

Department of Inorganic Polymers, “Petru Poni” Institute of Macromolecular Chemistry of Romanian Academy, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(17), 8368; https://doi.org/10.3390/ijms26178368 (registering DOI)

Submission received: 31 July 2025 / Revised: 26 August 2025 / Accepted: 28 August 2025 / Published: 28 August 2025

(This article belongs to the Section Molecular Pharmacology)

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Abstract

Three new series of indolizines (5a–f, 6a–f and 7a–g), functionalized with bromine or ethyl ester substituents on the pyridine ring, were designed and synthesized as promising anticancer agents. The synthesis of indolizine derivatives was carried out using the 1,3-dipolar cycloaddition of pyridinium N-ylides to ethyl propiolate as a key step. Spectral characterization (using NMR, FT-IR, HRMS and X-ray diffraction) showed that two types of cycloadducts 5a–f and 6a–f were obtained when the ylides generated by the 3-bromopyridinium salts were used as 1,3-dipoles in Huisgen cycloaddition reactions to ethyl propiolate. The anticancer effect of selected compounds was in vitro assessed against the National Cancer Institute (NCI) panel of 60 human tumor cells, at 10 μM concentration, with three compounds (5c, 6c and 7g) showing promising inhibitory activity on the growth of several cell lines including lung, brain, renal cancer and melanoma, as well as a cytotoxic effect against HOP-62 non-small cell lung cells (34% for compound 5c and 15% for compound 7g) and SNB-75 glioblastoma cells (15% for compound 5c and 14% for derivative 7c). Molecular docking revealed favorable binding affinities for 5c, 6c and 7g (–9.22 to –9.88 kcal/mol) at the colchicine-binding site of tubulin with key interactions involving βASN-258, βALA-317, and βLYS-352 residues for 5c, βASN-258 in case of 6c, and αVAL-181 and βLYS-254 for derivative 7g. According to the in silico ADMET analysis, the active compounds are predicted to exhibit good oral bioavailability, promising drug-like qualities and low toxicity risks.

Keywords: substituted indolizines; 3+2 cycloaddition; anticancer; molecular docking; ADMET

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MDPI and ACS Style

Ciorteanu, R.; Ciobanu, C.I.; Cibotariu, N.; Shova, S.; Antoci, V.; Mangalagiu, I.I.; Danac, R. Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations. Int. J. Mol. Sci. 2025, 26, 8368. https://doi.org/10.3390/ijms26178368

AMA Style

Ciorteanu R, Ciobanu CI, Cibotariu N, Shova S, Antoci V, Mangalagiu II, Danac R. Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations. International Journal of Molecular Sciences. 2025; 26(17):8368. https://doi.org/10.3390/ijms26178368

Chicago/Turabian Style

Ciorteanu, Roxana, Catalina Ionica Ciobanu, Narcis Cibotariu, Sergiu Shova, Vasilichia Antoci, Ionel I. Mangalagiu, and Ramona Danac. 2025. "Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations" International Journal of Molecular Sciences 26, no. 17: 8368. https://doi.org/10.3390/ijms26178368

APA Style

Ciorteanu, R., Ciobanu, C. I., Cibotariu, N., Shova, S., Antoci, V., Mangalagiu, I. I., & Danac, R. (2025). Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations. International Journal of Molecular Sciences, 26(17), 8368. https://doi.org/10.3390/ijms26178368

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Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations

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