Novel acrylonitrile derived imidazo[4,5-b]pyridines as antioxidants and potent antiproliferative agents for pancreatic adenocarcinoma

Boček Pavlinac, Ida; Persoons, Leentje; Daelemans, Dirk; Starčević, Kristina; Vianello, Robert; Hranjec, Marijana (2024) Novel acrylonitrile derived imidazo[4,5-b]pyridines as antioxidants and potent antiproliferative agents for pancreatic adenocarcinoma. International Journal of Biological Macromolecules, 266 . ISSN 014-18130

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Abstract

We present the design, synthesis, computational analysis, and biological assessment of several acrylonitrile derived imidazo[4,5-b]pyridines, which were evaluated for their anticancer and antioxidant properties. Our aim was to explore how the number of hydroxy groups and the nature of nitrogen substituents influence their biological activity. The prepared derivatives exhibited robust and selective antiproliferative effects against several pancreatic adenocarcinoma cells, most markedly targeting Capan-1 cells (IC50 1.2–5.3 μM), while their selectivity was probed relative to normal PBMC cells. Notably, compound 55, featuring dihydroxy and bromo substituents, emerged as a promising lead molecule. It displayed the most prominent antiproliferative activity without any adverse impact on the viability of normal cells. Furthermore, the majority of studied derivatives also exhibited significant antioxidative activity within the FRAP assay, even surpassing the reference molecule BHT. Computational analysis rationalized the results by highlighting the dominance of the electron ionization for the antioxidant features with the trend in the computed ionization energies well matching the observed activities. Still, in trihydroxy derivatives, their ability to release hydrogen atoms and form a stable O–H⋯O•⋯H–O fragment upon the H• abstraction prevails, promoting them as excellent antioxidants in DPPH• assays as well.

Item Type:	Article
Uncontrolled Keywords:	acrylonitriles; antioxidant activity; antiproliferative activity; computational chemistry; Imidazo[4,5-b]pyridines; pancreatic cancer
Subjects:	NATURAL SCIENCES NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Physical Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Istraživanje antioksidativnog djelovanja benzazolskog skeleta u dizajnu novih antitumorskih agensa-AntioxPot Marijana Hranjec IP-2018-01-4379 HRZZ Dizajn, sinteza i računalna analiza novih optičkih kemijskih pH osjetilnih derivata benzazola-BenzpHSens Robert Vianello IP-2020-02-8090 HRZZ
Depositing User:	Robert Vianello
Date Deposited:	13 Jan 2026 10:01
URI:	http://fulir.irb.hr/id/eprint/10829
DOI:	10.1016/j.ijbiomac.2024.131239

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