Proton and Metal Dication Affinities of Tetracyclic Imidazo[4,5-b]Pyridine-Based Molecules: Insights from Mass Spectrometry and DFT Analysis

Vrban, Lucija; Martinac, Ingrid Ana; Hranjec, Marijana; Pocrnić, Marijana; Galić, Nives; Kobetić, Renata; Vianello, Robert (2025) Proton and Metal Dication Affinities of Tetracyclic Imidazo[4,5-b]Pyridine-Based Molecules: Insights from Mass Spectrometry and DFT Analysis. Molecules, 30 (13). ISSN 1420-3049

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Abstract

The imidazo[4,5-b]pyridine scaffold, a versatile heterocyclic system, is renowned for its biological and chemical significance, yet its coordination chemistry with biologically relevant metal dications remains underexplored. This study investigates the proton and metal dication affinities of twelve tetracyclic organic molecules based on the imidazo[4,5-b]pyridine core, focusing on their interactions with Ca(II), Mg(II), Zn(II), and Cu(II). Employing a dual approach of electrospray ionization mass spectrometry (ESI-MS) and density functional theory (DFT) calculations, we characterized the formation, stability, and structural features of metal–ligand complexes. ESI-MS revealed distinct binding behaviors, with Cu(II) and Zn(II) forming stable mono- and dinuclear complexes, often accompanied by reduction processes (e.g., Cu(II) to Cu(I)), while Ca(II) and Mg(II) exhibited lower affinities. DFT analysis elucidated the electronic structures and thermodynamic stabilities, highlighting the imidazole nitrogen as the primary binding site and the influence of regioisomeric variations on affinity. Substituent effects were found to modulate binding strength, with electron-donating groups enhancing basicity and metal coordination. These findings provide a comprehensive understanding of the coordination chemistry of imidazo[4,5-b]pyridine derivatives, offering insights into their potential applications in metalloenzyme modulation, metal-ion sensing, and therapeutic chelation.

Item Type:	Article
Uncontrolled Keywords:	imidazo[4,5-b]pyridine; metal dication affinity; proton affinity; mass spectrometry; DFT calculations; coordination chemistry; tetracyclic molecules; regioisomers
Subjects:	NATURAL SCIENCES NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Physical Chemistry
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Dizajn, sinteza i računalna analiza novih optičkih kemijskih pH osjetilnih derivata benzazola-BenzpHSens Robert Vianello; Marijana Hranjec; Ida Boček IP-2020-02-8090 HRZZ Molekularno prepoznavanje DNA:RNA hibridnih i višelančanih struktura u bioanalitičkim i in vitro sustavima-DNARNAHyB-MolBio Marijana Radić Stojković IP-2018-01-4694 HRZZ
Depositing User:	Kristina Ciglar
Date Deposited:	07 Nov 2025 14:24
URI:	http://fulir.irb.hr/id/eprint/10181
DOI:	10.3390/molecules30132684

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