Mechanism of formation and ion mobility separation of protomers and deprotomers of diaminobenzoic acids and aminophthalic acids

Valadbeigi, Younes; Causon, Tim J.

doi:10.1039/d3cp01968c

Cited by 2 publications

(2 citation statements)

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“…Furthermore, because the alkyl chain present in their structures can provide additional flexibility, all neutral, mono- and diprotonated forms of these drugs may take the form of several different conformers that can be studied with ion mobility-mass spectrometry (IM-MS), which has already been proven as a valuable approach for studying various related drugs including the assessment of their physicochemical properties. , Separation of protomers and conformers of ions with IM is possible due to differences in their collision cross section (CCS) . Hence, IM-MS in combination with computational methods has been used in chemistry, biophysics, and biology to study the structure of biomolecules and small molecules , and to determine the protonation sites in compounds with more than one proton acceptor site. , Furthermore, as the ionization of compounds in ESI-IM-MS is based on protonation/deprotonation, this technique can be used to estimate the p K a values of different compounds. , In this work, the protonation of nine quinoline-based antimalarial drugs is experimentally studied by IM-MS using ESI and atmospheric pressure chemical ionization (APCI) ion sources. The site of protonation and the most probable conformers of the protonated forms of the drugs are determined using the IM-derived collisional cross sections ( DT CCS N2 ) and computational methods with the aim of obtaining correct p K a values to predict the relative abundances of mono- and diprotonated forms of these drugs at different pH values.…”

Section: Introductionmentioning

confidence: 99%

“…36 Hence, IM-MS in combination with computational methods has been used in chemistry, biophysics, and biology to study the structure of biomolecules and small molecules 37,38 and to determine the protonation sites in compounds with more than one proton acceptor site. 39,40 Furthermore, as the ionization of compounds in ESI-IM-MS is based on protonation/deprotonation, this technique can be used to estimate the pK a values of different compounds. 41,42 In this work, the protonation of nine quinoline-based antimalarial drugs is experimentally studied by IM-MS using ESI and atmospheric pressure chemical ionization (APCI) ion sources.…”

Section: Introductionmentioning

confidence: 99%

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Computational and Experimental IM-MS Determination of the Protonated Structures of Antimalarial Drugs

Valadbeigi,

Causon

2024

J. Am. Soc. Mass Spectrom.

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A combination of ion mobility-mass spectrometry (IM-MS) measurements and computational methods were used to study structural and physicochemical properties of a range of quinoline-based drugs: amodiaquine (AQ), cinchonine (CIN), chloroquine (CQ), mefloquine (MQ), pamaquine (PQ), primaquine (PR), quinacrine (QR), quinine (QN), and sitamaquine (SQ). In experimental studies, ionization of these compounds using atmospheric pressure chemical ionization (APCI) yields monoprotonated species in the gas phase while electrospray ionization (ESI) also produces diprotonated forms of AQ, CQ, and QR and also for PQ, SQ, and QN in the presence of formic acid as an additive. Comparison of the trajectory-method-calculated and experimental IM-derived collisional cross sections (CCS N2 ) were used to assign both the protonation sites and conformer geometry of all drugs considered with biases of 0.7−2.8% between calculated and experimental values. It was found that, in solution, AQ and QR are protonated at the ring nitrogen of the quinoline group, whereas the other drugs are protonated at the amine group of the alkyl chain. Finally, the conformers of [M + H] + and [M + 2H] 2+ assigned according to the lowest energies and CCS N2 calculations were used to calculate the pK a values of the antimalarial drugs and the relative abundance of these ions at different pH values that provided validation of the computational and experimental IM-MS results.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computational and Experimental IM-MS Determination of the Protonated Structures of Antimalarial Drugs

Valadbeigi,

Causon

2024

J. Am. Soc. Mass Spectrom.

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Using dopants in the atmospheric pressure chemical ionization ion source to determine the site of protonation by ion mobility spectrometry

Valadbeigi,

Mirzahosseini,

Ilbeigi

et al. 2024

Rapid Comm Mass Spectrometry

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RationaleCompounds like caffeine metabolites with more than one proton acceptor site can produce a mixture of isomeric protonated ions (protomers) in electrospray ionization and atmospheric pressure chemical ionization (APCI) ion sources. Discrimination between the protomers is of interest as the charge location influences ion structure and chemical and physical properties.MethodsProtonation of caffeine in an APCI ion source was studied using ion mobility spectrometry. The hydronium ions, H3O+(H2O)n, are the main reactant ions in the APCI ion source. Different dopant gases including NO2, NH3, and CH3NH2 were used to produce new reactant ions NO+, NH4+, and CH3NH3+, respectively. Density functional theory was employed to explain the experimental results and calculate the energies of the ionization reactions.ResultsThe ion mobility spectrum of caffeine showed three peaks. In the presence of NO2 dopant and NO+ reactant ion, caffeine was ionized via charge transfer and formation of M+ ion. As NH3 and CH3NH2 are stronger bases than H2O, the reactant ions NH4+ and CH3NH3+ selectively protonated the more basic site of caffeine, that is, the imidazole nitrogen. Using these dopants, we could attribute the first ion mobility peak to M+ ion, the second peak to the protonation of caffeine at the carbonyl oxygen atom, and the third peak to the protonation of the imidazole nitrogen atom. The calculated collisional cross‐sections of M+ and the protomers of caffeine confirmed the peaks' assignment.ConclusionsThe criterion for the selection of an appropriate dopant is that its proton affinity (PA) should be between those of the proton acceptor sites of the molecule studied.

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Mechanism of formation and ion mobility separation of protomers and deprotomers of diaminobenzoic acids and aminophthalic acids

Abstract: Protonation and deprotonation sites of diaminobenzoic acid and aminophthalic acid isomers were investigated using ion mobility-mass spectrometry and computational methods.

Cited by 2 publications

References 50 publications

Computational and Experimental IM-MS Determination of the Protonated Structures of Antimalarial Drugs

Computational and Experimental IM-MS Determination of the Protonated Structures of Antimalarial Drugs

Using dopants in the atmospheric pressure chemical ionization ion source to determine the site of protonation by ion mobility spectrometry

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