Structural variety of clofaziminium salts: effect of the counter-ion on clofaziminium conformation and on crystal packing

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Abstract

Clofazimine (CFZ), is a water-insoluble antimycobacterial agent gaining attention as a multi-drug and extensively-drug resistant tuberculosis treatment. Novel salts of clofazimine are reported with fumaric, succinic, 2,4-dihydroxybenzoic and terephthalic acids as well as with saccharin. The salt structures were obtained by single-crystal X-ray diffraction. Salt with 2,4-dihydroxybenzoic acid and with saccharin are solvated (methanol and acetonitrile respectively). Clofazimine reaction with terephthalic acid led to two cocrystals of salt, one solvated and a non-solvated one. New clofaziminium salts were compared to the currently known ones in terms of crystal packing and clofazimine/ium conformations. Clofaziminium hydrogen succinate presents isostructurality with clofaziminium hydrogen malonate, an already described salt. In structures of clofaziminium terephthalate terephthalic acid cocrystal of salt, solvent evaporation leads to packing and H-bonding modifications. In all structures, clofaziminium conformation is quite well conserved and steric hindrance is observed around the protonated site. Conformational optimization of clofaziminium reveals that this steric hindrance energy penalty is compensated by H-bond interactions with clofaziminium counter-ion.
Original languageEnglish
JournalActa Crystallographica. Section B: Structural Science
Publication statusAccepted/In press - 26 May 2019

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Radiation counters
Conformations
Clofazimine
Salts
Ions
Crystals
Saccharin
Succinic Acid
Hydrogen
Extensively Drug-Resistant Tuberculosis
X-Ray Diffraction
Pharmaceutical Preparations
Methanol
Evaporation
Single crystals
Anti-Bacterial Agents
X ray diffraction
terephthalic acid
Water

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@article{32b82f01b76c419fb4040c1758e5de83,
title = "Structural variety of clofaziminium salts: effect of the counter-ion on clofaziminium conformation and on crystal packing",
abstract = "Clofazimine (CFZ), is a water-insoluble antimycobacterial agent gaining attention as a multi-drug and extensively-drug resistant tuberculosis treatment. Novel salts of clofazimine are reported with fumaric, succinic, 2,4-dihydroxybenzoic and terephthalic acids as well as with saccharin. The salt structures were obtained by single-crystal X-ray diffraction. Salt with 2,4-dihydroxybenzoic acid and with saccharin are solvated (methanol and acetonitrile respectively). Clofazimine reaction with terephthalic acid led to two cocrystals of salt, one solvated and a non-solvated one. New clofaziminium salts were compared to the currently known ones in terms of crystal packing and clofazimine/ium conformations. Clofaziminium hydrogen succinate presents isostructurality with clofaziminium hydrogen malonate, an already described salt. In structures of clofaziminium terephthalate terephthalic acid cocrystal of salt, solvent evaporation leads to packing and H-bonding modifications. In all structures, clofaziminium conformation is quite well conserved and steric hindrance is observed around the protonated site. Conformational optimization of clofaziminium reveals that this steric hindrance energy penalty is compensated by H-bond interactions with clofaziminium counter-ion.",
keywords = "clofazimine, salt, conformational comparison, crystal packing comparison, counter-ion effect on clofazimine conformation",
author = "Laurie Bodart and Nikolay Tumanov and Johan Wouters",
year = "2019",
month = "5",
day = "26",
language = "English",
journal = "Acta Crystallographica. Section B: Structural Science",
issn = "0108-7681",
publisher = "International Union of Crystallography",

}

TY - JOUR

T1 - Structural variety of clofaziminium salts

T2 - effect of the counter-ion on clofaziminium conformation and on crystal packing

AU - Bodart, Laurie

AU - Tumanov, Nikolay

A2 - Wouters, Johan

PY - 2019/5/26

Y1 - 2019/5/26

N2 - Clofazimine (CFZ), is a water-insoluble antimycobacterial agent gaining attention as a multi-drug and extensively-drug resistant tuberculosis treatment. Novel salts of clofazimine are reported with fumaric, succinic, 2,4-dihydroxybenzoic and terephthalic acids as well as with saccharin. The salt structures were obtained by single-crystal X-ray diffraction. Salt with 2,4-dihydroxybenzoic acid and with saccharin are solvated (methanol and acetonitrile respectively). Clofazimine reaction with terephthalic acid led to two cocrystals of salt, one solvated and a non-solvated one. New clofaziminium salts were compared to the currently known ones in terms of crystal packing and clofazimine/ium conformations. Clofaziminium hydrogen succinate presents isostructurality with clofaziminium hydrogen malonate, an already described salt. In structures of clofaziminium terephthalate terephthalic acid cocrystal of salt, solvent evaporation leads to packing and H-bonding modifications. In all structures, clofaziminium conformation is quite well conserved and steric hindrance is observed around the protonated site. Conformational optimization of clofaziminium reveals that this steric hindrance energy penalty is compensated by H-bond interactions with clofaziminium counter-ion.

AB - Clofazimine (CFZ), is a water-insoluble antimycobacterial agent gaining attention as a multi-drug and extensively-drug resistant tuberculosis treatment. Novel salts of clofazimine are reported with fumaric, succinic, 2,4-dihydroxybenzoic and terephthalic acids as well as with saccharin. The salt structures were obtained by single-crystal X-ray diffraction. Salt with 2,4-dihydroxybenzoic acid and with saccharin are solvated (methanol and acetonitrile respectively). Clofazimine reaction with terephthalic acid led to two cocrystals of salt, one solvated and a non-solvated one. New clofaziminium salts were compared to the currently known ones in terms of crystal packing and clofazimine/ium conformations. Clofaziminium hydrogen succinate presents isostructurality with clofaziminium hydrogen malonate, an already described salt. In structures of clofaziminium terephthalate terephthalic acid cocrystal of salt, solvent evaporation leads to packing and H-bonding modifications. In all structures, clofaziminium conformation is quite well conserved and steric hindrance is observed around the protonated site. Conformational optimization of clofaziminium reveals that this steric hindrance energy penalty is compensated by H-bond interactions with clofaziminium counter-ion.

KW - clofazimine

KW - salt

KW - conformational comparison

KW - crystal packing comparison

KW - counter-ion effect on clofazimine conformation

M3 - Article

JO - Acta Crystallographica. Section B: Structural Science

JF - Acta Crystallographica. Section B: Structural Science

SN - 0108-7681

ER -