The influence of bio-isosteric replacement on the formation of templating methanol and acetonitrile solvates in lophines

Kitchen, T.; Melvin, C.; Bin Mohd Najib, M.N.; Batsanov, A.S.; Edkins, K.

Abstract

Bio-isosteric replacement is a frequently used tool in medicinal chemistry. Whilst the pharmacological activity is not influence by the exchange of substituents, the solid-state characteristics and formation of different crystal forms may well be altered dramatically, jeopardising the processability and safety of the drug compound. In this study we investigate a series of triphenylimidazole (TPI) derivatives as model compounds with the bio-isosteric exchange of only one halogen position (F, Cl, Br, I). Crystallisation from two industrially used solvents (methanol and acetonitrile) reveals solvate formation of all TPIs, for which the basic hydrogen bonded motif does not change. The three-dimensional packing depends on the size of the substituent and changes from fluoro- to chloro- and bromo-substitution but remains the same for the larger iodo-substituent. From acetonitrile, only F-TPI and Cl-TPI form an isomorphic channel solvate, which in both cases desolvates reversibly to an isomorphic crystal form. Due to the halogen atom lining of the channels, bromine and iodine are too large to generate a stable packing. This study illustrates the importance of understanding the influence of bio-isosteric substitution on the solid-state, in order to best utilize this common tool.

Citation

Kitchen, T., Melvin, C., Bin Mohd Najib, M., Batsanov, A., & Edkins, K. (2016). The influence of bio-isosteric replacement on the formation of templating methanol and acetonitrile solvates in lophines. Crystal Growth and Design, 16(8), 4531-4538. https://doi.org/10.1021/acs.cgd.6b00655

• Journal Article Type: Article
• Acceptance Date: Jun 17, 2016
• Online Publication Date: Jun 20, 2016
• Publication Date: Aug 3, 2016
• Deposit Date: Jun 20, 2016
• Publicly Available Date: Jun 21, 2017
• Journal: Crystal Growth and Design
• Print ISSN: 1528-7483
• Electronic ISSN: 1528-7505
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 8
• Pages: 4531-4538
• DOI: https://doi.org/10.1021/acs.cgd.6b00655
• Public URL: https://durham-repository.worktribe.com/output/1380722