Influence of Bio-Isosteric Replacement on the Formation of Templating Methanol and Acetonitrile Solvates in Lophines

Thomas Kitchen, Connor Melvin, Mohd Nadzri Mohd Najib, Andrei S. Batsanov, Katharina Edkins

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Bio-isosteric replacement is a frequently used tool in medicinal chemistry. While the pharmacological activity is not influenced by the exchange of substituents, the solid-state characteristics and formation of different crystal forms may well be altered dramatically, jeopardizing 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). Crystallization 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.
Original languageEnglish
Pages (from-to)4531-4538
Number of pages8
JournalCrystal Growth and Design
Volume16
Issue number8
Early online date12 Jul 2016
DOIs
Publication statusPublished - 3 Aug 2016

Keywords

  • alcohols
  • crystal structure
  • crystals
  • solvates
  • solvents

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