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Issue 33, 2018, Issue in Progress
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The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond

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Abstract

The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C–H⋯O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.

Graphical abstract: The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond

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Publication details

The article was received on 11 Apr 2018, accepted on 15 May 2018 and first published on 22 May 2018


Article type: Paper
DOI: 10.1039/C8RA03107J
RSC Adv., 2018,8, 18672-18681
  • Open access: Creative Commons BY-NC license
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    The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond

    J. Kalinowska-Tłuścik, J. Staroń, A. Krawczuk, S. Mordalski, D. Warszycki, G. Satała, A. S. Hogendorf and A. J. Bojarski, RSC Adv., 2018, 8, 18672
    DOI: 10.1039/C8RA03107J

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