Structural systematics of drug-like molecules: from benzamides to tennimides
Mocilac, Pavle (2012) Structural systematics of drug-like molecules: from benzamides to tennimides. PhD thesis, Dublin City University.
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A structural systematic study was undertaken on benzamides, carbamates and substituted benzamide derivatives as 3×3 isomer grids comprising N-(pyridyl)benzamide (Fxx and Mxx) (x = para-/meta-/ortho-) and N-(phenyl)pyridinecarboxamide (NxxF and NxxM) grids. These were synthesised and characterised, with their crystal structures determined by single crystal X-ray diffraction. Five series of CxxR (R = CH3, OCH3, F, Cl, Br) carbamate isomer grids have been synthesised and characterised, with some pertinent structures determined by X-ray diffraction. Ab initio modelling, conformational analysis and comparisons of
experimental solid state with optimised molecular geometries have facilitated an examination of the relationships between conformations and inter/intramolecular
interactions, rationalisation of differences between the solid state and calculated structures, as well as the presence of molecular disorder and polymorphism.
New classes of macrocycles have been developed including tetramers and trimers, based on our earlier research on benzamides and carbamates. These systems include various para-substituted derivatives (F, Cl, Br, CH3 CO2CH3) and have been fully characterized by 1H, 13C, 19F NMR and IR spectroscopy, while their crystal and molecular structures have been determined by single crystal X-ray diffraction.
The development of tennimides and trezimides as new macrocycles based on an imide backbone, presents an important entry point into a potentially fruitful area.
Furthermore, discovery of trezimides is especially important since no analogous macrocycle has been reported. Synthesis of tennimides and trezimides has been accomplished using a one-step synthetic strategy over a range of derivatives and presents a basis for synthesis of analogous macrocycles. Tennimides and trezimides proved to be rigid and stable compounds. The determining factors in the cyclisation are (i) the presence of the imide ortho-pyridine/pyrimidine rings and (ii) the inherent ability
of the imide group to twist by 80-120°, as measured by the 'CO···CO' torsion angle, providing a 'hinge' for ring closure or helical assembly. The trezimides can adopt two
distinct conformations in the solid state, (though one is preferred), whereas the tennimides adopt discrete conformational states as oc, cc and oo that highlight subtle
macrocyclic geometric changes on cavity opening (o) and closing (c) (though these interconvert in solution).
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