Abstract
A systematic DFT investigation of 3-hydroxy-N-phenylnaphthalene-2-carboxamide and its sixteen para-derivatives is presented. The structural analysis showed that the energetically preferred conformation of all derivatives is practically planar and it is stabilised via intramolecular hydrogen bonds occurring between (C)O...H(3)O atomic pairs. The quantum chemically evaluated partition coefficients logarithms correlate well with Quantitative Structure-Activity Relationship models as well as with experimentally determined isocratic retention factors logarithm. Theoretical gas-phase proton affinities of amido and hydroxyl group together with selected partial atomic charges reflect the terminal phenyl substitution effect. These quantities are linearly dependent on the in vitro activity against the Mycobacterium Kansasii. Obtained linear correlation functions based on quantum chemically evaluated microscopic properties and selected experimental data may serve as the effective tool in modern drug design for the description of substitution effect.
Highlights
In the last two decades, much effort has been paid to the development and the synthesis of new antimicrobial chemotherapeutics due to the dramatic increase of drug-resistant bacteria.[1]
The possible orientations of carbonyl atoms with respect to the hydroxyl group at the naphthyl moiety lead to four conformations. As it is presented for the parental molecule (R = H) in Fig. 1S, the energetically preferred conformation 1a is stabilised via the 1.708 Å intramolecular hydrogen bond between (C)O and H(3)O atoms
The maximal distortion of 8 degrees is between the naphthyl moiety and CO or CN bonds. It seems that the presence of two aromatic moieties connected via the alternating single and double bonds ensures the impact on the whole molecular electron structure by phenyl ring substitution
Summary
In the last two decades, much effort has been paid to the development and the synthesis of new antimicrobial chemotherapeutics due to the dramatic increase of drug-resistant bacteria.[1]. Due to its electronic properties, the amide functional group is able to interact with a number of enzymes/receptors and affect the biological response.[2] the reason for widespread occurrence of amides in pharmaceutical research is obvious. Properties of the amide group can be tuned by various chemical modifications. In this context, we can mention salicylanilides.[3,4] These N-substituted hydroxybenzamides represent compounds with a wide range of pharmacological activities.[5,6] The exact mechanism of action is still under investigation, but these compounds are known to act as inhibitors of protein kinase epidermal growth factor receptor.[7] the salicylanilides were found to inhibit bacterial enzymes.[8,9,10,11]
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