Binding benzamides

Samanta, S., Debnath, B., Gayen, S., Ghosh, B Basu, A., Srikanth, K., Jha, T. QSAR modeling on dopamine D2 receptor binding affinity of 5-methoxy benzamides. Farmaco 2005, 60, 818-825. 

Figure 13 Series of de novo designed nonpeptides containing a benzamide template (exemplified by compound 12, AP21 733) designed to interact favorably with Src SH2 and specifically to displace structural waters found in complexed Src SH2 structures [14,27]. The Src SH2 binding IC50 is shown for each compound, as well as a comparative IC50 for Ac-pTyr-Glu-Glu-lle-NH2 (compound 9).

Another retrospective analysis of already known H DAC inhibitors was carried out by You et al. [68]. They generated a 3D chemical-feature-based pharmacophore model and compared the ligand-based model with the structural-functional requirements for the binding of the HDAC inhibitors. Using this model, the interactions between the benzamide MS-275 and HDAC were explored. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme-inhibitor interaction pattern identified from molecular docking. However, also in this study no experimental validation of the modeling results was provided. 

A series of benzamides as replacement for the zinc-binding hydrox-amic acid was also synthesized and investigated for HDAC inhibitory activity [62,63]. A clear SAR could be derived from the examples prepared (Fig. 10). 

As a prelude to the use of olefination reactions to introduce the fluoroolefin amide isostere, the synthesis of fluoroolefin analogs of CGP 49823 is described where a nonpeptidic amide bond was replaced with a fluoroolefin [55]. Comparison of the binding affinities of these analogs for the NK1 receptor enabled determination of the active conformation of the amide containing compound CGP 49823. It was otherwise not easy to establish that the syn orientation of the aromatic ring of the benzamide towards the 2-benzyl substituent was the active conformation (Scheme 10). 

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