Ring-aromatic features

Figure 16.3 P-gp-verapamil binding inhibition pharmacophore (orange, ring aromatic feature green, hydrogen bond acceptor cyan, hydrophobic features). Reprinted with permission from ref. [45], Copyright 2002 American Society for Pharmacology and Experimental Therapeutics.

Pharmacophoric features are red for positively ionizable, green for hydrogen bond acceptors, light blue for hydrophobic and orange for ring aromatic. Shape restraints are shown in light... 

The C-H bends are chciracteristic of the substitution ciround the ciromatic ring. Aromatic compounds have a characteristic C-H peak near 3,030 cm. In addition, the infrared spectra can contain the following features ... 

Compounds and their conformational models were imported to Catalyst and subjected to the HypoGen routine to build chemical feature-based pharmacophore models using hydrogen bond acceptor lipid (HBA), hydrogen bond donor (HBD), positive ionizable (PI), ring aromatic (RA) and hydrophobic ... 

Thus, the nature of chemical features might differ between two hypotheses and the most specific is generally favored. For instance, models with more features will be favored as well as models with directional features (H-bond donor/ acceptors, ring aromatics). 

In the case of absence of the saturated carbon atoms, the bending and 1,2-allylic strains cannot be considered as the reasons for a flat potential energy surface around minimum. Therefore, it was suggested [27, 28] that the deviation of characteristics of cyclic conjugated systems from their aromatic features is responsible for conformational flexibility of such dihydroaromatic rings. In addition, it was demonstrated... 

It has been shown that single ring aromatic alkylation reactions such as benzene to ethylbenzene take place primarily within the 12- ring (12-MR) system, and that the 10-ring (10-MR) system contributes little to the ethylbenzene reaction. A key feature of MCM-22 is its ability to operate stably at low benzene-to-ethylene ratios with minimal production of polyethylbenzenes (PEBs) or ethylene oligomers. The excellent ethylbenzene selectivity of the MCM-22 catalyst is likely due to confinement effects within this 12-MR pore system and to the very facile desorption... 

There are molecular systems exhibiting 7r-bond fixation patterns that are entirely opposite to that induced by the Mills-Nixon effect [82,83,67]. Typical examples of this kind are provided by benzoborirene 33 and benzocyclopropenyl cation 34 (Fig. 19) These compounds represent extended 7r-systems relative to benzene itself since they encompass now empty 7r-orbitals at B and C+ atoms, respectively. The structural parameters offered by HF/6-31G [82] and MP2(fc)/6-31G [43] models are given in Table 10. Both molecules are planar. A salient feature of the aromatic CC bonds is their stretching relative to benzene at ortho and para positions. In contrast, meta bonds are more localized and shortened. Another striking property is a pronounced delocalization within the three-membered ring (aromatic pattern involving 27t electrons) as easily visualized by the resonance structures shown in Scheme 4. The same resonance mechanism is operative in benzocyclopropenyl cation. 

To test the proposition that one of the phenyl rings of fentanyl was equivalent to the aromatic feature of morphine, Lobbezzo et al 33) prepared analogs of fentanyl with a phenolic OH group in either the 7V-phenethyl side... 

The spirane ring is formed by treating amides derived from 16 with formamide and reducing the product.(20,56) In the solid state the 4-NPh moiety adopts an equatorial rather than an axial conformation in relation to the piperidine ring,(57) akin to the solid and probable solute state conformation of fentanyl, for which there is X-ray<58) and H-nmr evidence (see 20). The activities of the spiranes 19 also provide evidence that anilido phenyl is a- rather than /3-oriented in active conformations of fentanyl derivatives (21). This aromatic feature is confined to the /3-orientation in the bicyclo analogs 22, neither of... 

The relatively low potencies of analgesics such as methadone and dex-tromoramide, also with dual aromatic features, are considered due to the fact that they cannot assume the critical conformation of rings A and F proposed for the potent derivatives. Conversely, however, it is difficult to account for the low orders of potencies (on the scale of the compounds of Fig. 13.9) of the 4-phenylpiperidines 35 that are capable of conversion to conformations appropriate to high activity (provided energy barriers may be overcome and/or compensated for) the derivative 36 presents little difficulty in this respect. There are clearly hazards in attempting the correlation of aromatic molecular features in ligands of disparate structure. 

Aromatic features can be modeled as layer 4 point features or as layer 3 features. In Catalyst, Phase, and LigandScout these features are also attributed with a ring plane normal defining the spatial orientation (layer 3 feature). In MOE, the selected pharmacophore scheme determines whether a ring plane orientation constraint is included or if aromaticity is modeled as a pure point feature with a tolerance sphere. 

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