Heteroaromatic π-Stacking Energy Landscapes

Abstract

In this study we investigate π-stacking interactions of a variety of aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. We find that dispersion contributes significantly to the interaction energy and is complemented by a varying degree of electrostatic interactions. We identify geometric preferences and minimum interaction energies for a set of 13 5- and 6-membered aromatic heterocycles frequently encountered in small drug-like molecules. We demonstrate that the electrostatic properties of these systems are a key determinant for their orientational preferences. The results of this study can be applied in lead optimization for the improvement of stacking interactions, as it provides detailed energy landscapes for a wide range of coplanar heteroaromatic geometries. These energy landscapes can serve as a guide for ring replacement in structure-based drug design.

The intricacies of the stacking interaction in a pyrrole–pyrrole system

“…Among NCI involving aromatic ring systems, the ones containing heteroaromatic rings have recently received greater attention [17][18][19][20][21][22]. Such rings are building blocks for anchoring substituents in defined positions and are a crucial component in most known drug molecules.…”

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“…It can be concluded that the replacement of CH by NH in the reported [14] antibacterial compound A and B has enhanced the biological activity and hence they are ideally suited for further modification to obtain more potent antimicrobial and antifungal compounds. Also compound 22a showed more potent analgesic activity than its bioisostere [16].…”

“…We can conclude from the preliminary antibacterial screening that the compounds have enhanced antimicrobial properties due to the presence of bioactive moieties as 1,2,4-triazol, 1,3,5-triazine, pyrimidine and imidazole [32]. Moreover, the presence of pyridine moiety in all the synthesized compounds enhance their antimicrobial activity in comparision to their reported [14] bioisoteres A and B.…”

“…Reaction of 1 with ketones namely cyclopentanone, cyclohexanone, thiazolidone, pyrazolone and barbituric acid in ethanol proceeded via (5+1) heterocyclization [14] and resulted in the formation of hitherto unknown 4-(het) aryl-2-aminopyrido [2,3:4,5] imidazo [1,2-a] [1, 3,5] triazines (2 -6) respectively. The structures of these com pounds are established on the basis of elemental analysis and spectral analysis.…”

“…The bioisostere concept is an over simplification of the role of scaffold's for activity, unless it plays a pivotal role for function or interaction such as for β-lactams in penicillins [9]. On the basis of these results and in continuation of our project directed towards the design and synthesis of biologically active isosteric heterocyclic lead compounds [10][11][12][13], we summarize that replacement of CH by N of the phenyl ring in the antibacterials [14] 3,4-dihydrobenzo [4,5] imidazo[1,2-a]triazine A and the dihydroimidazole derivatives B, could give their biological isosteres 2-6 and 7-11 respectively ( Figure 1), with more potent antibacterial and antifungal activity. These were carried out by illustrating the old and well known isosterism pyridine/phenyl are having some similar geometry and electronic features [15].…”