Computational Study of Some Double Headed Acyclo-C-Nucleosides

In the present paper we have a focus in a study of theoretical characterization of three double headed acyclo-C-nucleosides, which are a recent target of experimental studies. The structural and electronic properties of double headed acyclo-C-nucleosides, 1,4-bis(3-mercapto-1H1,2,4-triazol-5-yl)butane-1,2,3,4-tetrol, 1,4-bis(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)butane1,2,3,4-tetrol and 5,5'-(1,2,3,4-tetrahydroxybutane-1,4-diyl)bis(1,3,4-oxadiazole-2(3H)-thione), have been investigated theoretically by performing semi-empirical molecular orbital, ab initio Hartree-Fock (HF) and Density Functional Theory (DFT) calculations. Geometries of the three molecules are optimized at the level of Austin Model 1 (AM1). The electronic properties and relative energies of the molecules have been calculated by HF and DFT in the ground state.


COMPUTATIONAL METHODS
All theoretical calculations in this work were performed using the computational methods implemented in the GAUSSIAN09 package. [39] Geometry optimization of the studied compounds was done by performing the semi-empirical molecular orbital theory at the level AM1. The electronic properties have been calculated by applying ab initio Hartree-Fock (HF) calculations with 6-31+G(d,p) basis set and the Density Functional Theory (DFT) at the B3LYP/6-31+G(d,p) levels of theory. The hybrid Becke 3-Lee-Yang-Parr (B3LYP) exchange correlation functional was applied for DFT calculations. [40,41]

RESULTS AND DISCUSSION
Some molecular data for the studied molecules are given in Table 1. The optimized structures of the studied molecules are shown in Figure 2. The geometry optimizations of AM1 method yield non-planar structures for the molecules 1, 2 and 3. The optimized structure parameters of each double headed acyclo-C-nucleoside by HF and DFT levels with 6-31+G(d,p) basis set are listed in Tables 2, 3   The total energy, highest occupied and the lowest unoccupied molecular orbital (HOMO and LUMO, respectively) energies, energetic gap (LUMO-HOMO, ΔE) and the dipole moment μ (in Debyes) for the studied molecules are given in Table 5.       The calculated dipole moments by the two methods indicate that each studied molecule is polar (hydrophilic) and active, and may interact with its environment strongly in solution. The high dipole moment value of the molecule 2 may make this double headed acyclo-C-nucleoside most reactive and attractive for the interaction with others systems than the molecules 1 and 3.
The spatial distributions of HOMO and LUMO are shown in Figures 6, 7 and 8. In general, HF and DFT methods give similar HOMO and LUMO orbitals. According to DFT calculations, for the first molecule, the HOMO orbital is mainly localized on the two triazol rings (Ring A and B), while the LUMO orbital is mainly localized on triazol ring (Ring A) and around carbon chain.
For the second molecule, the HOMO orbital is mainly localized on amino-triazol ring (Ring A), while the LUMO orbital is mainly localized around carbon chain and on amino-triazol ring (Ring B).
However, for the molecule 3, the HOMO orbital is mainly localized on the oxadiazol ring (Ring A). In contrast, the LUMO orbital is mainly localized on oxadiazol ring (Ring B) in molecule 3.

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This means that these molecules don't have the same reactivity in the ground and excited states, and may be more active in the excitation state.
In order to probe the electronic differences between the molecules 1, 2 and 3, an electrostatic surface potential (ESP) was generated. Figures 9, 10 and 11 display the ESP surface of these molecules. The gross molecular electron distribution is relatively similar with a few key differences.  -1H-1,2,4-triazol-5-yl)butane-1,2,3,4-tetrol (1): The geometry optimization of AM1, HF and DFT methods yields a non-planar structure for the molecule 1.

1,4-bis(4-amino
For the carbon atoms, some of the carbon atoms have positive excess charge, the others have negative excess charge. According to HF calculations, the magnitude of positive charges vary from + 0.035 to + 0.961, whereas the magnitude of negative charges vary from -1.109 to -0.427. However, by DFT calculations, the magnitude of positive charges vary from + 0.013 to + 0.547, whereas the magnitude of negative charges vary from -1.077 to -0.088. All the oxygen atoms have negative excess charge, their magnitude vary from -0.713 to -0.611 (HF) and -0.616 to -0.536 (DFT). For the nitrogen atoms, some of the nitrogen atoms have positive excess charge, the others have negative excess charge. The magnitude of positive charges vary from + 0.026 to + 0.247 (HF) and + 0.107 to + 0.381 (DFT). However, the magnitude of negative charges vary from -0.897 to -0.096 (HF) and -0.888 to -0.071 (DFT). The sulfur atoms have positive excess charge, their magnitude vary from + 0.013 to + 0.082 (HF) and + 0.080 to + 0.150 (DFT). Finally, the hydrogen atoms have positive excess charge, their magnitude vary from + 0.068 to + 0.451 (HF) and + 0.088 to + 0.429 (DFT).
The large charge accumulation takes place on the oxygen and nitrogen atoms. These results shown that oxygen and nitrogen atoms have more negative excess charges in compare with other atoms. This means that oxygen and nitrogen atoms undergo protonation reaction with acidic reagents.
However, further work is necessary to complete a full analysis of these double headed acyclo-Cnucleosides at a higher level of theory. The relationship between structure and biological activity of variety of double headed acyclo-C-nucleosides, appears to be one of the next logical steps.