Tautomeric transformation of temozolomide, their proton affinities and chemical reactivities: A theoretical approach

• The bare, mono- and dihydrated complexes of TMZ isomers and protonated species were carried out using DFT calculation at the M06-2X/6-31+G(d,p) level of the theory.
• The transformation of TMZ follows as I1 ↔ TZM ↔ HIa ↔ HIb ↔ I2 ↔ I3.
• The reaction pathway TZM ↔ HIa is more kinetically and thermodynamically than those of TZM ↔  I1 suggesting that the formation of hydroxy imide (HIa,HIb) prevent the formation of imide (I1).
• Explicit water molecule and binding site of water to the TMZ play crucial effect on the tautomerization.
• TMZ becomes lesser active when presented in protonated form especially as in its species N3.

The gas-phase geometry optimizations of bare, mono- and dihydrated complexes of temozolomide isomers were carried out using density functional calculation at the M06 − 2X/6 − 31 + G(d,p) level of the theory. The structures and protonation energies of protonated species of temozolomide are reported. Chemical indices of all isomers and protonated species are also reported. Energies, thermodynamic quantities, rate constants and equilibrium constants of tautomeric and rotameric transformations of all isomers I1 ↔ TZM ↔ HIa ↔ HIb ↔ I2 ↔ I3 in bare and hydrated systems were obtained.

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