Computationally Designed Atovaquone Prodrugs Based on Bruices Enzyme Model
DFT molecular orbital calculations at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels and molecular
mechanics (MM2) calculations of kinetic properties for Bruice’s systems 1-5 indicate that the rate enhancement in the
cyclization of di-carboxylic semi-esters 1-5 is solely the result of strain effects and not proximity orientation ‘reactive
Furthermore, it was found that the activation energy in systems 1-5 and atovaquone ProD1- ProD5 is largely dependent
on the difference in the strain energies of the tetrahedral intermediates and reactants, and no correlation was found
between the cyclization rate and distance between the nucleophile and the electrophile (rGM).
Using the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) value for the
cyclization reaction of di-carboxylic semi-ester 1 and the calculated log krel values for prodrugs ATQ ProD1- ProD5 the
t1/2 values for the interconversion of ATQ ProD1- ProD5 to the parent drug were calculated. Thet1/2 values were: ATQ
ProD3, 22.44 hours; ATQ ProD1, ATQ ProD2 and ATQ ProD4, few seconds and ATQ ProD5 few years. Therefore, the
interconversion rate of atovaquone prodrugs to atovaquone can be programmed according to the nature of the prodrug
Keywords: Antimalarial prodrugs, atovaquone prodrugs, Bruice’s rotamer effect, DFT calculations, Intramolecular hydrolysis,
di-carboxylic semi-esters, bioavailability, strain energy.
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