Design, Synthesis and In-vitro Kinetic Study of Atovaquone Prodrug for the Treatment of Malaria

Abstract

Using DFT molecular orbital at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels and molecular mechanics (MM2) calculations of the hydrolysis of Bruice’s di-carboxylic semi-esters 1–5 several atovaquone prodrugs were designed. It was found that the interconversion rate of the designed atovaquone prodrugs is largely determined on the strain energies of the reaction’s tetrahedral intermediates and reactants. Further, no correlation was found between the active parent drug’s release and the distance between the nucleophile and the electrophile in the dicarboxylic semi-ester (atovaquone prodrug). Using the half time needed for the interconversion of 50% of di-carboxylic semi-ester 1 and the calculated log krel values for the designed atovaquone prodrugs the t1/2 values for interconversion of those prodrugs to their active parent drug were calculated. The calculated t½ value for atovaquone ProD 1 was about 26.4 hours. Utilizing the information gained from the prodrugs design, atovaquone ProD 1 was synthesized and fully characterized. In vitro kinetic study on the interconversion of atovaquone ProD 1 to atovaquone was studied in four different aqueous media mimicking the stomach, intestine and blood circulation. The kinetic results revealed that atovaquone ProD 1underwent hydrolysis in all studied media however with different interconversion rates. The interconversion t1/2 values were: in 1N HCl (11.4 hours), pH 2.2 (10.9 days), pH 5.5 (24 hours) and pH 7.4 (28.8 hours).