Design, Synthesis and In-vitro Kinetic Study of Atovaquone Prodrug for the Treatment of Malaria
Date
2015-09-23
Authors
Karaman, Rafik
Fattash, Beesan
Karaman, Donia
Journal Title
Journal ISSN
Volume Title
Publisher
WJPR,Tara Pal,WJPR
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).
Description
Keywords
Malaria , prodrugs , atovaquone , dicarboxylic semi-esters , intramolecularity , atovaquone prodrugs