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Computationally designed atovaquone prodrugs based on Bruice's enzyme model
Rafik Karaman, Beesan Fattash, Genarro Mecca
1Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Israel. dr_karaman@yahoo.com.
Current Computer-Aided Drug Design
|October 22, 2013
Summary
Strain effects, not proximity, enhance cyclization rates in di-carboxylic semi-esters. Activation energy depends on strain energy differences, enabling programmed interconversion rates for atovaquone prodrugs.
Area of Science:
- Computational Chemistry
- Organic Chemistry
- Medicinal Chemistry
Background:
- Cyclization reactions are crucial in organic synthesis and drug development.
- Understanding factors influencing reaction rates, such as strain and proximity, is key to designing efficient processes.
- Atovaquone prodrugs aim to improve drug delivery and efficacy.
Purpose of the Study:
- To elucidate the factors governing the rate enhancement in the cyclization of di-carboxylic semi-esters.
- To investigate the relationship between activation energy, strain energy, and reaction rates in these systems and atovaquone prodrugs.
- To calculate the interconversion rates of atovaquone prodrugs to the parent drug.
Main Methods:
- Density Functional Theory (DFT) molecular orbital calculations at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels.
- Molecular Mechanics (MM2) calculations for kinetic properties.
- Utilizing experimental half-life (t1/2) data and calculated relative rate constants (log krel).
Main Results:
- Rate enhancement in di-carboxylic semi-ester cyclization is attributed solely to strain effects, not the reactive rotamer effect.
- Activation energy is primarily dependent on the difference in strain energies between tetrahedral intermediates and reactants.
- No correlation was observed between cyclization rate and the distance between nucleophile and electrophile.
- Calculated half-life values for atovaquone prodrugs range from seconds to years, demonstrating tunable interconversion rates.
Conclusions:
- Strain effects are the dominant factor in the cyclization rate enhancement of di-carboxylic semi-esters.
- The activation energy of these systems and atovaquone prodrugs is dictated by strain energy differences.
- The interconversion rate of atovaquone prodrugs to atovaquone can be precisely controlled by modifying the prodrug linker's nature.
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