Computationally-designed phenylephrine prodrugs – a model for enhancing bioavailability

Karaman, Donia; Zeiadeh, Isra’

doi:10.1080/00268976.2013.779395

Cited by 8 publications

(4 citation statements)

References 70 publications

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“…Unraveling the reaction mechanism would allow for better design of an efficient chemical device to be utilized as a prodrug linker that can be covalently linked to a drug which can chemically, but not enzymatically, be cleaved to release the active drug in a programmable manner. For example, studying the mechanism for a proton transfer in Kirby's acetals has led to a design and synthesis of novel prodrugs of aza‐nucleosides for the treatment for myelodysplastic syndromes , atovaquone prodrugs for the treatment for malaria , less bitter paracetamol prodrugs to be administered to children and elderly as antipyretic and pain killer , and prodrugs of phenylephrine as decongestant . In these examples, the prodrug moiety was linked to the hydroxyl group of the active drug such that the drug‐linker moiety (prodrug) has the potential to interconvert when exposed into physiological environments such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby's enzyme model).…”

Section: Calculation Methods Used In the Prodrugs Designmentioning

confidence: 99%

Prodrugs Design Based on Inter‐ and Intramolecular Chemical Processes

Karaman

2013

Chem Biol Drug Des

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This review provides the reader a concise overview of the majority of prodrug approaches with the emphasis on the modern approaches to prodrug design. The chemical approach catalyzed by metabolic enzymes which is considered as widely used among all other approaches to minimize the undesirable drug physicochemical properties is discussed. Part of this review will shed light on the use of molecular orbital methods such as DFT, semiempirical and ab initio for the design of novel prodrugs. This novel prodrug approach implies prodrug design based on enzyme models that were utilized for mimicking enzyme catalysis. The computational approach exploited for the prodrug design involves molecular orbital and molecular mechanics (DFT, ab initio, and MM2) calculations and correlations between experimental and calculated values of intramolecular processes that were experimentally studied to assign the factors determining the reaction rates in certain processes for better understanding on how enzymes might exert their extraordinary catalysis.

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Section: Calculation Methods Used In the Prodrugs Designmentioning

confidence: 99%

Prodrugs Design Based on Inter‐ and Intramolecular Chemical Processes

Karaman

2013

Chem Biol Drug Des

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“…DFT calculations of the prodrugs showed that the rate-limiting step is the transfer of a proton from the carboxylic hydroxyl group to the neighboring acetal oxygen. In addition, the driving force of proton transfer is largely dependent on the geometric variations (the distance between the two reactive centers and the angle of attack), and the half-life for the conversion of the prodrugs to the parent drug can be programmed according to the nature of the prodrug linker [ 173 ].…”

Section: The Prodrug Approachmentioning

confidence: 99%

Enzyme Models—From Catalysis to Prodrugs

Breijyeh

2021

Molecules

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Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.

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“…Unraveling the reaction mechanism would allow for an accurate design of an efficient chemical device to be utilized as a prodrug promoiety that can be covalently linked to a parent drug to provide chemically and not enzymatically the parent drug in a programmable manner upon exposure to physiological environments. For example, exploring the mechanism for proton transfer in Kirby's acetals has led to design and synthesis of novel prodrugs of aza-nucleosides to treat myelodysplastic syndromes [ 62 ], statins to treat high cholesterol blood levels [ 63 ], bitterless paracetamol prodrugs to be administered to children and elderly as antipyretic and pain killer [ 25 ], and prodrugs of phenylephrine as decongestants [ 64 ]. In the above-mentioned examples, the prodrug moiety was attached to the hydroxyl group of the active drug such that the drug promoiety (prodrug) has a potential to degrade upon exposure to physiological environment such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby's enzyme model).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, andIn VitroKinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations

Qtait

Dajani

Lafi

2014

The Scientific World Journal

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Based on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby's N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is determined based on the nature of the amine leaving group. In addition, a linear correlation of the calculated and experimental rate values has drawn credible basis for designing atenolol prodrugs that are bitterless, are stable in neutral aqueous solutions, and have the potential to release the parent drug in a sustained release manner. For example, based on the calculated B3LYP/6-31 G (d,p) rates, the predicted t 1/2 (a time needed for 50% of the prodrug to be converted into drug) values for atenolol prodrugs ProD 1-ProD 2 at pH 2 were 65.3 hours (6.3 hours as calculated by GGA: MPW1K) and 11.8 minutes, respectively. In vitro kinetic study of atenolol prodrug ProD 1 demonstrated that the t 1/2 was largely affected by the pH of the medium. The determined t 1/2 values in 1N HCl, buffer pH 2, and buffer pH 5 were 2.53, 3.82, and 133 hours, respectively.

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Computationally-designed phenylephrine prodrugs – a model for enhancing bioavailability

Cited by 8 publications

References 70 publications

Prodrugs Design Based on Inter‐ and Intramolecular Chemical Processes

Prodrugs Design Based on Inter‐ and Intramolecular Chemical Processes

Enzyme Models—From Catalysis to Prodrugs

Design, Synthesis, andIn VitroKinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations

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