Ester Groups as Carriers of Antivirally Active Tricyclic Analogue of Acyclovir in Prodrugs Designing: Synthesis, Lipophilicity – Comparative Statistical Study of the Chromatographic and Theoretical Methods, Validation of the HPLC Method

Lesniewska, Monika A; Ostrowski, Tomasz; Zeidler, Joanna; Muszalska, Izabela

doi:10.2174/1386207317666140526100532

Cited by 5 publications

(4 citation statements)

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“…3,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-6-(4-methoxyphenyl)-9-oxo-5Himidazo[1,2-a]-purine (6-(4-MeOPh)-TACV) and its esters: acetyl (Ac), iso-butyryl (iBut), pivaloyl (Piv), ethoxycarbonyl (Etc) and nicotinoyl (Nic) ( Fig. 1), were synthesized as previously reported in a laboratory scale [16,19]. Acetonitrile for HPLC (isocratic basis) was from Avantor Performance Materials Poland S.A. (Gliwice, Poland).…”

Section: Methodsmentioning

confidence: 99%

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Comparative analysis of stability of tricyclic analogues of acyclovir in an acidic environment

Muszalska

Lesniewska-Kowiel

Ostrowski

2019

Reac Kinet Mech Cat

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In the presented studies, the effect of hydrogen ions on the stability of the tricyclic aciclovir derivative (i.e. 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6-(4methoxyphenyl)-9-oxo-5H-imidazo[1,2-a]purine; 6-(4-MeOPh)-TACV) and its esters (acetyl (Ac-), iso-butyryl (iBut-), pivaloyl (Piv-), ethoxycarbonyl (Etc-) and nicotinoyl (Nic-)) has been assessed. The HPLC chromatographic method (Lichrospher RP-18 column, 5 μm, 250 mm × 4 mm) with UV detection (262 nm) was used to observe changes in the concentration of the tested compounds. The mobile phase consisted of acetonitrile-phosphate buffer (pH 6; 20 mM; 17 mM KH 2 PO 4 , 3 mM K 2 HPO 4) (35:65, v/v). The studies were carried out in the pH range 0.42-1.38 in the water-organic environment at constant ionic strength (0.50 M). The observed rate constants of the degradation reactions of the tested compounds were determined, kinetic equations describing the dependence of k pH as a function of pH for the proper acid catalysis were determined and the parameters of the equations describing the reaction of formation the observed product were determined. The dependence of durability on the chemical structure of the tested compounds was indicated and the mechanism of observed reactions was proposed.

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Section: Methodsmentioning

confidence: 99%

“…The flow rate of the mobile phases was 1.0 or 1.5 mL/ min (Table 1) and the injection volume was 20 μL. The UV detection was carried out at 262 nm [19].…”

Section: Chromatographic Conditions (Hplc-uv)mentioning

confidence: 99%

Comparative analysis of stability of tricyclic analogues of acyclovir in an acidic environment

Muszalska

Lesniewska-Kowiel

Ostrowski

2019

Reac Kinet Mech Cat

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“…Several prodrugs based on the chemical approach have been developed in the past few decades, such as the following: (a) ester prodrugs owe in vitro chemical stability and susceptibility to esterases that result in a rapid conversion to the parent drug once it enters the body. Ester prodrugs are used to improve lipophilicity and increase membrane permeation by masking the charge of polar functional groups such as ibuprofen guaiacol ester, acyclovir aliphatic ester prodrugs, thioester of erythromycin, and palmitate ester of clindamycin [ 101 , 109 , 110 , 111 , 112 , 113 , 114 ]. (b) Amide prodrugs enhance stability, change lipophilicity, and provide targeted drug delivery.…”

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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“…Esterification of these groups with short or long aliphatic alcohol is the most widely used method [32][33][34].…”

Section: Prodrugs With Improved Lipophilicitymentioning

confidence: 99%

Prodrug Strategy in Drug Development

Kelemen

Hancu

Rusu

et al. 2016

Acta Medica Marisiensis

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Prodrugs are chemically modified derivatives introduced in therapy due to their advantageous physico-chemical properties (greater stability, improved solubility, increased permeability), used in inactive form. Biological effect is exerted by the active derivatives formed in organism through chemical transformation (biotransformation). Currently, 10% of pharmaceutical products are used as prodrugs, nearly half of them being converted to active form by hydrolysis, mainly by ester hydrolysis. The use of prodrugs aims to improve the bioavailability of compounds in order to resolve some unfavorable characteristics and to reduce first-pass metabolism. Other objectives are to increase drug absorption, to extend duration of action or to achieve a better tissue/organ selective transport in case of non-oral drug delivery forms. Prodrugs can be characterized by chemical structure, activation mechanism or through the presence of certain functional groups suitable for their preparation. Currently we distinguish in therapy traditional prodrugs prepared by chemical derivatisation, bioprecursors and targeted delivery systems. The present article is a review regarding the introduction and applications of prodrug design in various areas of drug development.

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Ester Groups as Carriers of Antivirally Active Tricyclic Analogue of Acyclovir in Prodrugs Designing: Synthesis, Lipophilicity – Comparative Statistical Study of the Chromatographic and Theoretical Methods, Validation of the HPLC Method

Cited by 5 publications

References 0 publications

Comparative analysis of stability of tricyclic analogues of acyclovir in an acidic environment

Comparative analysis of stability of tricyclic analogues of acyclovir in an acidic environment

Enzyme Models—From Catalysis to Prodrugs

Prodrug Strategy in Drug Development

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