In silico and in vivo screening of triamterene synthetic analogues as promising diuretics

Authors

DOI:

https://doi.org/10.26641/2307-0404.2022.3.265739

Keywords:

design, triamterene, pteridines, structural modification, molecular docking, diuretic activity, SAR analysis

Abstract

The modification of lead-compound aimed to the increasing of activity, decrement of toxicity or improvement of selectivity is one of the most important methods used for elaboration of novel medications. Natural compounds, approved or investigational drugs or just compounds with proved biological activity could be the lead-compound. Often the chemical modification of lead compounds is directed at the enhancement of ligand-biological target interactions. Abovementioned approach, namely structural modification of known drug triamterene was used for purposeful search for novel diuretics. The preliminary prognostication of ligand-target interactions and affinity levels allow to reduce quantity of experimental animals, synthesis, and pharmacological studies costs. Conducted studies revealed the series of promising 6,7-disubstituted pteridine-2,4(1H,3H)-diones with diuretic activity that comparable with pharmacological effect of triamterene. Aim – purposeful search for promising diuretics among structural analogues of triamterene that includes preliminary in silico studies, synthesis and in vivo screening of novel compounds for diuretic activity. Methods used: organic synthesis, physicochemical methods of analysis of organic compounds (NMR 1H-spectroscopy, chromato-mass spectrometry, elemental analysis). Prediction of affinity for a biological target, prediction of toxicity and lipophilicity of the combinatorial library, which was created on the basis of the drug triamterene, was carried out using computer services. Studies of compounds that affect the excretory function of the kidneys of rats were performed according to the generally accepted method of E.B. Berkhin with water load. Research of the probable mechanism was conducted by flexible molecular docking, as an approach of finding molecules with affinity to a specific biological target. Macromolecular data were downloaded from the Protein Data Bank (PDB) namely, the crystal structures of epithelial sodium channel (ENaC) ((PDB ID – 6WTH). The substantiation of potential diuretics design was conducted by in silico methods (prediction of affinity, ligand-enzyme interactions and pharmacokinetic characteristics). The structural modification of triamterene molecule was carried out by replacing of amino-group in positions 2, 4 and 7 by others “pharmacophore” fragments. Abovementioned transformation is aimed at the changing of ligand-enzyme interactions in active site, lipophility and toxicity. Synthesis of 6,7-disubstituted pteridine-2,4(1H,3H)-diones was conducted by condensation 5,6-diamino-2-oxo-(thioxo-)-2,3-dihydropyrimidin-4(1H)-ones with carbonyl-containing compounds or oxocarboxylic acids.  The further modification of obtained compounds was performed by alkylation, hydrazinolysis and nucleophilic addition/elimination. The structure of obtained compounds was proven by elemental analysis, chromato-mass and 1H NMR-spectral analysis. The studies of synthesized compounds effect on excretion function of kidneys allowed to detect series of promising structural analogues of triamterene that exceed it in pharmacological activity by 27.3-99.0%. The “structure-biological activity” relationship was discussed and perspective of the further search of diuretics among abovementioned compounds were shown. The design of new biologically active compounds with diuretic activity was performed using in silico methodologies and realized by structural modification of the well-known diuretic triamterene. Traditional organic synthesis was used for preparation of target compounds, in vivo experiments were used to detect compounds with significant biological activity. Several effective compounds were identified among pteridines, which exceed the reference drug triamterene in terms of daily diuresis. The obtained results substantiate further purposeful search, in-depth research on experimental pathologies and study of the mechanism of action of potential diuretics among this class of compounds.

References

Paul D, Sanap G, Shenoy S, Kalyane D, Kiran K, Tekade RK. Artificial intelligence in drug discovery and development. Drug Discov Today. 2021;26(1):80-93. doi: https://doi.org/10.1016/j.drudis.2020.10.010

Epithelial sodium channels (ENaC). British Jour-nal of Pharmacology. 2009;158:S137-8. doi: https://doi.org/10.1111/j.1476-5381.2009.00503_9.x

Kellenberger S, Schild L. International Union of Basic and Clinical Pharmacology. XCI. Structure, Func-tion, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+ Channel. Pharmacological Reviews. 2015;67:1-35. doi: http://dx.doi.org/10.1124/pr.114.009225

Carmona-Martínez V, Ruiz-Alcaraz AJ, Vera M, Guirado A, Martínez-Esparza M, García-Peñarrubia P. Therapeutic potential of pteridine derivatives: A comprehensive review. Med Res Rev. 2018;1-56. doi: https://doi.org/10.1002/med.21529

Roush GC, Sica DA. Diuretics for Hypertension: A Review and Update. American Journal of Hypertension. 2016;29(10):1130-7. doi: https://doi.org/10.1093/ajh/hpw030

Rossiter S, Ostovar M. Bicyclic 6-6 Systems: Pte-ridines, Reference Module in Chemistry, Molecular Scien-ces and Chemical Engineering. Comprehensive Hetero-cyclic Chemistry IV. 2022;10:796-855. doi: https://doi.org/10.1016/B978-0-12-818655-8.00040-8

Sokolova KV, Stavytskyi VV, Kovalenko SI, Pod¬pletnya OA. Directed search for diuretics among 6-substituted pteridine-2,4,7(1H,3H,8H)-triones. Medicni perspektivi. 2022;2:4-15. https://doi.org/10.26641/2307-0404.2022.2.260051

Protein Data Bank. [Internet]; [сited 2022 May 11]. Available from: http://www.rcsb.org/pdb/home/home.-do

MarvinSketch version 20.20.0, ChemAxon. [Inter¬net]. Available from: http://www.chemaxon.com

Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-61. doi: https://doi.org/10.1002/jcc.21334

Discovery Studio Visualizer v19.1.018287. Accel-rys Software Inc., [Internet]. [сited 2022 May 11]. Avai-lable from: https://www.3dsbiovia.com.

ProTox-II – Prediction of toxicity of chemicals. [Internet]. [сited 2022 May 11]. Available from: https://tox-new.charite.de/protox_II/index.php?site=home.-do

European convention for the protection of ver-tebrate animal used for experimental and other scientific purposes. Council of Europe, Strasbourg; 1986.

Briukhanov VM, Zverev YuF, Lampatov VV, Zharikov AYu. [Methodological approaches to the study of kidney function in animal experiments]. Nefrolohiia. 2009;13(3):52-62.

Stefanov OV. [Preclinical studies of drugs]. Kyiv: Avitsena; 2001.

Lapach SN, Chubenko AV, Babich PN. [Statisti-cal methods in biomedical research using EXCEL]. Kyiv: Morion; 2000.

Kazunin M, Voskoboynik O, Nosulenko I, Be-rest G, Sergeieva T, Okovytyi S, et al. Synthesis, tauto-merism and antiradical activity of 1-methyl-6-(2-(aryl-(hetaryl-))-2-oxoethyl)pteridine-2,4,7(1H, 3H, 6H)-trio-nes. J. Heterocyclic Chem. 2018;4:1033-41. doi: https://doi.org/10.1002/jhet.3135

Kazunin M, Voskoboynik O, Nosulenko I, Be-rest G, Kholodnyak S, Pryшmenko B, Kovalenko S. Synthesis, antiradical and antimicrobial activity of new pteridine-2,4,7-trione derivatives. J. Heterocyclic Chem. 2019;1-13. doi: https://doi.org/10.1002/jhet.3774

Breitmaier E. Structure Elucidation by NMR in Organic Chemistry: A Practical Guide’, Eberhard Breit-maier, 3rd Revised Edition. Wiley; 2002. doi: https://doi.org/10.1002/0470853069

Carruthers W, Coldham I. Modern Methods of Organic Synthesis 4th edition, Cambridge University Press. 2004. doi: https://doi.org/10.1017/CBO9780511811494

Downloads

Published

2022-09-30

How to Cite

1.
Sokolova K, Stavytskyi V, Voskoboinik O, Podpletnya O, Kovalenko S. In silico and in vivo screening of triamterene synthetic analogues as promising diuretics. Med. perspekt. [Internet]. 2022Sep.30 [cited 2024Mar.29];27(3):4-15. Available from: https://journals.uran.ua/index.php/2307-0404/article/view/265739

Issue

Section

THEORETICAL MEDICINE