Design and Synthesis of New Pyrimidine-Quinolone Hybrids As Novel LDHA Inhibitors

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2022 Jul 27

PMID 35890090

Authors

Ivan Diaz

Sofia Salido

Manuel Nogueras

Justo Cobo

Affiliations

Soon will be listed here.

Abstract

A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (hLDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (10-21 and 24−31) were studied in silico, and those with the 2-aminophenylsulfide (U-shaped) and 4-aminophenylsulfide linkers (24−31) were finally selected. These new pyrimidine-quinolone hybrids (24−31)(a−c) were easily synthesized in good to excellent yields by a green catalyst-free microwave-assisted aromatic nucleophilic substitution reaction between 3-(((2/4-aminophenyl)thio)methyl)quinolin-2(1H)-ones 22/23(a−c) and 4-aryl-2-chloropyrimidines (1−4). The inhibitory activity against hLDHA of the synthesized hybrids was evaluated, resulting IC50 values of the U-shaped hybrids 24−27(a−c) much better than the ones of the 1,4-linked hybrids 28−31(a−c). From these results, a preliminary structure−activity relationship (SAR) was established, which enabled the design of novel 1,3-linked pyrimidine-quinolone hybrids (33−36)(a−c). Compounds 35(a−c), the most promising ones, were synthesized and evaluated, fitting the experimental results with the predictions from docking analysis. In this way, we obtained novel pyrimidine-quinolone hybrids (25a, 25b, and 35a) with good IC50 values (<20 μM) and developed a preliminary SAR.

Citing Articles

Synthesis and LDHA Inhibitory Activity of New Stiripentol-Related Compounds of Potential Use in Primary Hyperoxaluria.

Rico-Molina M, Ortega-Vidal J, Molina-Canteras J, Cobo J, Altarejos J, Salido S Int J Mol Sci. 2025; 25(24.

PMID: 39769031 PMC: 11675970. DOI: 10.3390/ijms252413266.

Tracking Selective Internalization and Intracellular Dynamics of Modified Chitosan Polymeric Micelles of Interest in Primary Hyperoxaluria Diseases.

Fernandez-Mimbrera M, Salido S, Marchal J, Alejo-Armijo A ACS Omega. 2024; 9(38):39503-39512.

PMID: 39346832 PMC: 11425826. DOI: 10.1021/acsomega.4c03415.

Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors.

Diaz I, Salido S, Nogueras M, Cobo J Int J Mol Sci. 2024; 25(17).

PMID: 39273691 PMC: 11396203. DOI: 10.3390/ijms25179744.

Synthesis and LDH Inhibitory Activity of Analogues to Natural Products with 2,8-Dioxabicyclo[3.3.1]nonane Scaffold.

Salido S, Alejo-Armijo A, Altarejos J Int J Mol Sci. 2023; 24(12).

PMID: 37373073 PMC: 10298284. DOI: 10.3390/ijms24129925.

References

Zhang S, He Y, Tam K . Targeting cancer metabolism to develop human lactate dehydrogenase (hLDH)5 inhibitors. Drug Discov Today. 2018; 23(7):1407-1415. DOI: 10.1016/j.drudis.2018.05.014. View

Dindo M, Conter C, Oppici E, Ceccarelli V, Marinucci L, Cellini B . Molecular basis of primary hyperoxaluria: clues to innovative treatments. Urolithiasis. 2018; 47(1):67-78. DOI: 10.1007/s00240-018-1089-z. View

Vandekerckhove S, Dhooghe M . Quinoline-based antimalarial hybrid compounds. Bioorg Med Chem. 2015; 23(16):5098-119. DOI: 10.1016/j.bmc.2014.12.018. View

Song R, Wang Y, Wang M, Gao R, Yang T, Yang S . Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity. Bioorg Chem. 2020; 103:104176. DOI: 10.1016/j.bioorg.2020.104176. View

Kaur H, Balzarini J, de Kock C, Smith P, Chibale K, Singh K . Synthesis, antiplasmodial activity and mechanistic studies of pyrimidine-5-carbonitrile and quinoline hybrids. Eur J Med Chem. 2015; 101:52-62. DOI: 10.1016/j.ejmech.2015.06.024. View

Wagman A, Boyce R, Brown S, Fang E, Goff D, Jansen J . Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3. J Med Chem. 2017; 60(20):8482-8514. DOI: 10.1021/acs.jmedchem.7b00922. View

Almaaty A, Elgrahy N, Fayad E, Abu Ali O, Mahdy A, Barakat L . Design, Synthesis and Anticancer Evaluation of Substituted Cinnamic Acid Bearing 2-Quinolone Hybrid Derivatives. Molecules. 2021; 26(16). PMC: 8400797. DOI: 10.3390/molecules26164724. View

Goto J, Kataoka R, Hirayama N . Ph4Dock: pharmacophore-based protein-ligand docking. J Med Chem. 2004; 47(27):6804-11. DOI: 10.1021/jm0493818. View

Singh K, Kaur H, Smith P, de Kock C, Chibale K, Balzarini J . Quinoline-pyrimidine hybrids: synthesis, antiplasmodial activity, SAR, and mode of action studies. J Med Chem. 2013; 57(2):435-48. DOI: 10.1021/jm4014778. View

10.

Wang S, Yuan X, Wang S, Zhao W, Chen X, Yu B . FDA-approved pyrimidine-fused bicyclic heterocycles for cancer therapy: Synthesis and clinical application. Eur J Med Chem. 2021; 214:113218. DOI: 10.1016/j.ejmech.2021.113218. View

11.

Pretorius S, Breytenbach W, de Kock C, Smith P, NDa D . Synthesis, characterization and antimalarial activity of quinoline-pyrimidine hybrids. Bioorg Med Chem. 2012; 21(1):269-77. DOI: 10.1016/j.bmc.2012.10.019. View

12.

Viegas-Junior C, Danuello A, da Silva Bolzani V, Barreiro E, Fraga C . Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem. 2007; 14(17):1829-52. DOI: 10.2174/092986707781058805. View

13.

Zhang X, Li D, Fan X, Wang X, Li X, Qu G . Ionic liquid-promoted multi-component reaction: novel and efficient preparation of pyrazolo[3,4-b]pyridinone, pyrazolo[3,4-b]-quinolinone and their hybrids with pyrimidine nucleoside. Mol Divers. 2009; 14(1):159-67. DOI: 10.1007/s11030-009-9168-2. View

14.

Li X, Xiao W, Zhao H . Discovery of potent human lactate dehydrogenase A (LDHA) inhibitors with antiproliferative activity against lung cancer cells: virtual screening and biological evaluation. Medchemcomm. 2018; 8(3):599-605. PMC: 6072527. DOI: 10.1039/c6md00670a. View

15.

Granchi C, Paterni I, Rani R, Minutolo F . Small-molecule inhibitors of human LDH5. Future Med Chem. 2013; 5(16):1967-91. PMC: 3952072. DOI: 10.4155/fmc.13.151. View

16.

Madia V, Nicolai A, Messore A, De Leo A, Ialongo D, Tudino V . Design, Synthesis and Biological Evaluation of New Pyrimidine Derivatives as Anticancer Agents. Molecules. 2021; 26(3). PMC: 7867324. DOI: 10.3390/molecules26030771. View

17.

Doak B, Norton R, Scanlon M . The ways and means of fragment-based drug design. Pharmacol Ther. 2016; 167:28-37. DOI: 10.1016/j.pharmthera.2016.07.003. View

18.

Kumar A, Voet A, Zhang K . Fragment based drug design: from experimental to computational approaches. Curr Med Chem. 2012; 19(30):5128-47. DOI: 10.2174/092986712803530467. View

19.

Mahmoud T, Ghandour E, Jaar B . A hidden cause of oxalate nephropathy: a case report. J Med Case Rep. 2021; 15(1):106. PMC: 7938566. DOI: 10.1186/s13256-021-02732-6. View

20.

Pineda J, Callender R, Schwartz S . Ligand binding and protein dynamics in lactate dehydrogenase. Biophys J. 2007; 93(5):1474-83. PMC: 1948035. DOI: 10.1529/biophysj.107.106146. View