MW Assisted Synthesis of New 4,6-diaryl-3,4-Didhydropyrimidines-2(1H)-thione Derivatives: Tyrosinase Inhibition, Antioxidant, and Molecular Docking Studies

Seda Fandaklı; Tayyibe Beyza Yücel; Elif Öztürk; Uğur Uzuner; Burak Barut; Fatih Mehmet Ateş; Nurettin Yaylı

doi:10.17776/csj.1299843

Research Article

MW Assisted Synthesis of New 4,6-diaryl-3,4-Didhydropyrimidines-2(1H)-thione Derivatives: Tyrosinase Inhibition, Antioxidant, and Molecular Docking Studies

Year 2023, , 687 - 696, 28.12.2023

Seda Fandaklı , Tayyibe Beyza Yücel , Elif Öztürk , Uğur Uzuner , Burak Barut , Fatih Mehmet Ateş , Nurettin Yaylı

https://doi.org/10.17776/csj.1299843

Abstract

A number of new methoxy-substituted 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thiones (DH-Pyr-S, 17-28) were designed and synthesized by the reaction of methoxy-substituted chalcones (1–14) with thiourea using solid-phase microwave method (MW) in view of the structural requirements as suggested in the pharmacophore model for tyrosinase inhibition (TI). Synthesized compounds were assessed for their in vitro TI potential and compounds 16, 17, and 21 exhibited notable tyrosinase inhibitory properties at the concentrations of 31.86 ± 2.45 µM, 44.58 ± 0.46 µM, and 48.47 ± 0.66 µM, respectively. Compounds (16, 17, and 21) were exhibited experimentally more potent TI than the standard used in terms of the IC50 value (Kojic acid, 55.38 ± 2.30 µM; p<0.0001). Additionally, DPPH activity of 15-28 were evaluated and compound 17 showed the moderate DPPH activity (45.64 ± 0.34%). Binding affinities of synthesized molecules to the tyrosinase catalytic core were further investigated through in silico molecular docking studies using AutoDock Vina (version 1.2.5), discovery studio accelyrs (BIOVIA, Dassault Systèmes) and predicting small-molecule pharmacokinetic properties using graph-based signatures (pkCSM) programs were used for ADMET calculations. Among synthesized compounds 15, 21, and 24 revealed high binding affinity to tyrosinase active site with lowest binding free energy (ΔG) values of -7.9 kcal/mol, thereby outperformed kojic acid affinity. In conclusion most modeling results were in agreement with their experimental data, suggesting the TI potential of lead compounds.

Keywords

Molecular docking, Dihydropyrimidine-2(1H)-thione, Tyrosinase inhibition, DPPH, ADMET

Supporting Institution

Karadeniz Teknik Üniversitesi

Project Number

KTU-BAP-02 FHD5395

Thanks

References

[1] Kabir E., Uzzaman M., A review on biological and medicinal impact of heterocyclic compounds, Result in Chemistry., 4 (2022) 100666.
[2] Lagoja I.M., Pyrimidine as constituent of natural biologically active compounds, Chem. Biodivers., 2(1) (2005) 1-50.
[3] Borge V.V., Vaze J.A., A comprehensive study of pyrimidine and its medicinal applications, Heterocycles. 104(3) 2022 431-445.
[4] Wang M., Song L.E., Zhao S., Wan X, Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones using Sodium Bisulfate as a Catalyst under Solvent-free Conditions, Org Prep Proced Int., 46 (2014) 457-462.
[5] Su, G., Formica, M., Yamazaki, K., Hamlin, T. A., & Dixon, D. J., Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α, β-Unsaturated Esters and Amides, J. Am. Chem. Soc., 145 (23) (2023) 12771–12782.
[6] Sunduru N., Nishi P., Chauhan P.M.S., Gupta S., Synthesis and antileishmanial activity of novel 2,4,6-trisubstituted pyrimidines and 1,3,5-triazines, Eur. J. Med. Chem., 44 (2009) 2473-2481.
[7] El-Naggar A.M., Hassan A.M.A., Elkaeed E.B., Alesawy M.S., Al-Karmalawy A.A., Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2, Bioorg. Chem., 123 (2022) 105770.
[8] Aghayan-Mirza M., Moradi A., Bolourtchion M., Cheap and efficient Protocol for the Synthesis of Tetrahydroguinazolinone, Dihydro pyrimidinone and Pyrimidinone and Pyrimidinone Derivatives, Synth. Commun., 40 (1) (2011) 8-20.
[9] Kaur R., Chaudhary S., Kumar K., Gupta M.K., Rawal R.K., Recent synthetic and medicinal perspectives of dihydropyrimidinones: A review, Eur. J. Med. Chem., 132 (2017) 108-134.
[10] Nazir Y., Rafique H., Kausar N., Abbas Q., Ashraf Z., Rachtanapun P., Jantanasakulwong K., Ruksiriwanich W., Methoxy-substituted tyramine derivatives synthesis, computational studies and tyrosinase inhibitory kinetics, Molecules., 26 (9) (2021) 2477-2482.
[11] Obaid R.J., Mughal E.U., Naeem N., Sadiq A., Alsantali R.I., Jassas R.S., Moussa Z., Ahmed S.A., Natural and synthetic flavonoid derivatives as new potential tyrosinase inhibitors: A systematic review, RSC Adv.,11 (36) (2021) 22159-22198.
[12] Liu P., Shu C., Liu L., Huang Q., Peng Y., Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors, Bioorg. Med. Chem., 24 (8) (2016)1866-1871.
[13] Lam K.W., Syahida A., Ul-Haq Z., Rahman M.B.A., Lajis N.H., Synthesis and biological activity of oxadiazole and triazolothiadiazole derivatives as tyrosinase inhibitors, Bioorg. Med.Chem. Lett., 20 (12) (2010) 3755-3759.
[14] Desta D., Sjoholm R., Lee L., Lee M., Dittenhafer K., Chanche S., Babu B., Chavda S., Dewar C., Yanow S., Best A.A., Lee M., Thiocarbohydrazone and chalcone-derived 3, 4-dihydropyrimidinethione as lipid peroxidation and soybean lipoxygenase inhibitors, Med Chem. Res., 20 (2011) 364-369.
[15] Upadhyay A., Gopal M., Srivastava C., Pandey N.D., Synthesis and insecticidal activity of 3, 4-dihydropyrimidine-2 (1H)-thiones against the pulse beetle, Callosobruchus chinensis, J. Pestic. Sci., 36(4) (2011) 467-472.
[16] Olsson M.H.M., Søndergaard C.R., Rostkowski M., Jensen J.N., PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pKa Predictions, J. Chem. Theory Comput. 7 (2011) 525-537.
[17] Søndergaard C.R., Olsson M.H.M., Rostkowski M., Jensen J.N., Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of pKa Values, J. Chem. Theory Comput. 7 (2011) 2284-95.
[18] Boyle N.M., Banck M., James C.A., Morley C., Vandermeersch T., Hutchison G.R., Open Babel: An open chemical toolbox, J. Cheminformatics. 3 (2011) 2-14.
[19] Albay C., Kahriman N., Iskender N.Y., Karaoglu Ş.A., Yaylı N., Synthesis and antimicrobial activity of methoxy azachalcones and N-alkyl substituted methoxy azachalconium bromides, Turk. J. Chem., 35(3) (2011) 441-454.
[20] Yaylı N., Küçük M., Üçüncü O., Yaşar A., Yaylı N., Karaoglu Ş.A., Synthesis of methyl (E)-2', 4''-thiazachalcones and their N-alkyl derivatives, photochemistry with theoretical calculations and antimicrobial activities, J. Photchem. and Photobio. A: Chem., 188 (2007) 161-168.
[21] Şöhretoğlu D., Bakır S.D., Barut B., Soral M., Sarı S., Multiple biological effects of secondary metabolites of Ziziphus jujuba: isolation and mechanistic insights through in vitro and in silico studies, Eur. Food Res. Technol., 248(4) (2022) 1059-1067.
[22] Yaylı N., Kılıç G., Kahriman N., Kanbolat Ş., Bozdeveci A., Karaoğlu Ş.A., Aliyazıcıoğlu R., Sellitepe H.E., Doğan İ. S., Aydın A., Tatar G., Synthesis, biological evaluation (antioxidant, antimicrobial, enzyme inhibition, and cytotoxic) and molecular docking study of hydroxy methoxy benzoin/benzil analogous, Bioorg. Chem., 115 (2021) 105183.
[23] Lee L., Davis R., Vanderham J., Hills P., Mackay H., Brown T., Mooberry S.L., Lee M., Synthesis and antiprotozoal activity of 1, 2, 3, 4-tetrahydro-2-thioxopyrimidine analogs of combretastatin A-4, Eur. J. Med. Chem., 43 (2008) 2011-2015.
[24] Sondhi S.M., Goyal R.N., Lahoti A.M., Singh N., Shukla R., Raghubir R., Synthesis, and biological evaluation of 2-thiopyrimidine derivatives, Bioorg. Med. Chem. 2005 13 (2005)3185-3195.
[25] Lakshmi H.V., Kumar K.R., Shaik A.B., Synthesis, characterization, and biological evaluation of 3, 4-dihydropyrimidin-2 (1H)-thione derivatives, Arch. Appl. Sci. Res. 6(6) (2014)121-127.
[26] Dinakaran V.S., Jacob D., Mathew J.E., Synthesis and biological evaluation of novel pyrimidine-2(1H)-ones/thiones as potent anti-inflammatory and anticancer agents, Med. Chem. Res., 21(11) (2012) 3598-3606.
[27] Rao C.M.M.P., Rajeswari T., Parmender K., Yadav S.K., Synthesis, characterization, anti-microbial and antioxidant activity of novel dihydropyrimidines, Asian J. Pharm. Anal. 10(1) (2022) 21-28.
[28] Mahmoud N.F.H., Ghareeb E.A., Synthesis of novel substituted tetrahydropyrimidine derivatives and evaluation of their pharmacological and antimicrobial activities, J. Heterocycl. Chem., 56(1) (2019) 81-91.
[29] Gondrui R., Peddi S.R., Manga V., Khanapur M., Gali R., Sirassu N., Bavantula R., One-pot synthesis, biological evaluation and molecular docking studies of fused thiazolo[2,3-b]pyrimidinone-pyrazolylcoumarin hybrids, Mol. Divers., 2018 22(4) (2018) 943-956.