Bui Thi Buu Hue * , Vinh Quang Hong , Cuong Quoc Nguyen and Quang De Tran

* Corresponding author (btbhue@ctu.edu.vn)

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Five thioether-linked hydroxamate/quinazolinone hybrid structures were synthesized and tested for their anti-inflammatory activities. The obtained results indicated that compounds 7a-c and 7e showed the inhibition on LPS-stimulated NO production with the IC50 values ranging from 58.03 to 66.19 mM. Molecular docking results showed that all synthesized compounds displayed affinity towards the 5-LOX, MK2, P2Y12, 15-PGDH, and DNA polymerase receptors based on the observed low binding energies and interactions with the key amino acids in the binding sites of the enzymes. Noticeably, compound 7e exhibited as a potential compound targeting six receptors including 5-LOX, MK2, mPGES-1, P2Y12, 15-PGDH, and DNA polymerase receptors.

Keywords: Anti-inflammatory, hydroxamates, molecular hybrid, in silico screening, quinazolinone.

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Abdel, G. N. M., Georgey, H. H., Youssef, R. M., & El-Sayed, N. A. (2010). Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-ones and 4,6- disubstituted- 1,2,3,4-tetrahydroquinazolin-2H-ones. European Journal of Medicinal Chemistry, 45(12), 6058–6067. https://doi.org/10.1016/j.ejmech.2010.10.008

Aktan, F., Henness, S., Roufogalis, B. D., & Ammit, A. J. (2003). Gypenosides derived from Gynostemma pentaphyllum suppress NO synthesis in murine macrophages by inhibiting iNOS enzymatic activity and attenuating NF-κB-mediated iNOS protein expression. Nitric Oxide, 8(4), 235–242. https://doi.org/10.1016/S1089-8603(03)00032-6

Alagarsamy, V., Meena, S., Ramaseshu, K. V., Solomon, V. R., Kumar, T. D. A., & Thirumurugan, K. (2007). Synthesis of Novel 3-Butyl-2-Substituted Amino-3H-Quinazolin-4-ones as Analgesic and Anti-inflammatory Agents. Chemical Biology & Drug Design, 70(3), 254–260. https://doi.org/10.1111/j.1747-0285.2007.00548.x

Alderton, W. K., Cooper, c. e., & Knowles, R. G. (2001). Nitric oxide synthases: Structure, function and inhibition. Biochemical Journal, 357(3), 593–615. https://doi.org/10.1042/bj3570593

Archana, null, Srivastava, V. K., & Kumar, A. (2002). Synthesis of newer thiadiazolyl and thiazolidinonyl quinazolin-4 3H-ones as potential anticonvulsant agents. European Journal of Medicinal Chemistry, 37(11), 873–882. https://doi.org/10.1016/s0223-5234(02)01389-2

Bertrand, S., Helesbeux, J.-J., Larcher, G., & Duval, O. (2013). Hydroxamate, a Key Pharmacophore Exhibiting a Wide Range of Biological Activities. Mini Reviews in Medicinal Chemistry, 13(9), 1311–1326.

Bogdan, C. (2001). Nitric oxide and the immune response. Nature Immunology, 2(10), 907–916. https://doi.org/10.1038/ni1001-907

Bui, H. T. B., Nguyen, P. H., Pham, Q. M., Tran, H. P., Tran, D. Q., Jung, H., Hong, Q. V., Nguyen, Q. C., Nguyen, Q. P., Le, H. T., & Yang, S.-G. (2022). Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety. Molecules, 27(7), 2204. https://doi.org/10.3390/molecules27072204

Chaitanya, P., Deepak Reddy, G., Varun, G., Srikanth, L. M., Prasad, V. V. S. R., & Ravindernath, A. (2014). Design and Synthesis of Quinazolinone Derivatives as Anti-inflammatory Agents: Pharmacophore Modeling and 3D QSAR Studies. Medicinal Chemistry, 10(7), 711–723.

Chandrika, P. M., Yakaiah, T., Rao, A. R. R., Narsaiah, B., Reddy, N. C., Sridhar, V., & Rao, J. V. (2008). Synthesis of novel 4,6-disubstituted quinazoline derivatives, their anti-inflammatory and anti-cancer activity (cytotoxic) against U937 leukemia cell lines. European Journal of Medicinal Chemistry, 43(4), 846–852. https://doi.org/10.1016/j.ejmech.2007.06.010

Chen, W.-C., Yen, C.-S., Huang, W.-J., Hsu, Y.-F., Ou, G., & Hsu, M.-J. (2015). WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in LPS-stimulated RAW264.7 macrophages. British Journal of Pharmacology, 172(7), 1894–1908. https://doi.org/10.1111/bph.13040

Dawn, B., & Bolli, R. (2002). Role of Nitric Oxide in Myocardial Preconditioning. Annals of the New York Academy of Sciences, 962(1), 18–41. https://doi.org/10.1111/j.1749-6632.2002.tb04053.x

Dkhil, M. A., Kassab, R. B., Al-Quraishy, S., Abdel-Daim, M. M., Zrieq, R., & Abdel Moneim, A. E. (2018). Ziziphus spina-christi (L.) leaf extract alleviates myocardial and renal dysfunction associated with sepsis in mice. Biomedicine & Pharmacotherapy, 102, 64–75. https://doi.org/10.1016/j.biopha.2018.03.032

Du, B., & Liu, M. (2014). Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Science China Life Sciences, 57(6), 645–646. https://doi.org/10.1007/s11427-014-4659-5

Frisch, M., Trucks, G., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., & Petersson, Ga. (2009). gaussian 09, Revision d. 01, Gaussian. Inc., Wallingford CT, 201.

Gaestel, M. (2006). MAPKAP kinases—MKs—Two’s company, three’s a crowd. Nature Reviews Molecular Cell Biology, 7(2), 120–130. https://doi.org/10.1038/nrm1834

Georgey, H., Abdel-Gawad, N., & Abbas, S. (2008). Synthesis and Anticonvulsant Activity of Some Quinazolin-4-(3H)-one Derivatives. Molecules, 13(10), 2557–2569. https://doi.org/10.3390/molecules13102557

Hillig, R. C., Eberspaecher, U., Monteclaro, F., Huber, M., Nguyen, D., Mengel, A., Muller-Tiemann, B., & Egner, U. (2007). Structural Basis for a High Affinity Inhibitor Bound to Protein Kinase MK2. Journal of Molecular Biology, 369(3), 735–745. https://doi.org/10.1016/j.jmb.2007.03.004

Ishida, T., Mizushina, Y., Yagi, S., Irino, Y., Nishiumi, S., Miki, I., Kondo, Y., Mizuno, S., Yoshida, H., Azuma, T., & Yoshida, M. (2011). Inhibitory Effects of Glycyrrhetinic Acid on DNA Polymerase and Inflammatory Activities. Evidence-Based Complementary and Alternative Medicine, 2012, e650514. https://doi.org/10.1155/2012/650514

Kerru, N., Singh, P., Koorbanally, N., Raj, R., & Kumar, V. (2017). Recent advances (2015–2016) in anticancer hybrids. European Journal of Medicinal Chemistry, 142, 179–212. https://doi.org/10.1016/j.ejmech.2017.07.033

Kotlyarov, A., Neininger, A., Schubert, C., Eckert, R., Birchmeier, C., Volk, H.-D., & Gaestel, M. (1999). MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis. Nature Cell Biology, 1(2), 94–97. https://doi.org/10.1038/10061

Kramer, B., Rarey, M., & Lengauer, T. (1999). Evaluation of the FLEXX incremental construction algorithm for protein–ligand docking. Proteins: Structure, Function, and Bioinformatics, 37(2), 228–241. https://doi.org/10.1002/(SICI)1097-0134(19991101)37:2<228::AID-PROT8>3.0.CO;2-8

Kröncke, K.-D., Fehsel, K., & Kolb-Bachofen, V. (1998). Inducible nitric oxide synthase in human diseases. Clinical and Experimental Immunology, 113(2), 147–156. https://doi.org/10.1046/j.1365-2249.1998.00648.x

Kügelgen, I. V., & Wetter, A. (2000). Molecular pharmacology of P2Y-receptors. Naunyn-Schmiedeberg’s Archives of Pharmacology, 362(4), 310–323. https://doi.org/10.1007/s002100000310

Kühn, H., & O’Donnell, V. B. (2006). Inflammation and immune regulation by 12/15-lipoxygenases. Progress in Lipid Research, 45(4), 334–356. https://doi.org/10.1016/j.plipres.2006.02.003

Kuyper, L. F., Baccanari, D. P., Jones, M. L., Hunter, R. N., Tansik, R. L., Joyner, S. S., Boytos, C. M., Rudolph, S. K., Knick, V., Wilson, H. R., Caddell, J. M., Friedman, H. S., Comley, J. C. W., & Stables, J. N. (1996). High-Affinity Inhibitors of Dihydrofolate Reductase: Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with Small Molecular Size. Journal of Medicinal Chemistry, 39(4), 892–903. https://doi.org/10.1021/jm9505122

Moilanen, E. (2014). Two Faces of Inflammation: An Immunopharmacological View. Basic & Clinical Pharmacology & Toxicology, 114(1), 2–6. https://doi.org/10.1111/bcpt.12180

Moncada, S., & Higgs, E. A. (1991). Endogenous nitric oxide: Physiology, pathology and clinical relevance. European Journal of Clinical Investigation, 21(4), 361–374. https://doi.org/10.1111/j.1365-2362.1991.tb01383.x

Niesen, F. H., Schultz, L., Jadhav, A., Bhatia, C., Guo, K., Maloney, D. J., Pilka, E. S., Wang, M., Oppermann, U., Heightman, T. D., & Simeonov, A. (2010). High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships. PLOS ONE, 5(11), e13719. https://doi.org/10.1371/journal.pone.0013719

Nwet N. W., Besse H., Hla N., Yoshihiro H. and Hiroyuki M. (2020). Anti‐infammatory activities of isopimara‐8(9),15‐diene diterpenoids and mode of action of kaempulchraols B–D from Kaempferia pulchra rhizomes. Journal of Natural Medicines, 74:487–494.

Osipov, V. N., Khachatryan, D. S., & Balaev, A. N. (2020). Biologically active quinazoline-based hydroxamic acids. Medicinal Chemistry Research, 29(5), 831–845. https://doi.org/10.1007/s00044-020-02530-7

Partridge, K. M., Antonysamy, S., Bhattachar, S. N., Chandrasekhar, S., Fisher, M. J., Fretland, A., Gooding, K., Harvey, A., Hughes, N. E., Kuklish, S. L., Luz, J. G., Manninen, P. R., McGee, J. E., Mudra, D. R., Navarro, A., Norman, B. H., Quimby, S. J., Schiffler, M. A., Sloan, A. V., … Yu, X.-P. (2017). Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1. Bioorganic & Medicinal Chemistry Letters, 27(6), 1478–1483. https://doi.org/10.1016/j.bmcl.2016.11.011

Rajput, C. S., & Singhal, S. (2013). Synthesis, Characterization, and Anti-Inflammatory Activity of Newer Quinazolinone Analogs. Journal of Pharmaceutics, 2013, e907525. https://doi.org/10.1155/2013/907525

Samuelsson, B., Morgenstern, R., & Jakobsson, P.-J. (2007). Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target. Pharmacological Reviews, 59(3), 207–224. https://doi.org/10.1124/pr.59.3.1

Smith, W. L., DeWitt, D. L., & Garavito, R. M. (2000). Cyclooxygenases: Structural, Cellular, and Molecular Biology. Annual Review of Biochemistry, 69(1), 145–182. https://doi.org/10.1146/annurev.biochem.69.1.145

Srivastava, P., Vyas, V. K., Variya, B., Patel, P., Qureshi, G., & Ghate, M. (2016). Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives. Bioorganic chemistry, 67, 130-138.

Tai, H.-H., Chi, X., & Tong, M. (2011). Regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins & Other Lipid Mediators, 96(1), 37–40. https://doi.org/10.1016/j.prostaglandins.2011.06.005

Vane, J. R., Bakhle, Y. S., & Botting, R. M. (1998). Cyclooxygenases 1 and 2. Annual Review of Pharmacology and Toxicology, 38(1), 97–120. https://doi.org/10.1146/annurev.pharmtox.38.1.97

Verhaeghe, P., Azas, N., Gasquet, M., Hutter, S., Ducros, C., Laget, M., Rault, S., Rathelot, P., & Vanelle, P. (2008). Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethylquinazolines. Bioorganic & Medicinal Chemistry Letters, 18(1), 396–401. https://doi.org/10.1016/j.bmcl.2007.10.027

Wdowiak, P., Matysiak, J., Kuszta, P., Czarnek, K., Niezabitowska, E., & Baj, T. (2021). Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy. Frontiers in Chemistry, 9, 765552. https://doi.org/10.3389/fchem.2021.765552

Yang, Z., Wang, T., Wang, F., Niu, T., Liu, Z., Chen, X., Long, C., Tang, M., Cao, D., Wang, X., Xiang, W., Yi, Y., Ma, L., You, J., & Chen, L. (2016). Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer. Journal of Medicinal Chemistry, 59(4), 1455–1470. https://doi.org/10.1021/acs.jmedchem.5b01342

Yin, Z., Wang, Y., Whittell, L. R., Jergic, S., Liu, M., Harry, E., Dixon, N. E., Kelso, M. J., Beck, J. L., & Oakley, A. J. (2014). DNA Replication Is the Target for the Antibacterial Effects of Nonsteroidal Anti-Inflammatory Drugs. Chemistry & Biology, 21(4), 481–487. https://doi.org/10.1016/j.chembiol.2014.02.009

Yu, C.-W., Chang, P.-T., Hsin, L.-W., & Chern, J.-W. (2013). Quinazolin-4-one Derivatives as Selective Histone Deacetylase-6 Inhibitors for the Treatment of Alzheimer’s Disease. Journal of Medicinal Chemistry, 56(17), 6775–6791. https://doi.org/10.1021/jm400564j

Zhang, K., Zhang, J., Gao, Z.-G., Zhang, D., Zhu, L., Han, G. W., Moss, S. M., Paoletta, S., Kiselev, E., Lu, W., Fenalti, G., Zhang, W., Müller, C. E., Yang, H., Jiang, H., Cherezov, V., Katritch, V., Jacobson, K. A., Stevens, R. C., … Zhao, Q. (2014). Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature, 509(7498), 115–118. https://doi.org/10.1038/nature13083

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