Pharmacochemical Study of Multitarget Amino Acids’ Hybrids: Design,
Synthesis, In vitro, and In silico Studies

Ioannis      Fotopoulos; Eleni      Pontiki; Dimitra      Hadjipavlou-Litina

doi:10.2174/0115734064279653240125081042

Abstract

Introduction: Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5, COX-2, pro-inflammatory enzymes, and amino acid neurotransmitters are tightly correlated to neuro-inflammatory pathologies. Developing drugs that interfere with these targets will offer treatment for various diseases.

Objective: Herein, we extend our previous research by synthesizing a series of multitarget hybrids of cinnamic acids with amino acids recognized as neurotransmitters.

Methods: The synthesis was based on an In silico study of a library of cinnamic amide hybrids with glycine, γ- aminobutyric, and L - glutamic acids. Drug-likeness and ADMET properties were subjected to In silico analysis. Cinnamic acids were derived from the corresponding aldehydes by Knoevenagel condensation. The synthesis of the amides followed a two-step reaction with 1- hydroxybenzotriazole monohydrate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dry dichloromethane and the corresponding amino acid ester hydrochloride salt in the presence of N,N,-diisopropyl-Nethylamine.

Results: The structure of the synthesized compounds was confirmed spectrophotometrically. The new compounds, such as lipoxygenase, cyclooxygenase-2, lipid peroxidation inhibitors, and antiinflammatories, were tested in vitro. The compounds exhibited LOX inhibition with IC₅₀ values in the low μM region).

Conclusion: Compounds 18a, 23b, and 11c are strong lipid peroxidation inhibitors (99%, 78%, and 92%). Compound 28c inhibits SLOX-1 with IC₅₀ =8.5 μM whereas 11a and 22a highly inhibit COX-2 (IC₅₀ 6 and 5 μM Hybrids 14c and 17c inhibit both enzymes. Compound 29c showed the highest anti-inflammatory activity (75%). The In silico ADMET properties of 14c and 11a support their drug-likeness.

Keywords: Multitarget, amino acids, hybrids, inflammation, cyclooxygenase inhibitors, lipoxygenase inhibitors, Alzheimer’s disease, neuro-inflammation.

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Graphical Abstract

[1]
Manev, H. 5-Lipoxygenase gene polymorphism and onset of Alzheimer’s disease. Med. Hypotheses,  2000, 54(1), 75-76.
 [http://dx.doi.org/10.1054/mehy.1998.0824] [PMID: 10790729]

[2]
Manev, H.; Manev, R. 5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer’s disease. Med. Hypotheses,  2006, 66(3), 501-503.
 [http://dx.doi.org/10.1016/j.mehy.2005.09.031] [PMID: 16278051]

[3]
Qu, T.; Manev, R.; Manev, H. 5-Lipoxygenase (5-LOX) promoter polymorphism in patients with early-onset and late-onset Alzheimer’s disease. J. Neuropsychiatry Clin. Neurosci.,  2001, 13(2), 304-305.
 [http://dx.doi.org/10.1176/jnp.13.2.304] [PMID: 11449041]

[4]
Giannopoulos, P.F.; Joshi, Y.B.; Praticò, D. Novel lipid signaling pathways in Alzheimer’s disease pathogenesis. Biochem. Pharmacol.,  2014, 88(4), 560-564.
 [http://dx.doi.org/10.1016/j.bcp.2013.11.005] [PMID: 24269629]

[5]
Chainoglou, E.; Siskos, A.; Pontiki, E.; Hadjipavlou-Litina, D. Hybridization of curcumin analogues with cinnamic acid derivatives as multi-target agents against alzheimer’s disease targets. Molecules,  2020, 25(21), 4958.
 [http://dx.doi.org/10.3390/molecules25214958] [PMID: 33114751]

[6]
Chu, J.; Giannopoulos, P.F.; Ceballos-Diaz, C.; Golde, T.E.; Praticò, D. 5‐Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of alzheimer disease. Ann. Neurol.,  2012, 72(3), 442-454.
 [http://dx.doi.org/10.1002/ana.23642] [PMID: 23034916]

[7]
Kang, K.H.; Liou, H.H.; Hour, M.J.; Liou, H.C.; Fu, W.M. Protection of dopaminergic neurons by 5-lipoxygenase inhibitor. Neuropharmacology,  2013, 73, 380-387.
 [http://dx.doi.org/10.1016/j.neuropharm.2013.06.014] [PMID: 23800665]

[8]
Mitchell, J.A.; Kirkby, N.S. Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system. Br. J. Pharmacol.,  2019, 176(8), 1038-1050.
 [http://dx.doi.org/10.1111/bph.14167] [PMID: 29468666]

[9]
Clària, J. Cyclooxygenase-2 biology. Curr. Pharm. Des.,  2003, 9(27), 2177-2190.
 [http://dx.doi.org/10.2174/1381612033454054] [PMID: 14529398]

[10]
Kumar, A.; Behl, T.; Jamwal, S.; Kaur, I.; Sood, A.; Kumar, P. Exploring the molecular approach of COX and LOX in Alzheimer’s and Parkinson’s disorder. Mol. Biol. Rep.,  2020, 47(12), 9895-9912.
 [http://dx.doi.org/10.1007/s11033-020-06033-x] [PMID: 33263931]

[11]
Bezzi, P.; Domercq, M.; Brambilla, L.; Galli, R.; Schols, D.; De Clercq, E.; Vescovi, A.; Bagetta, G.; Kollias, G.; Meldolesi, J.; Volterra, A. CXCR4-activated astrocyte glutamate release via TNFα: Amplification by microglia triggers neurotoxicity. Nat. Neurosci.,  2001, 4(7), 702-710.
 [http://dx.doi.org/10.1038/89490] [PMID: 11426226]

[12]
Sarasa, S.B.; Mahendran, R.; Muthusamy, G.; Thankappan, B.; Selta, D.R.F.; Angayarkanni, J. A brief review on the non-protein amino acid, gamma-amino butyric acid (GABA): Its production and role in microbes. Curr. Microbiol.,  2020, 77(4), 534-544.
 [http://dx.doi.org/10.1007/s00284-019-01839-w] [PMID: 31844936]

[13]
Cioffi, C.L. Modulation of glycine-mediated spinal neurotransmission for the treatment of chronic pain. J. Med. Chem.,  2018, 61(7), 2652-2679.
 [http://dx.doi.org/10.1021/acs.jmedchem.7b00956] [PMID: 28876062]

[14]
Stroebel, D.; Mony, L.; Paoletti, P. Glycine agonism in ionotropic glutamate receptors. Neuropharmacology,  2021, 193, 108631.
 [http://dx.doi.org/10.1016/j.neuropharm.2021.108631] [PMID: 34058193]

[15]
Chatterton, J.E.; Awobuluyi, M.; Premkumar, L.S.; Takahashi, H.; Talantova, M.; Shin, Y.; Cui, J.; Tu, S.; Sevarino, K.A.; Nakanishi, N.; Tong, G.; Lipton, S.A.; Zhang, D. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature,  2002, 415(6873), 793-798.
 [http://dx.doi.org/10.1038/nature715] [PMID: 11823786]

[16]
Yao, Y.; Mayer, M.L. Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A. J. Neurosci.,  2006, 26(17), 4559.
 [http://dx.doi.org/10.1523/JNEUROSCI.0560-06.2006]

[17]
Yao, Y.; Harrison, C.B.; Freddolino, P.L.; Schulten, K.; Mayer, M.L. Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors. EMBO J.,  2008, 27(15), 2158-2170.
 [http://dx.doi.org/10.1038/emboj.2008.140]

[18]
Pham, T.V.; Hoang, H.N.T.; Nguyen, H.T.; Nguyen, H.M.; Huynh, C.T.; Vu, T.Y.; Do, A.T.; Nguyen, N.H.; Do, B.H. Anti-inflammatory and antimicrobial activities of compounds isolated from distichochlamys benenica. BioMed Res. Int.,  2021, 2021, 1-10.
 [http://dx.doi.org/10.1155/2021/6624347] [PMID: 33880371]

[19]
Jachak, G.G.A. Natural product inhibitors of Cyclooxygenase (COX) enzyme: A review on current status and future perspectives. Curr. Med. Chem.,  2021, 28(10), 1877-1905.

[20]
Szwajgier, D.; Borowiec, K.; Pustelniak, K. The neuroprotective effects of phenolic acids: Molecular mechanism of action. Nutrients,  2017, 9(5), 477.
 [http://dx.doi.org/10.3390/nu9050477] [PMID: 28489058]

[21]
Fotopoulos, I.; Pontiki, E.; Litina, H.D. Targeting inflammation with conjugated cinnamic amides, ethers and esters. Lett. Drug Des. Discov.,  2020, 17, 3-11.

[22]
Peperidou, A.; Bua, S.; Bozdag, M.; Hadjipavlou-Litina, D.; Supuran, C. Novel 6- and 7-substituted coumarins with inhibitory action against lipoxygenase and tumor-associated carbonic anhydrase IX. Molecules,  2018, 23(1), 153.
 [http://dx.doi.org/10.3390/molecules23010153] [PMID: 29329232]

[23]
Pontiki, E.; Peperidou, A.; Fotopoulos, I.; Hadjipavlou-Litina, D. Cinnamate hybrids: A unique family of compounds with multiple biological activities. Curr. Pharm. Biotechnol.,  2019, 19(13), 1019-1048.
 [http://dx.doi.org/10.2174/1389201019666181112102702] [PMID: 30417783]

[24]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera-A visualization system for exploratory research and analysis. J. Comput. Chem.,  2004, 25(13), 1605-1612.
 [http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]

[25]
Fiser, A.; Šali, A.B.T-M. Modeller: Generation and refinement of homology-based protein structure models. Methods Enzymol.,  2003, 374, 461-491.
 [http://dx.doi.org/10.1016/S0076-6879(03)74020-8]

[26]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform.,  2011, 3(1), 33.
 [http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]

[27]
Halgren, T.A. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem.,  1996, 17(5-6), 490-519.
 [http://dx.doi.org/10.1002/(SICI)1096-987X(199604)17:5/6<490:AID-JCC1>3.0.CO;2-P]

[28]
Sousa da Silva, A.W.; Vranken, W.F. ACPYPE - AnteChamber PYthon Parser interfacE. BMC Res. Notes,  2012, 5(1), 367.
 [http://dx.doi.org/10.1186/1756-0500-5-367] [PMID: 22824207]

[29]
Wang, J.; Wang, W.; Kollman, P.A.; Case, D.A. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model.,  2006, 25(2), 247-260.
 [http://dx.doi.org/10.1016/j.jmgm.2005.12.005] [PMID: 16458552]

[30]
Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput.,  2008, 4(3), 435-447.
 [http://dx.doi.org/10.1021/ct700301q] [PMID: 26620784]

[31]
Lindorff-Larsen, K.; Piana, S.; Palmo, K.; Maragakis, P.; Klepeis, J.L.; Dror, R.O.; Shaw, D.E. Improved side‐chain torsion potentials for the Amber ff99SB protein force field. Proteins,  2010, 78(8), 1950-1958.
 [http://dx.doi.org/10.1002/prot.22711] [PMID: 20408171]

[32]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem.,  2010, 31(2), 455-461.
 [http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]

[33]
Molinspiration.  Available from: 
          https://www.molinspiration.com/ (Cited 2021 Jun 14).

[34]
Liu, H.; Sun, D.; Du, H.; Zheng, C.; Li, J.; Piao, H.; Li, J.; Sun, L. Synthesis and biological evaluation of tryptophan-derived rhodanine derivatives as PTP1B inhibitors and anti-bacterial agents. Eur. J. Med. Chem.,  2019, 172, 163-173.
 [http://dx.doi.org/10.1016/j.ejmech.2019.03.059] [PMID: 30978561]

[35]
Allegretta, G.; Weidel, E.; Empting, M.; Hartmann, R.W. Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD. Eur. J. Med. Chem.,  2015, 90, 351-359.
 [http://dx.doi.org/10.1016/j.ejmech.2014.11.055] [PMID: 25437621]

[36]
Ghalehshahi, G.; Balalaie, H.; Aliahmadi, S.; Peptides, A. N-connected to hydroxycoumarin and cinnamic acid derivatives: Synthesis and fluorescence spectroscopic, antioxidant and antimicrobial properties. New J. Chem.,  2018, 42(11), 8831-8842.
 [http://dx.doi.org/10.1039/C8NJ00383A]

[37]
Schramm, S.; Huang, G.; Gunesch, S.; Lang, F.; Roa, J.; Högger, P.; Sabaté, R.; Maher, P.; Decker, M. Regioselective synthesis of 7-O-esters of the flavonolignan silibinin and SARs lead to compounds with overadditive neuroprotective effects. Eur. J. Med. Chem.,  2018, 146, 93-107.
 [http://dx.doi.org/10.1016/j.ejmech.2018.01.036] [PMID: 29407994]

[38]
Sun, X.L.; Wang, S.Y.; Qi, Z.M.; Wan, N.; Zhang, B.L.; He, W. Design, synthesis, and biological evaluation of novel Tempol derivatives as effective antitumor agents. Res. Chem. Intermed.,  2016, 42(10), 7659-7673.
 [http://dx.doi.org/10.1007/s11164-016-2560-5]

[39]
Fotopoulos, I.; Papaioannou, G.C.; Hadjipavlou-Litina, D. Ethyl (E)-(3-(4-((4-bromobenzyl)oxy)phenyl)acryloyl)glycinate. Molbank,  2022, 2022(2), M1378.
 [http://dx.doi.org/10.3390/M1378]

[40]
Lu, M.; Zhou, S.; Guan, J.; Xu, X.; Fan, Y.; Xu, D. Synthesis of key intermediate of phosphonosulfonates (BPH-652), 1-(3-Iodopropyl)-3-phenoxy benzene. Asian J. Chem.,  2014, 26(22), 7619-7621.
 [http://dx.doi.org/10.14233/ajchem.2014.17034]

[41]
Shil, A.K.; Kumar, S.; Reddy, C.B.; Dadhwal, S.; Thakur, V.; Das, P. Supported palladium nanoparticle-catalyzed carboxylation of aryl halides, alkenylsilanes, and organoboronic acids employing oxalic acid as the C 1 source. Org. Lett.,  2015, 17(21), 5352-5355.
 [http://dx.doi.org/10.1021/acs.orglett.5b02701] [PMID: 26479944]

[42]
Atmaram Upare, A.; Gadekar, P.K.; Sivaramakrishnan, H.; Naik, N.; Khedkar, V.M.; Sarkar, D.; Choudhari, A.; Mohana Roopan, S. Design, synthesis and biological evaluation of (E)-5-styryl-1,2,4-oxadiazoles as anti-tubercular agents. Bioorg. Chem.,  2019, 86, 507-512.
 [http://dx.doi.org/10.1016/j.bioorg.2019.01.054] [PMID: 30776681]

[43]
Song, C.; Chen, P.; Tang, Y. Carboxylation of styrenes with CBr 4 and DMSO via cooperative photoredox and cobalt catalysis. RSC Advances,  2017, 7(19), 11233-11243.
 [http://dx.doi.org/10.1039/C6RA28744A]

[44]
Du, F.; Zhou, Q.; Fu, X.; Shi, Y.; Chen, Y.; Fang, W.; Yang, J.; Chen, G. Synthesis and biological evaluation of 2,2-dimethylbenzopyran derivatives as potent neuroprotection agents. RSC Advances,  2019, 9(5), 2498-2508.
 [http://dx.doi.org/10.1039/C8RA10424G] [PMID: 35520520]

[45]
Liu, S.; Wei, W.; Li, Y.; Liu, X.; Cao, X.; Lei, K.; Zhou, M. Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents. Eur. J. Med. Chem.,  2015, 95, 473-482.
 [http://dx.doi.org/10.1016/j.ejmech.2015.03.056] [PMID: 25847765]

[46]
Feng, L.; Li, Y.; Song, Z.; Li, H.; Huai, Q. Synthesis and biological evaluation of curcuminoid derivatives. Chem. Pharm. Bull.,  2015, 63(11), 873-881.
 [http://dx.doi.org/10.1248/cpb.c15-00470] [PMID: 26521852]

[47]
Bua, S.; Di Cesare Mannelli, L.; Vullo, D.; Ghelardini, C.; Bartolucci, G.; Scozzafava, A.; Supuran, C.T.; Carta, F. Design and synthesis of novel nonsteroidal anti-inflammatory drugs and carbonic anhydrase inhibitors hybrids (NSAIDs-CAIs) for the treatment of rheumatoid arthritis. J. Med. Chem.,  2017, 60(3), 1159-1170.
 [http://dx.doi.org/10.1021/acs.jmedchem.6b01607] [PMID: 28075587]

[48]
Acheson, R.M.; Booth, D.A.; Brettle, R.; Harris, A.M. 694. The synthesis of some acylglycines and related oxazolones. J. Chem. Soc.,  1960, (0), 3457-3461.
 [http://dx.doi.org/10.1039/jr9600003457]

[49]
Pokhodylo, N.T.; Shyyka, O.Y.; Obushak, M.D. A convenient one-pot synthesis of 1,5-disubstituted tetrazoles containing an amino or a carboxy group. Russ. J. Org. Chem.,  2020, 56(5), 802-812.
 [http://dx.doi.org/10.1134/S1070428020050127]

[50]
De Pooter, H.; Ali, H.; van Sumere, C.F. N‐acylamino acids and peptides I. The synthesis of N‐feruloylamino acids. Bull. Soc. Chim. Belg.,  1973, 82(3-4), 243-257.
 [http://dx.doi.org/10.1002/bscb.19730820307]

[51]
Wei, Q.Y.; Jiang, H.; Zhang, J.X.; Guo, P.F.; Wang, H. Synthesis of N-hydroxycinnamoyl amino acid ester analogues and their free radical scavenging and antioxidative activities. Med. Chem. Res.,  2012, 21(8), 1905-1911.
 [http://dx.doi.org/10.1007/s00044-011-9713-2]

[52]
Liang, S.; Ying, S.S.; Wu, H.H.; Liu, Y.T.; Dong, P.Z.; Zhu, Y.; Xu, Y.T. A novel sesquiterpene and three new phenolic compounds from the rhizomes of Acorus tatarinowii Schott. Bioorg. Med. Chem. Lett.,  2015, 25(19), 4214-4218.
 [http://dx.doi.org/10.1016/j.bmcl.2015.08.001] [PMID: 26296476]

[53]
Wissner, P.; Dahse, H.M.; Schlitzer, M. Structure activity relationship of antiproliferative N-acyl-aspartic acid dimethyl ester. 2. Variation of the aspartyl moiety. Pharmazie,  2001, 56(1), 33-35.
 [PMID: 11210664]

[54]
Centini, M.; Rossato, M.S.; Sega, A.; Buonocore, A.; Stefanoni, S.; Anselmi, C. New multifunctional surfactants from natural phenolic acids. J. Agric. Food Chem.,  2012, 60(1), 74-80.
 [http://dx.doi.org/10.1021/jf203133w] [PMID: 22142033]

[55]
Wang, D.; Zhu, J.; Xu, J.R.; Ji, D.D. Synthesis of N-hydroxycinnamoyl amide derivatives and evaluation of their anti-oxidative and anti-tyrosinase activities. Bioorg. Med. Chem.,  2019, 27(20), 114918.
 [http://dx.doi.org/10.1016/j.bmc.2019.05.031] [PMID: 31178269]

[56]
Peperidou, A.; Kapoukranidou, D.; Kontogiorgis, C.; Hadjipavlou-Litina, D. Multitarget molecular hybrids of cinnamic acids. Molecules,  2014, 19(12), 20197-20226.
 [http://dx.doi.org/10.3390/molecules191220197] [PMID: 25474291]

[57]
Juhász, L.; Varga, G.; Sztankovics, A.; Béke, F.; Docsa, T.; Kiss-Szikszai, A.; Gergely, P.; Kóňa, J.; Tvaroška, I.; Somsák, L. Structure-activity relationships of glycogen phosphorylase inhibitor FR258900 and its analogues: A combined synthetic, enzyme kinetics, and computational study. ChemPlusChem,  2014, 79(11), 1558-1568.
 [http://dx.doi.org/10.1002/cplu.201402181]

[58]
Pontiki, E.; Hadjipavlou-Litina, D.; Litinas, K.; Geromichalos, G. Novel cinnamic acid derivatives as antioxidant and anticancer agents: design, synthesis and modeling studies. Molecules,  2014, 19(7), 9655-9674.
 [http://dx.doi.org/10.3390/molecules19079655] [PMID: 25004073]

[59]
Pontiki, E.; Hadjipavlou-Litina, D.; Litinas, K.; Nicolotti, O.; Carotti, A. Design, synthesis and pharmacobiological evaluation of novel acrylic acid derivatives acting as lipoxygenase and cyclooxygenase-1 inhibitors with antioxidant and anti-inflammatory activities. Eur. J. Med. Chem.,  2011, 46(1), 191-200.
 [http://dx.doi.org/10.1016/j.ejmech.2010.10.035] [PMID: 21106277]

[60]
Tariq, S.; Alam, O.; Amir, M. Synthesis, p38α MAP kinase inhibition, anti‐inflammatory activity, and molecular docking studies of 1,2,4‐triazole‐based benzothiazole‐2‐amines. Arch. Pharm.,  2018, 351(3-4), 1700304.
 [http://dx.doi.org/10.1002/ardp.201700304]

[61]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep.,  2017, 7(1), 42717.
 [http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]

[62]
Guan, L.; Yang, H.; Cai, Y.; Sun, L.; Di, P.; Li, W.; Liu, G.; Tang, Y. ADMET-score - a comprehensive scoring function for evaluation of chemical drug-likeness. MedChemComm,  2019, 10(1), 148-157.
 [http://dx.doi.org/10.1039/C8MD00472B] [PMID: 30774861]

[63]
Gupta, M.; Lee, H.J.; Barden, C.J.; Weaver, D.F. The Blood-Brain Barrier (BBB). Score. J. Med. Chem.,  2019, 62(21), 9824-9836.
 [http://dx.doi.org/10.1021/acs.jmedchem.9b01220] [PMID: 31603678]

[64]
Pedretti, A.; Mazzolari, A.; Vistoli, G.; Testa, B. MetaQSAR: An integrated database engine to manage and analyze metabolic data. J. Med. Chem.,  2018, 61(3), 1019-1030.
 [http://dx.doi.org/10.1021/acs.jmedchem.7b01473] [PMID: 29244953]

[65]
Testa, B.; Pedretti, A.; Vistoli, G. Reactions and enzymes in the metabolism of drugs and other xenobiotics. Drug Discov. Today,  2012, 17(11-12), 549-560.
 [http://dx.doi.org/10.1016/j.drudis.2012.01.017] [PMID: 22305937]

[66]
Stork, C.; Embruch, G.; Šícho, M.; de Bruyn Kops, C.; Chen, Y.; Svozil, D.; Kirchmair, J. NERDD: A web portal providing access to in silico tools for drug discovery. Bioinformatics,  2020, 36(4), 1291-1292.
 [http://dx.doi.org/10.1093/bioinformatics/btz695] [PMID: 32077475]

[67]
de Bruyn Kops, C.; Šícho, M.; Mazzolari, A.; Kirchmair, J. GLORYx: Prediction of the metabolites resulting from phase 1 and phase 2 biotransformations of xenobiotics. Chem. Res. Toxicol.,  2021, 34(2), 286-299.
 [http://dx.doi.org/10.1021/acs.chemrestox.0c00224] [PMID: 32786543]

[68]
Shao, C.Y.; Su, B.H.; Tu, Y.S.; Lin, C.; Lin, O.A.; Tseng, Y.J. CypRules: A rule-based P450 inhibition prediction server. Bioinformatics,  2015, 31(11), 1869-1871.
 [http://dx.doi.org/10.1093/bioinformatics/btv043] [PMID: 25617412]

[69]
LiverTox Workspace.  Available from:
          https://livertox.univie.ac.at/ (Cited 2021 Jul 20).

[70]
Gleason, M.M.; Rojas, C.J.; Learn, K.S.; Perrone, M.H.; Bilder, G.E. Characterization and inhibition of 15-lipoxygenase in human monocytes: Comparison with soybean 15-lipoxygenase. Am. J. Physiol. Cell Physiol.,  1995, 268(5), C1301-C1307.
 [http://dx.doi.org/10.1152/ajpcell.1995.268.5.C1301] [PMID: 7762624]

[71]
Lapenna, D.; Ciofani, G.; Pierdomenico, S.D.; Giamberardino, M.A.; Cuccurullo, F. Dihydrolipoic acid inhibits 15-lipoxygenase-dependent lipid peroxidation. Free Radic. Biol. Med.,  2003, 35(10), 1203-1209.
 [http://dx.doi.org/10.1016/S0891-5849(03)00508-2] [PMID: 14607519]

[72]
Maccarrone, M.; van Aarle, P.G.M.; Veldink, G.A.; Vliegenthart, J.F.G. In vitro oxygenation of soybean biomembranes by lipoxygenase-2. Biochim. Biophys. Acta Biomembr.,  1994, 1190(1), 164-169.
 [http://dx.doi.org/10.1016/0005-2736(94)90046-9] [PMID: 8110809]

[73]
Konstantinidou, M.; Gkermani, A.; Hadjipavlou-Litina, D. Synthesis and pharmacochemistry of new pleiotropic pyrrolyl derivatives. Molecules,  2015, 20(9), 16354-16374.
 [http://dx.doi.org/10.3390/molecules200916354] [PMID: 26378503]

[74]
Meshram, M.A.; Bhise, U.O.; Makhal, P.N.; Kaki, V.R. Synthetically-tailored and nature-derived dual COX-2/5-LOX inhibitors: Structural aspects and SAR. Eur. J. Med. Chem.,  2021, 225, 113804.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113804] [PMID: 34479036]

[75]
Mizushima, Y. Screening test for antirheumatic drugs. Lancet,  1966, 288(7460), 443.
 [http://dx.doi.org/10.1016/S0140-6736(66)92756-5]

[76]
Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol.,  2011, 31(5), 986-1000.
 [http://dx.doi.org/10.1161/ATVBAHA.110.207449] [PMID: 21508345]

[77]
Opie, E.L. On the relation of necrosis and inflammation to denaturation of proteins. J. Exp. Med.,  1962, 115(3), 597-608.
 [http://dx.doi.org/10.1084/jem.115.3.597] [PMID: 14482110]

[78]
Mizushima, Y.; Kobayashi, M. Interaction of anti-inflammatory drugs with serum proteins, especially with some biologically active proteins. J. Pharm. Pharmacol.,  2011, 20(3), 169-173.
 [http://dx.doi.org/10.1111/j.2042-7158.1968.tb09718.x] [PMID: 4385045]

[79]
Kasthuri, J.K.; Singh Jadav, S.; Thripuram, V.D.; Gundabolu, U.R.; Ala, V.; Kolla, J.N.; Jayaprakash, V.; Ahsan, M.J.; Bollikolla, H.B. Synthesis, characterization, docking and study of inhibitory action of some novel C-alkylated chalcones on 5-LOX enzyme. ChemistrySelect,  2017, 2(28), 8771-8778.
 [http://dx.doi.org/10.1002/slct.201700517]

[80]
Kostopoulou, I.; Tzani, A.; Polyzos, N.I.; Karadendrou, M.A.; Kritsi, E.; Pontiki, E.; Liargkova, T.; Hadjipavlou-Litina, D.; Zoumpoulakis, P.; Detsi, A. Exploring the 2′-hydroxy-chalcone framework for the development of dual antioxidant and soybean lipoxygenase inhibitory agents. Molecules,  2021, 26(9), 2777.
 [http://dx.doi.org/10.3390/molecules26092777] [PMID: 34066803]

[81]
Mavridis, E.; Bermperoglou, E.; Pontiki, E.; Hadjipavlou-Litina, D. 5-(4H)-oxazolones and their benzamides as potential bioactive small molecules. Molecules,  2020, 25(14), 3173.
 [http://dx.doi.org/10.3390/molecules25143173] [PMID: 32664550]

[82]
Mantzanidou, M.; Pontiki, E.; Hadjipavlou-Litina, D. Pyrazoles and pyrazolines as anti-inflammatory agents. Molecules,  2021, 26(11), 3439.
 [http://dx.doi.org/10.3390/molecules26113439] [PMID: 34198914]

[83]
Kouzi, O.; Pontiki, E.; Hadjipavlou-Litina, D. 2-Arylidene-1-indandiones as pleiotropic agents with antioxidant and inhibitory enzymes activities. Molecules,  2019, 24(23), 4411.
 [http://dx.doi.org/10.3390/molecules24234411] [PMID: 31816866]

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DOI https://dx.doi.org/10.2174/0115734064279653240125081042	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638

Medicinal Chemistry

Pharmacochemical Study of Multitarget Amino Acids’ Hybrids: Design, Synthesis, In vitro, and In silico Studies

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