![conference banner](/images/conference-banner.jpeg)
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.
[http://dx.doi.org/10.1054/mehy.1998.0824] [PMID: 10790729]
[http://dx.doi.org/10.1016/j.mehy.2005.09.031] [PMID: 16278051]
[http://dx.doi.org/10.1176/jnp.13.2.304] [PMID: 11449041]
[http://dx.doi.org/10.1016/j.bcp.2013.11.005] [PMID: 24269629]
[http://dx.doi.org/10.3390/molecules25214958] [PMID: 33114751]
[http://dx.doi.org/10.1002/ana.23642] [PMID: 23034916]
[http://dx.doi.org/10.1016/j.neuropharm.2013.06.014] [PMID: 23800665]
[http://dx.doi.org/10.1111/bph.14167] [PMID: 29468666]
[http://dx.doi.org/10.2174/1381612033454054] [PMID: 14529398]
[http://dx.doi.org/10.1007/s11033-020-06033-x] [PMID: 33263931]
[http://dx.doi.org/10.1038/89490] [PMID: 11426226]
[http://dx.doi.org/10.1007/s00284-019-01839-w] [PMID: 31844936]
[http://dx.doi.org/10.1021/acs.jmedchem.7b00956] [PMID: 28876062]
[http://dx.doi.org/10.1016/j.neuropharm.2021.108631] [PMID: 34058193]
[http://dx.doi.org/10.1038/nature715] [PMID: 11823786]
[http://dx.doi.org/10.1523/JNEUROSCI.0560-06.2006]
[http://dx.doi.org/10.1038/emboj.2008.140]
[http://dx.doi.org/10.1155/2021/6624347] [PMID: 33880371]
[http://dx.doi.org/10.3390/nu9050477] [PMID: 28489058]
[http://dx.doi.org/10.3390/molecules23010153] [PMID: 29329232]
[http://dx.doi.org/10.2174/1389201019666181112102702] [PMID: 30417783]
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[http://dx.doi.org/10.1016/S0076-6879(03)74020-8]
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[http://dx.doi.org/10.1002/(SICI)1096-987X(199604)17:5/6<490:AID-JCC1>3.0.CO;2-P]
[http://dx.doi.org/10.1186/1756-0500-5-367] [PMID: 22824207]
[http://dx.doi.org/10.1016/j.jmgm.2005.12.005] [PMID: 16458552]
[http://dx.doi.org/10.1021/ct700301q] [PMID: 26620784]
[http://dx.doi.org/10.1002/prot.22711] [PMID: 20408171]
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[http://dx.doi.org/10.1016/j.ejmech.2019.03.059] [PMID: 30978561]
[http://dx.doi.org/10.1016/j.ejmech.2014.11.055] [PMID: 25437621]
[http://dx.doi.org/10.1039/C8NJ00383A]
[http://dx.doi.org/10.1016/j.ejmech.2018.01.036] [PMID: 29407994]
[http://dx.doi.org/10.1007/s11164-016-2560-5]
[http://dx.doi.org/10.3390/M1378]
[http://dx.doi.org/10.14233/ajchem.2014.17034]
[http://dx.doi.org/10.1021/acs.orglett.5b02701] [PMID: 26479944]
[http://dx.doi.org/10.1016/j.bioorg.2019.01.054] [PMID: 30776681]
[http://dx.doi.org/10.1039/C6RA28744A]
[http://dx.doi.org/10.1039/C8RA10424G] [PMID: 35520520]
[http://dx.doi.org/10.1016/j.ejmech.2015.03.056] [PMID: 25847765]
[http://dx.doi.org/10.1248/cpb.c15-00470] [PMID: 26521852]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01607] [PMID: 28075587]
[http://dx.doi.org/10.1039/jr9600003457]
[http://dx.doi.org/10.1134/S1070428020050127]
[http://dx.doi.org/10.1002/bscb.19730820307]
[http://dx.doi.org/10.1007/s00044-011-9713-2]
[http://dx.doi.org/10.1016/j.bmcl.2015.08.001] [PMID: 26296476]
[PMID: 11210664]
[http://dx.doi.org/10.1021/jf203133w] [PMID: 22142033]
[http://dx.doi.org/10.1016/j.bmc.2019.05.031] [PMID: 31178269]
[http://dx.doi.org/10.3390/molecules191220197] [PMID: 25474291]
[http://dx.doi.org/10.1002/cplu.201402181]
[http://dx.doi.org/10.3390/molecules19079655] [PMID: 25004073]
[http://dx.doi.org/10.1016/j.ejmech.2010.10.035] [PMID: 21106277]
[http://dx.doi.org/10.1002/ardp.201700304]
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[http://dx.doi.org/10.1039/C8MD00472B] [PMID: 30774861]
[http://dx.doi.org/10.1021/acs.jmedchem.9b01220] [PMID: 31603678]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01473] [PMID: 29244953]
[http://dx.doi.org/10.1016/j.drudis.2012.01.017] [PMID: 22305937]
[http://dx.doi.org/10.1093/bioinformatics/btz695] [PMID: 32077475]
[http://dx.doi.org/10.1021/acs.chemrestox.0c00224] [PMID: 32786543]
[http://dx.doi.org/10.1093/bioinformatics/btv043] [PMID: 25617412]
[http://dx.doi.org/10.1152/ajpcell.1995.268.5.C1301] [PMID: 7762624]
[http://dx.doi.org/10.1016/S0891-5849(03)00508-2] [PMID: 14607519]
[http://dx.doi.org/10.1016/0005-2736(94)90046-9] [PMID: 8110809]
[http://dx.doi.org/10.3390/molecules200916354] [PMID: 26378503]
[http://dx.doi.org/10.1016/j.ejmech.2021.113804] [PMID: 34479036]
[http://dx.doi.org/10.1016/S0140-6736(66)92756-5]
[http://dx.doi.org/10.1161/ATVBAHA.110.207449] [PMID: 21508345]
[http://dx.doi.org/10.1084/jem.115.3.597] [PMID: 14482110]
[http://dx.doi.org/10.1111/j.2042-7158.1968.tb09718.x] [PMID: 4385045]
[http://dx.doi.org/10.1002/slct.201700517]
[http://dx.doi.org/10.3390/molecules26092777] [PMID: 34066803]
[http://dx.doi.org/10.3390/molecules25143173] [PMID: 32664550]
[http://dx.doi.org/10.3390/molecules26113439] [PMID: 34198914]
[http://dx.doi.org/10.3390/molecules24234411] [PMID: 31816866]
![Wayfinder Image](/images/wayfinder.jpg)