Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis, Characterization, and in vitro Anti-Inflammatory Activity of Novel Ferrocenyl(Piperazine-1-Yl)Methanone-based Derivatives

Author(s): Banfeng Ruan, Jin Li, Qinglei Guo, Min Zhang, Zhouyang Pei* and Yong Hu*

Volume 19, Issue 9, 2023

Published on: 27 February, 2023

Page: [915 - 924] Pages: 10

DOI: 10.2174/1573406419666230214112800

Price: $65

Abstract

Background: Inflammation is closely related to the occurrence and development of various diseases in the clinical scope. Finding effective anti-inflammatory agents is of great significance for clinical treatment. A series of novel ferrocenyl(piperazine-1-yl)methanone-based sulfamides and carboxamides were synthesized to discover potent anti-inflammatory agents.

Methods: The compounds were characterized by 1H NMR, 13C NMR, and MS spectra. Compound 5h was further determined by single crystal X-ray diffraction. All the target compounds were screened for anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW264.7 macrophages. The novel compound (4i) is the preliminary anti-inflammatory mechanism detected by western blot.

Results: In a multi-stage screening campaign, compound 4i was shortlisted, which exhibited physicochemical properties suitable for human administration. Among them, compound 4i was found to be most potent in inhibiting NO production (IC50 = 7.65 μM) with low toxicity. This compound also exhibited significant inhibition of the production of iNOS and COX-2. Preliminary mechanism studies indicated that compound 4i could inhibit the activation of the LPS-induced TLR4/NF-κB signaling pathway.

Conclusion: The promising anti-inflammatory activity of compound 4i compared with the reference drug suggests that this compound may contribute as a lead compound in the search for new potential anti-inflammatory agents.

« Previous Next »
Graphical Abstract

[1]
Chung, L.; Maestas, D.R., Jr; Housseau, F.; Elisseeff, J.H. Key players in the immune response to biomaterial scaffolds for regenerative medicine. Adv. Drug Deliv. Rev., 2017, 114, 184-192.
[http://dx.doi.org/10.1016/j.addr.2017.07.006] [PMID: 28712923]
[2]
Fullerton, J.N.; Gilroy, D.W. Resolution of inflammation: A new therapeutic frontier. Nat. Rev. Drug Discov., 2016, 15(8), 551-567.
[http://dx.doi.org/10.1038/nrd.2016.39] [PMID: 27020098]
[3]
Fang, M.; Zou, T.; Yang, X.; Zhang, Z.; Cao, P.; Han, J.; Duan, Y.; Ruan, B.F.; Li, Q.S. Discovery of novel pterostilbene derivatives that might treat sepsis by attenuating oxidative stress and inflflammation through modulation of MAPKs/NF-κB signaling pathways. Antioxidants, 2021, 10(9), 1333.
[http://dx.doi.org/10.3390/antiox10091333] [PMID: 34572964]
[4]
Chen, L.Z.; Zhang, X.X.; Liu, M.M.; Wu, J.; Ma, D.; Diao, L.Z.; Li, Q.; Huang, Y.S.; Zhang, R.; Ruan, B.F.; Liu, X.H. Discovery of novel pterostilbene-based derivatives as potent and orally active NLRP3 inflammasome inhibitors with inflammatory activity for colitis. J. Med. Chem., 2021, 64(18), 13633-13657.
[http://dx.doi.org/10.1021/acs.jmedchem.1c01007] [PMID: 34506712]
[5]
Chen, L.Z.; Yao, L.; Jiao, M.M.; Shi, J.B.; Tan, Y.; Ruan, B.F.; Liu, X.H. Novel resveratrol-based flavonol derivatives: Synthesis and anti-inflammatory activity in vitro and in vivo. Eur. J. Med. Chem., 2019, 175, 114-128.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.004] [PMID: 31077997]
[6]
Chen, L.Z.; Wu, J.; Li, K.; Wu, Q.Q.; Chen, R.; Liu, X.H.; Ruan, B.F. Novel phthalide derivatives: Synthesis and anti-inflammatory activity in vitro and in vivo. Eur. J. Med. Chem., 2020, 206, 112722.
[http://dx.doi.org/10.1016/j.ejmech.2020.112722] [PMID: 32823004]
[7]
Patra, M.; Gasser, G. Gasser, the medicinal chemistry of ferrocene and its derivatives. Nat. Rev. Chem., 2017, 1(9), 0066.
[8]
Ochiai, K.; Fujii, S. Structure-property and structure–activity relationships of phenylferrocene derivatives as androgen receptor antagonists. Bioorg. Med. Chem. Lett., 2021, 46, 128141.
[http://dx.doi.org/10.1016/j.bmcl.2021.128141] [PMID: 34048883]
[9]
Xiao, J.; Sun, Z.; Kong, F.; Gao, F. Current scenario of ferrocene-containing hybrids for antimalarial activity. Eur. J. Med. Chem., 2020, 185, 111791.
[http://dx.doi.org/10.1016/j.ejmech.2019.111791] [PMID: 31669852]
[10]
Wang, R.; Chen, H.; Yan, W.; Zheng, M.; Zhang, T.; Zhang, Y. Ferrocene-containing hybrids as potential anticancer agents: Current developments, mechanisms of action and structure-activity relationships. Eur. J. Med. Chem., 2020, 190, 112109.
[http://dx.doi.org/10.1016/j.ejmech.2020.112109] [PMID: 32032851]
[11]
Ornelas, C. Application of ferrocene and its derivatives in cancer research. New J. Chem., 2011, 35(10), 1973-1985.
[http://dx.doi.org/10.1039/c1nj20172g]
[12]
Jaouen, G.; Vessières, A.; Top, S. Ferrocifen type anti cancer drugs. Chem. Soc. Rev., 2015, 44(24), 8802-8817.
[http://dx.doi.org/10.1039/C5CS00486A] [PMID: 26486993]
[13]
Li, L.; Ma, L.; Sun, J. The antiproliferative activity of ferrocene derivatives against drug resistant cancer cell lines: a mini review. Curr. Top. Med. Chem., 2021, 21(19), 1756-1772.
[http://dx.doi.org/10.2174/1568026621666210728093527] [PMID: 34323188]
[14]
Huang, X.F.; Wang, L.Z.; Tang, L.; Lu, Y.X.; Wang, F.; Song, G.Q.; Ruan, B.F. Synthesis, characterization and antitumor activity of novel ferrocene derivatives containing pyrazolyl-moiety. J. Organomet. Chem., 2014, 749, 157-162.
[http://dx.doi.org/10.1016/j.jorganchem.2013.08.043]
[15]
Guo, Y.; Wang, S.Q.; Ding, Z.Q.; Zhou, J.; Ruan, B.F. Synthesis, characterization and antitumor activity of novel ferrocene bisamide derivatives containing pyrimidine-moiety. J. Organomet. Chem., 2017, 851, 150-159.
[http://dx.doi.org/10.1016/j.jorganchem.2017.09.032]
[16]
Liu, Y.W.; Cheng, H-J.; Ruan, B.F.; Hu, Q. Synthesis, characterization and antitumor activity of (E)-2-methyl-3-ferrocenyl-N-acrylamide derivatives. J. Organomet. Chem., 2019, 887, 71-79.
[http://dx.doi.org/10.1016/j.jorganchem.2019.02.021]
[17]
Wani, W.A.; Jameel, E.; Baig, U.; Mumtazuddin, S.; Hun, L.T. Ferroquine and its derivatives: New generation of antimalarial agents. Eur. J. Med. Chem., 2015, 101, 534-551.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.009] [PMID: 26188909]
[18]
Bruyère, C.; Mathieu, V.; Vessières, A.; Pigeon, P.; Top, S.; Jaouen, G.; Kiss, R. Ferrocifen derivatives that induce senescence in cancer cells: Selected examples. J. Inorg. Biochem., 2014, 141, 144-151.
[http://dx.doi.org/10.1016/j.jinorgbio.2014.08.015] [PMID: 25261808]
[19]
Guo, W.Y.; Chen, L.Z.; Shen, B.N.; Liu, X.H.; Tai, G.P.; Li, Q.S.; Gao, L.; Ruan, B.F. Synthesis and in vitro and in vivo anti-inflammatory activity of novel 4-ferrocenylchroman-2-one derivatives. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1678-1689.
[http://dx.doi.org/10.1080/14756366.2019.1664499] [PMID: 31530032]
[20]
Chiaramonte, N.; Bua, S.; Angeli, A.; Ferraroni, M.; Picchioni, I.; Bartolucci, G.; Braconi, L.; Dei, S.; Teodori, E.; Supuran, C.T.; Romanelli, M.N. Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I, II, IV and IX inhibitors. Bioorg. Chem., 2019, 91, 103130.
[http://dx.doi.org/10.1016/j.bioorg.2019.103130] [PMID: 31374520]
[21]
Bungard, C.J.; Williams, P.D.; Schulz, J.; Wiscount, C.M.; Holloway, M.K.; Loughran, H.M.; Manikowski, J.J.; Su, H.P.; Bennett, D.J.; Chang, L.; Chu, X.J.; Crespo, A.; Dwyer, M.P.; Keertikar, K.; Morriello, G.J.; Stamford, A.W.; Waddell, S.T.; Zhong, B.; Hu, B.; Ji, T.; Diamond, T.L.; Bahnck-Teets, C.; Carroll, S.S.; Fay, J.F.; Min, X.; Morris, W.; Ballard, J.E.; Miller, M.D.; McCauley, J.A. Design and synthesis of piperazine sulfonamide cores leading to highly potent HIV-1 protease inhibitors. ACS Med. Chem. Lett., 2017, 8(12), 1292-1297.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00386] [PMID: 29259750]
[22]
Kowalski, P.; Śliwa, P.; Satała, G.; Kurczab, R.; Bartos, I.; Zuchowicz, K. The effect of carboxamide/sulfonamide replacement in arylpiperazinylalkyl derivatives on activity to serotonin and dopamine receptors. Arch. Pharm., 2017, 350(10), 1700090.
[http://dx.doi.org/10.1002/ardp.201700090] [PMID: 28846141]
[23]
Sheldrick, G.M. SHELXTL V5.1 Software Reference Manual; Bruker AXS, Inc.: Madison, WI, USA, 1997.
[24]
Jiang, D.; Chen, J.; Zan, N.; Li, C.; Hu, D.; Song, B. Discovery of novel chromone derivatives containing a sulfonamide moiety as anti-ToCV agents through the tomato chlorosis virus coat protein-oriented screening method. J. Agric. Food Chem., 2021, 69(41), 12126-12134.
[http://dx.doi.org/10.1021/acs.jafc.1c02467] [PMID: 34633811]
[25]
Chen, L.Z.; Shu, H.Y.; Wu, J.; Yu, Y.L.; Ma, D.; Huang, X.; Liu, M.M.; Liu, X.H.; Shi, J.B. Discovery and development of novel pyrimidine and pyrazolo/thieno-fused pyrimidine derivatives as potent and orally active inducible nitric oxide synthase dimerization inhibitor with efficacy for arthritis. Eur. J. Med. Chem., 2021, 213, 113174.
[http://dx.doi.org/10.1016/j.ejmech.2021.113174] [PMID: 33515864]
[26]
Shi, J.B.; Chen, L.Z.; Wang, B.S.; Huang, X.; Jiao, M.M.; Liu, M.M.; Tang, W.J.; Liu, X.H. Novel pyrazolo[4,3-d]pyrimidine as potent and orally active inducible nitric oxide synthase (iNOS) dimerization inhibitor with efficacy in rheumatoid arthritis mouse model. J. Med. Chem., 2019, 62(8), 4013-4031.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00039] [PMID: 30925056]
[27]
Chae, U.; Kim, H.S.; Kim, K.M.; Lee, H.; Lee, H.S.; Park, J.W.; Lee, D.S. IDH2 deficiency in microglia decreases the pro-inflammatory response via the ERK and NF-κB Pathways. Inflammation, 2018, 41(5), 1965-1973.
[http://dx.doi.org/10.1007/s10753-018-0840-5] [PMID: 29987482]
[28]
Facchini, F.A.; Zaffaroni, L.; Minotti, A.; Rapisarda, S.; Calabrese, V.; Forcella, M.; Fusi, P.; Airoldi, C.; Ciaramelli, C.; Billod, J.M.; Schromm, A.B.; Braun, H.; Palmer, C.; Beyaert, R.; Lapenta, F.; Jerala, R.; Pirianov, G.; Martin-Santamaria, S.; Peri, F. Structure-activity relationship in monosaccharide-based toll-like receptor 4 (TLR4) antagonists. J. Med. Chem., 2018, 61(7), 2895-2909.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01803] [PMID: 29494148]
[29]
Yang, H.Z.; Wang, J.P.; Mi, S.; Liu, H.Z.; Cui, B.; Yan, H.M.; Yan, J.; Li, Z.; Liu, H.; Hua, F.; Lu, W.; Hu, Z.W. TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury. Am. J. Pathol., 2012, 180(1), 275-292.
[http://dx.doi.org/10.1016/j.ajpath.2011.09.019] [PMID: 22062220]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy