Login Register Cart 0
Generic placeholder image

Current Organic Chemistry

Editor-in-Chief

ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

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

Bioisosteric Replacement through 1,2,3-triazolyl Linkage Significantly Potentiate Biological Activity in Lidocaine and Etidocaine Analogs: Rational Design and Local Anesthetic Activity

Author(s): Adarsh Sahu* and Ram Kishore Agrawal

Volume 27, Issue 19, 2023

Published on: 18 October, 2023

Page: [1697 - 1703] Pages: 7

DOI: 10.2174/0113852728250971231010065525

Price: $65

Abstract

Cytochrome P450 3A4, the most abundant form of isoenzyme, in combination with several other isoforms, metabolizes lignocaine into mono-ethylglycine xylidide (MEGX) and glycylxylidide (GX), through N-dealkylation, ring hydroxylation, amide cleavage, and conjugation process which contribute the toxic effects. Inspiring by the rationality, functional approaches, and predictable facts lay by the emerging research groups, we were unquestionably fascinated by the rational development of novel lignocaine and etidocaine compounds, which are highly metabolically stable by applying non-classical bioisosteric principles. Distinctively, we have investigated the efficacy of 1,4- disubstituted-1,2,3-triazoles as metabolically stable trans-amide bond mimics. The 1,2,3- triazoles have been described in the literature as amide bond bioisosteres, which are analogous in stipulations of size, planarity, hydrogen bonding properties, and dipole moment. The systematic replacement of the single amide bonds by the 1,2,3-triazole heterocycle in the backbone of the peptide, often termed a “triazole scan,” provided several stabilized analogs with marked improved in-vivo local anesthetic properties. The analogs were synthesized using azide-alkyne cycloaddition. The 2a-b was coupled with aromatic and aliphatic alkynes using click chemistry in the presence of copper sulfate pentahydrate and L-sodium ascorbate in a Fritsch ball mill under solvent-free conditions at 300 rpm, furnishing the conjugates 4a-n in 80- 85% yields. The study perceptively opened new avenues of systematic replacement of the single amide bonds by the 1,2,3-triazole heterocycle in the backbone of the peptide, thereby providing several stabilized analogs with marked improved in-vivo local anesthetic properties. The best active candidates 4a, 4b and 4g produced analogous local anesthetic activity with that of the lignocaine.

Keywords: Lignocaine, etidocaine, 3-triazoles, metabolism, analogous, amide bonds.

« Previous Next »
Graphical Abstract

[1]
Beale, J.M.; Block, J.H. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry; Lippincott Williams & Wilkins, 2011.
[2]
Lemke, T.L.; Williams, D.A. Foye’s Principles of Medicinal Chemistry; Lippincott Williams & Wilkins, 2012.
[3]
Becker, D.E.; Reed, K.L. Local anesthetics: Review of pharmacological considerations. Anesth. Prog., 2012, 59(2), 90-102.
[http://dx.doi.org/10.2344/0003-3006-59.2.90] [PMID: 22822998]
[4]
Caracas, H.C.P.M.; Maciel, J.V.B.; Martins, P.M.R.S.; de Souza, M.M.G.; Maia, L.C. The use of lidocaine as an anti-inflammatory substance: A systematic review. J. Dent., 2009, 37(2), 93-97.
[http://dx.doi.org/10.1016/j.jdent.2008.10.005] [PMID: 19058888]
[5]
Bill, T.; Clayman, M.A.; Morgan, R.F.; Gampper, T.J. Lidocaine metabolism pathophysiology, drug interactions, and surgical implications. Aesthet. Surg. J., 2004, 24(4), 307-311.
[http://dx.doi.org/10.1016/j.asj.2004.05.001] [PMID: 19336170]
[6]
Narang, P.K.; Crouthamel, W.G.; Carliner, N.H.; Fisher, M.L. Lidocaine and its active metabolites. Clin. Pharmacol. Ther., 1978, 24(6), 654-662.
[http://dx.doi.org/10.1002/cpt1978246654] [PMID: 710024]
[7]
Imaoka, S.; Enomoto, K.; Oda, Y.; Asada, A.; Fujimori, M.; Shimada, T.; Fujita, S.; Guengerich, F.P.; Funae, Y. Lidocaine metabolism by human cytochrome P-450s purified from hepatic microsomes: Comparison of those with rat hepatic cytochrome P-450s. J. Pharmacol. Exp. Ther., 1990, 255(3), 1385-1391.
[PMID: 2262908]
[8]
Bargetzi, M.J.; Aoyama, T.; Gonzalez, F.J.; Meyer, U.A. Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4. Clin. Pharmacol. Ther., 1989, 46(5), 521-527.
[http://dx.doi.org/10.1038/clpt.1989.180] [PMID: 2582709]
[9]
Torp, K.D.; Simon, L.V. Toxicity, Lidocaine; StatPearls: Treasure Island, FL, 2018.
[10]
Weinberg, L.; Peake, B.; Tan, C.; Nikfarjam, M. Pharmacokinetics and pharmacodynamics of lignocaine: A review. World J. Anesthesiol., 2015, 4(2), 17-29.
[http://dx.doi.org/10.5313/wja.v4.i2.17]
[11]
Blake, K.J.; Baral, P.; Voisin, T.; Lubkin, A.; Pinho-Ribeiro, F.A.; Adams, K.L.; Roberson, D.P.; Ma, Y.C.; Otto, M.; Woolf, C.J.; Torres, V.J.; Chiu, I.M. Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat. Commun., 2018, 9(1), 37.
[http://dx.doi.org/10.1038/s41467-017-02448-6] [PMID: 29295977]
[12]
Stueber, T.; Eberhardt, M.J.; Hadamitzky, C.; Jangra, A.; Schenk, S.; Dick, F.; Stoetzer, C.; Kistner, K.; Reeh, P.W.; Binshtok, A.M.; Leffler, A. Quaternary lidocaine derivative QX-314 activates and permeates human TRPV1 and TRPA1 to produce inhibition of sodium channels and cytotoxicity. Anesthesiology. Anesthesiology, 2016, 124(5), 1153-1165.
[http://dx.doi.org/10.1097/ALN.0000000000001050] [PMID: 26859646]
[13]
Fuseya, S.; Yamamoto, K.; Minemura, H.; Yamaori, S.; Kawamata, T.; Kawamata, M. Systemic QX-314 reduces bone cancer pain through selective inhibition of transient receptor potential vanilloid subfamily 1-expressing primary afferents in mice. Anesthesiology, 2016, 125(1), 204-218.
[http://dx.doi.org/10.1097/ALN.0000000000001152] [PMID: 27176211]
[14]
Yoon, J.H.; Son, J.Y.; Kim, M.J.; Kang, S.H.; Ju, J.S.; Bae, Y.C.; Ahn, D.K. Preemptive application of QX-314 attenuates trigeminal neuropathic mechanical allodynia in rats. Korean J. Physiol. Pharmacol., 2018, 22(3), 331-341.
[http://dx.doi.org/10.4196/kjpp.2018.22.3.331] [PMID: 29719455]
[15]
Ongun, S.; Sarkisian, A.; McKemy, D.D. Selective cold pain inhibition by targeted block of TRPM8-expressing neurons with quaternary lidocaine derivative QX-314. Commun. Biol., 2018, 1(1), 53.
[http://dx.doi.org/10.1038/s42003-018-0062-2] [PMID: 30271936]
[16]
Yin, Q.; Li, J.; Zheng, Q.; Yang, X.; Lv, R.; Ma, L.; Liu, J.; Zhu, T.; Zhang, W. The quaternary lidocaine derivative QX-314 in combination with bupivacaine for long-lasting nerve block: Efficacy, toxicity, and the optimal formulation in rats. PLoS One, 2017, 12(3), e0174421.
[http://dx.doi.org/10.1371/journal.pone.0174421] [PMID: 28334014]
[17]
Zhao, W.; Yin, Q.; Liu, J.; Zhang, W.; Yang, L. Addition of dexmedetomidine to QX-314 enhances the onset and duration of sciatic nerve block in rats. Can. J. Physiol. Pharmacol., 2018, 96(4), 388-394.
[http://dx.doi.org/10.1139/cjpp-2017-0331] [PMID: 28886259]
[18]
Zhang, Y.; Yang, J.; Yin, Q.; Yang, L.; Liu, J.; Zhang, W.Q.X-O.H. a QX-314 derivative agent, produces long-acting local anesthesia in rats. Eur. J. Pharm. Sci., 2017, 105, 212-218.
[http://dx.doi.org/10.1016/j.ejps.2017.05.039] [PMID: 28529036]
[19]
Lim, T.K.Y.; MacLeod, B.A.; Ries, C.R.; Schwarz, S.K.W. The quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia in animal models in vivo. Anesthesiology, 2007, 107(2), 305-311.
[http://dx.doi.org/10.1097/01.anes.0000270758.77314.b4] [PMID: 17667576]
[20]
Binshtok, A.M.; Gerner, P.; Oh, S.B.; Puopolo, M.; Suzuki, S.; Roberson, D.P.; Herbert, T.; Wang, C.F.; Kim, D.; Chung, G.; Mitani, A.A.; Wang, G.K.; Bean, B.P.; Woolf, C.J. Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. Anesthesiology, 2009, 111(1), 127-137.
[http://dx.doi.org/10.1097/ALN.0b013e3181a915e7] [PMID: 19512868]
[21]
Sahu, A.; Sahu, P.; Agrawal, R. A recent review on drug modification using 1,2,3-triazole. Curr. Chem. Biol., 2020, 14(2), 71-87.
[http://dx.doi.org/10.2174/2212796814999200807214519]
[22]
Sahu, A.; Agrawal, R.K.; Pandey, R. Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency. Bioorg. Chem., 2019, 88, 102939.
[http://dx.doi.org/10.1016/j.bioorg.2019.102939] [PMID: 31028993]
[23]
Sahu, A.; Sahu, P.; Agrawal, R. Synthesis, pharmacological and toxicological screening of Penicillin-Triazole Conjugates (PNTCs). ACS Omega, 2019, 4(17), 17230-17235.
[http://dx.doi.org/10.1021/acsomega.9b01724] [PMID: 31656896]
[24]
Sahu, A.; Das, D.; Sahu, P.; Mishra, S.; Sakthivel, A.; Gajbhiye, A.; Agrawal, R. Bioisosteric replacement of amide group with 1,2,3-triazoles in acetaminophen addresses reactive oxygen species-mediated hepatotoxic insult in wistar albino rats. Chem. Res. Toxicol., 2020, 33(2), 522-535.
[http://dx.doi.org/10.1021/acs.chemrestox.9b00392] [PMID: 31849220]
[25]
Sahu, A.; Das, D.; Agrawal, R.K.; Gajbhiye, A. Bio-isosteric replacement of amide group with 1,2,3-triazole in phenacetin improves the toxicology and efficacy of phenacetin-triazole conjugates (PhTCs). Life Sci., 2019, 228, 176-188.
[http://dx.doi.org/10.1016/j.lfs.2019.05.004] [PMID: 31059688]
[26]
Zou, H.; Chen, G.; Zhou, S. Design, synthesis and biological activity evaluation of benzoate compounds as local anesthetics. RSC Adv., 2019, 9(12), 6627-6635.
[http://dx.doi.org/10.1039/C9RA00476A] [PMID: 35518493]

Rights & Permissions Print Cite
Article Metrics
22
2
© 2024 Bentham Science Publishers | Privacy Policy