Generic placeholder image

Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

In Silico Analysis, Synthesis, and Biological Evaluation of Triazole Derivatives as H1 Receptor Antagonist

Author(s): Sandip N. Badeliya*, Ishan I. Panchal, Bibhuranjan Panigrahi and C. N. Patel

Volume 18, Issue 4, 2021

Published on: 21 April, 2020

Page: [492 - 502] Pages: 11

DOI: 10.2174/1568009620666200421082221

Price: $65

Open Access Journals Promotions 2
Abstract

Introduction: Histamine, a biological amine, is considered as a principal mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. Numerous derivatives have been developed that strive with histamine at the H1 receptor and prevent binding of histamine at the H1 receptor, thereby preventing allergic reactions. Molecules containing a triazole ring fused with six-membered ring systems are found to possess broad applications in the field of medicine and industry. The present study is an attempt to characterize the impact of the nature of the substituent introduced at 5 positions of the-4H-1,2,4-triazole-3-thiol on their capacities to bind with the H1 receptor.

Methods: Molecular docking (PDB ID: 3RZE) revealed that synthesized derivatives and target proteins were actively involved in binding with Tyr-108, Thr-112, Ala-216, and Phe-432 subunits. A pharmacophore model, new 5-(4-substituted phenyl)-4-(phenylamino)-4-H-1,2,4-triazole-3- thiols (5a-5h) were designed and evaluated for H1-blocking activity using isolated segments from the guinea pig ileum.

Results: According to in silico analysis, all the compounds have a topological polar surface area (TPSA) less than 140 Å squared, so they tend to easily penetrate cell membranes. The results show that most of the compounds are non-inhibitors of CYP450 substrates that play a fundamental role in drug metabolism. Compounds 5d (50.53±12.03), 5h (50.62±12.33) and 7a (55.07±12.41) are more active than others.

Conclusion: Finally, these derivatives were screened for H1 receptor antagonist activity using guinea pig ileum, taking chlorpheniramine maleate as a standard. Most of the compounds were found to possess better antihistamine activity.

Keywords: Histamine, molecular docking, 1, 2, 4-triazole, TPSA, guinea pig ileum, H1 Receptor.

Graphical Abstract
[1]
Ring J, Kramer U, Shafer T, and Behrendt H. Why are allergies increasing? Curr Opin Immunol 2001; 13: 701-8.
[2]
Martins P, Jesus J, Santos S, et al. Heterocyclic anticancer compounds: recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules 2015; 20: 16852-91.
[3]
Godhani DR, Jogel AA, Sanghani AM and, Mehta JP. Synthesis and biological screening of 1,2,4-triazole derivatives. Ind J Chem 2015; 54B: 556-64.
[4]
Simons FE and, Simons KJ. Histamine and H1-antihistamines: Celebrating a century of progress. J Allergy Clin Immunol 2011; 128: 1139-50.
[5]
Gushchin IS. Inverse agonists of H1 receptors as promising antiallergy agents. Pharm Chem J 2010; 44: 1-6.
[6]
Baroody FM, and Naclerio RM. Antiallergic effects of H1-receptor antagonists. Allergy 2000; 55: 17-27.
[7]
Chen MD, Lu SJ, Yuan GP, Yang SY, Du XL. Synthesis and antibacterial activity of some heterocyclic beta-enamino ester derivatives with 1,2,3-triazole. Heterocyclic Comm 2000; 6: 421-6.
[8]
Sheremet EA, Tomanov RI, Trukhin EV, Berestovitskaya VM. Synthesis of 4-aryl-5-nitro-1,2,3-triazoles. Russ J Org Chem 2004; 40: 594-5.
[9]
Hafez HN, Abbas HA, El-Gazzar AR. Synthesis and evaluation of analgesic, anti-inflammatory and ulcerogenic activities of some triazolo- and 2-pyrazolyl-pyrido[2,3-d]-pyrimidines. Acta Pharm 2008; 58: 359-78.
[10]
Banu KM, Dinakar A, Ananthanarayanan C. Synthesis, characterization, antimicrobial studies and pharmacological screening of some substituted 1,2,3-triazoles. Indian J Pharm Sci 1999; 61: 202-5.
[11]
Guan LP, Jin QH, Tian GR, Chai KY, Quan ZS. Synthesis of some quinoline-2(1H)-one and 1,2,4-triazolo [4,3-a]quinoline derivatives as potent anticonvulsants. J Pharm Sci 2007; 10: 254-62.
[12]
Passannanti A, Diana P, Barraja P, Mingoia F, Lauria A, Cirrincione G. Pyrrolo[2,3-d][1,2,3]triazoles as potential antineoplastic agents. Heterocycles 1998; 48: 1229-35.
[13]
Gujjar R, Marwaha A, El Mazouni F, et al. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J Med Chem 2009; 52: 1864-72.
[14]
Johns BA, Weatherhead JG, Allen SH, et al. The use of oxadiazole and triazole substituted naphthyridines as HIV-1 integrase inhibitors Part 1: Establishing the pharmacophore. Bioorg Med Chem Lett 2009; 19: 1802-6.
[15]
Manfredini S, Vicentini CB, Manfrini M, et al. Pyrazolo-triazoles as light activable DNA cleaving agents. Bioorg Med Chem 2000; 8: 2343-6.
[16]
Duran A, Dogan HN, Rollas S. Synthesis and preliminary anticancer activity of new 1,4-Dihydro-3-(3-hydroxy-2- naphthyl)-4-substituted-5H-1,2,4-triazoline-5-thiones. Farmaco 2002; 57: 559-64.
[17]
Sztanke K, Tuzimski T, Rzymowska J, et al. Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives. Eur J Med Chem 2008; 43: 404-19.
[18]
Sadek B, Alisch R, Buschauer A, Elz S. Synthesis and dual histamine H1 and H2 receptor antagonist activity of cyanoguanidine derivatives. Molecules 2013; 18: 14186-202.
[19]
Elbayaa RY. Computer-aided design, synthesis and biological evaluation of 5- substituted aminomethylenepyrimidine-2,4,6-triones as H1 antihistaminic agents (Part2). Med Chem 2014; 10: 66-73.
[20]
Gobinath M, Subramanian N, Alagarsamy V. Design, synthesis and H1-antihistaminic activity of novel 1-substituted-4-(3-chlorophenyl)-[1,2,4] triazolo [4,3-a] quinazolin-5(4H)-ones. J Saudi Chem Soc 2015; 19(3): 282-6.
[21]
Shaikh MH, Subhedar DD, Nawale L, et al. 1,2,3-Triazole derivatives as antitubercular agents: synthesis, biological evaluation and molecular docking study. Med Chem Commun 2015; 6: 1104-16.
[22]
Sadeghpour H, Khabnadideh S, Zomorodian K, et al. Design, Synthesis, and Biological Activity of New Triazole and Nitro-Triazole Derivatives as Antifungal Agents. Molecules 2017; 22: 1150-61.
[23]
Loustaud-Ratti V, Debette-Gratien M, Jacques J, et al. Ribavirin: Past, present and future. World J Hepatol 2016; 8(2): 123-30.
[24]
Panchal II, Rajput R, Patel AD. Design, synthesis and pharmacological evalution of 1,3,4-oxadiazole derivatives as collapsin response mediator protein 1 (CRMP 1) inhibitors. Curr Drug Discov Technol 2018; 5: 10.
[http://dx.doi.org/10.2174/1570163815666181106090708]
[25]
Shimamura T, Shiroishi M, Weyand S, et al. Structure of the human histamine H1 receptor complex with doxepin. Nature 2011; 475: 65-70.
[26]
Lalitha P, Sivakamasundari S. Calculation of molecular lipophilicity and drug likeness for few heterocycles. Orient J Chem 2010; 26(1): 135-41.
[27]
Panchal II, Shah AP, Devgirkar A, et al. In silico analysis and molecular docking studies of novel 6,7-dihydropyrano[2,3-d]pyrimidin-5-one derivatives as Human Epidermal Growth Factor Receptor 2 (HER2) and Epidermal Growth Factor Receptor (EGFR) Inhibitors. Curr Cancer Ther Rev 2019; 15(3): 235-47.
[28]
Furniss BS, Hannaford AJ, Smith PW, and Tatchell AR. In Vogel’s text book of Practical Organic Chemistry. 5th Edn;. Longman Scientific & Technical 1989; p. 1077.
[29]
Furniss BS, Hannaford AJ, Smith PW, and Tatchell AR. In Vogel’s text book of Practical Organic Chemistry. 5th Edn;. Longman Scientific & Technical 1989; p. 1269.
[30]
Reid JR, and Heindel ND. Improved syntheses of 5-substituted-4-amino-3-mercapto-(4-H)-1,2,4-triazoles. J Het Chem 1976; 13: 925-6.
[31]
Dave TK, Purohit DH, Akbari JD and, Joshi HS. Synthesis and pharmacological study of thiazolidinones and mannich bases of 4-amino-3-mercapto-5-pyridin-3’-yl-[1,2,4]-triazole. Ind J Chem 2007; 46(B): 352-6.

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