Login Register Cart 0
Generic placeholder image

Current Drug Discovery Technologies

Editor-in-Chief

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

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

Computational Studies and Synthesis of New Heterocyclics as CNS Agents

Author(s): Pooja Saini* and Sushil Kumar

Volume 21, Issue 3, 2024

Published on: 22 September, 2023

Article ID: e180923221195 Pages: 10

DOI: 10.2174/1570163820666230918100218

Price: $65

Abstract

Aim: This research work aimed to design and synthesize some new molecules of phenothiazine. The work’s emphasis was on forming new phenothiazines in two series, 1-(10H-phenothiazin- 10-yl)-2-((4-(1-(phenylimino)ethyl)phenyl)amino)ethan-1-one derivatives (4a-4j) and 1-(4-((2-oxo-2- (10H-phenothiazin-10-yl)ethyl)amino)phenyl)-3-phenylprop-2-en-1-one derivatives (P1-P5).

Methods: Chloroacetylation of phenothiazine was done to afford 2-chloro-1-(10H-phenothiazin-10- yl)ethan-1-one, which was further reacted with 4-amino acetophenone to produce 2-((4- acetylphenyl)amino)-1-(10H-phenothiazin-10-yl)ethan-1-one. Then, it was treated with substituted anilines and substituted benzaldehydes to produce the final derivatives 4a-4j and P1-P5, respectively.

Results: All 15 derivatives (4a-4j and P1-P5) were characterized by evaluating their Rf value, melting point, solubility, IR spectroscopy, and 1HNMR spectroscopy. Molecular docking was performed by using AutoDock Vina v.1.2.0 (The Scripps Research Institute, La Jolla, CA, USA) docking software, and the anxiolytic activity of the derivatives was assessed by using the elevated plus maze model.

Conclusion: The designed scheme was executed in the departmental laboratory. The chemical structure of the compounds was confirmed on the basis of TLC, IR, and 1HNMR analyses. The docking study revealed a good docking score of the compounds. The Log P value of the compounds indicated their good penetration into CNS. The compounds were also screened for anxiolytic activity. Among them, compounds 4f, 4h, and P3 showed maximum activity as anti-anxiolytic agents.

Keywords: Heterocyclic agents, anxiolytic activity, molecular docking, docking score, diazepam, aromatic molecules.

Graphical Abstract

[1]
Bernthsen B. Ultrasound-mediated synthesis of phenothiazine derivatives and their in vitro antibacterial and antioxidant studies. Dent Chem Ges 1883; 16: 2996.
[2]
Barbara W, Joseph D, Terry S, Cecily D. Pharmacotherapy Handbook. 8thEdi. McGraw Hill Professional pp. 1164.
[3]
Kurihara T, Motohashi N, Pang GL, Higano M, Kiguchi K, Molnár J. Correlations between topological resonance energy of methyl-substituted benz[c]acridines, benzo[a]phenothiazines and chrysenes, and their carcinogenic or antitumor activities. Anticancer Res 1996; 16(5A): 2757-65.
[PMID: 8917383]
[4]
Kumar VD, Gupta AK, Yadav YC. Synthesis, characterization and antimicrobial activity of benzimidazolyl-phenothiazine derivatives. Int J PharmRes 2010; 2(2): 45-50.
[5]
Pluta K, Morak-Młodawska B, Jeleń M. Recent progress in biological activities of synthesized phenothiazines. Eur J Med Chem 2011; 46(8): 3179-89.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.013] [PMID: 21620536]
[6]
Meyer M, Lang PT, Gerber S, et al. Synthesis and testing of a focused phenothiazine library for binding to HIV-1 TAR RNA. Chem Biol 2006; 13(1): 993.
[http://dx.doi.org/10.1016/j.chembiol.2006.07.009] [PMID: 16984889]
[7]
Kalkanidis M, Klonis N, Tilley L, Deady LW. Novel phenothiazine antimalarials: Synthesis, antimalarial activity, and inhibition of the formation of β-haematin. Biochem Pharmacol 2002; 63(5): 833-42.
[http://dx.doi.org/10.1016/S0006-2952(01)00840-1] [PMID: 11911834]
[8]
Bishnoi A, Pandey VK, Saxena R, Indian J. Chem, Sect B. Org Chem Incl Med Chem 2002; 41(1): 1978.
[9]
Chopde HN, Pagadala R, Jetti V. An efficient synthesis of novel bioactive azetidinones and thiazolidinones of 1, 5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one. Int J Pharm Biosci 2011; 2(1): 19-22.
[10]
Saranya AV, Ravi S. Int J Clin Exp Pathol 2013; 3(2): 9-21.
[11]
Saranya AV, Ravi S. Synthesis of 5-phenyl-3-(10H-phenothiazinyl)-Δ2-cyclohexen-1-ones by conventional and microwave-assisted methods and their antifungal activity. Res Chem Intermed 2014; 40(8): 3085-93.
[http://dx.doi.org/10.1007/s11164-013-1153-9]
[12]
Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: New docking methods, expanded force field, and python bindings. J Chem Inf Model 2021; 61(8): 3891-8.
[http://dx.doi.org/10.1021/acs.jcim.1c00203] [PMID: 34278794]
[13]
Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
[14]
SAMSON. Software for Adaptive Modeling and Simulation of Nanosystems. Available from: https://www.samson-connect.net (accessed on 11 November 2022)
[15]
Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE. Structure of a human synaptic GABAA receptor. Nature 2018; 559(7712): 67-72.
[http://dx.doi.org/10.1038/s41586-018-0255-3] [PMID: 29950725]
[16]
Molecular Operating Environment (MOE). (202202)Chemical computing group ULC. Montreal, QC, Canada 2022
[17]
Edelsbrunner H, Liang J, Fu P, Facello M. Measuring proteins and voids in proteins. Proceedings of the Twenty-Eighth Annual Hawaii International Conference on System Sciences,. 256-64. 03-06 January 1995, Wailea, HI, USA
[http://dx.doi.org/10.1109/HICSS.1995.375331]
[18]
Gabriel de Oliveira M, Kelle da Silva Moreira L, Turones LC. Mechanism of action involved in the anxiolytic-like effects of Hibalactone isolated from Hydrocotyle umbellata L. J Tradit Complement Med 2021; 12(4): 318-29.
[19]
Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 1996; 54(1): 21-30.
[http://dx.doi.org/10.1016/0091-3057(95)02126-4] [PMID: 8728535]
[20]
Kumar D, Bhat ZA, Kumar V, Shah M. Nature: Anxiolytics in the lap of nature. Webmed Cent Pharmac Sci 2011; 2(9): WMC002140.
[21]
Rodgers RJ, Cao BJ, Dalvi A, Holmes A. Animal models of anxiety: An ethological perspective. Braz J Med Biol Res 1997; 30(3): 289-304.
[http://dx.doi.org/10.1590/S0100-879X1997000300002] [PMID: 9246227]

Rights & Permissions Print Cite
Article Metrics
9
2
© 2024 Bentham Science Publishers | Privacy Policy