Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Review Article

Importance of Pharmacophore in Designing Anticonvulsant Agents

Author(s): Amol Kale*, Rajendra Kakde, Smita Pawar, Vishal Jagtap and Rahul Dorugade

Volume 22, Issue 4, 2023

Published on: 21 July, 2022

Page: [500 - 511] Pages: 12

DOI: 10.2174/1871527321666220401115529

Price: $65

Abstract

Drug design is one of the critical aspects of the drug development process. The present review focused on different heterocyclic molecules having anticonvulsant activity with structural diversity and common pharmacophoric features. For the first time (1995), Dimmock and his team introduced specific arrangements of three important pharmacophores for anticonvulsant activity. These pharmacophores include two hydrophobic binding sites and one hydrogen binding site. After a few years (2012), Pandeya modified Dimmock’s concept by adding one more pharmacophoric feature as an electron donor in the previously suggested pharmacophoric arrangement of the anticonvulsant. As a result, numerous scientists designed anticonvulsant drugs based on Dimmock’s and Pandeya’s concept. In addition, marketed anticonvulsant preparation containing Riluzole, Phenobarbital, Progabide, Ralitoline, etc., also holds the suggested pharmacophores by Dimmock and Pandeya’s pharmacophoric concept. This review mainly focuses on the compilation of reported scientific literature in the last decade on the pharmacophoric features of different heterocyclic anticonvulsants, which will help develop new anticonvulsants.

Keywords: Pharmacophore models, anticonvulsant, maximal electroshock seizure, drug development, electron donor, pharmacophoric features.

Graphical Abstract
[1]
Saravanan G, Alagarsamy V, Prakash CR. Design, synthesis and anticonvulsant activities of novel 1-(substituted/unsubstituted benzylidene)-4-(4-(6,8-dibromo-2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)phenyl) semicarbazide derivatives. Bioorg Med Chem Lett 2012; 22(9): 3072-8.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.068] [PMID: 22487180]
[2]
Sadarangani IR, Bhatia S, Amarante D, Lengyel I, Stephani RA. Synthesis, resolution and anticonvulsant activity of chiral N-1′-ethyl,N-3′-(1-phenylethyl)-(R,S)-2‘H,3H,5’H-spiro-(2-benzofuran-1,4′-imidazolidine)-2′,3,5′-trione diastereomers. Bioorg Med Chem Lett 2012; 22(7): 2507-9.
[http://dx.doi.org/10.1016/j.bmcl.2012.02.005] [PMID: 22401865]
[3]
Pandeya SN. Semicarbazone-a versatile therapeutic pharmacophore for fragment based anticonvulsant drug design. Acta Pharm 2012; 62(3): 263-86.
[http://dx.doi.org/10.2478/v10007-012-0030-1] [PMID: 23470343]
[4]
Kamiński K, Obniska J, Wiklik B, Atamanyuk D. Synthesis and anticonvulsant properties of new acetamide derivatives of phthalimide, and its saturated cyclohexane and norbornene analogs. Eur J Med Chem 2011; 46(9): 4634-41.
[http://dx.doi.org/10.1016/j.ejmech.2011.07.043] [PMID: 21840629]
[5]
Siddiqui N, Alam MS, Sahu M, et al. Design, synthesis, anticonvulsant evaluation and docking study of 2-[(6-substitutedbenzo[d]thiazol-2-ylcarbamoyl)methyl]-1-(4-substituted phenyl)isothioureas. Bioorg Chem 2017; 71: 230-43.
[http://dx.doi.org/10.1016/j.bioorg.2017.02.009] [PMID: 28238402]
[6]
Pandeya SN, Yogeeswari P, Stables JP. Synthesis and anticonvulsant activity of 4-bromophenyl substituted aryl semicarbazones. Eur J Med Chem 2000; 35(10): 879-86.
[http://dx.doi.org/10.1016/S0223-5234(00)01169-7] [PMID: 11121613]
[7]
Pandeya SN, Raja AS, Stables JP. Synthesis of isatin semicarbazones as novel anticonvulsants--role of hydrogen bonding. J Pharm Pharm Sci 2002; 5(3): 266-71.
[PMID: 12553895]
[8]
Rajak H, Deshmukh R, Aggarwal N, Kashaw S, Kharya MD, Mishra P. Synthesis of novel 2,5-disubstituted 1,3,4-thiadiazoles for their potential anticonvulsant activity: Pharmacophoric model studies. Arch Pharm (Weinheim) 2009; 342(8): 453-61.
[http://dx.doi.org/10.1002/ardp.200800213] [PMID: 19565600]
[9]
Kashaw SK, Kashaw V, Mishra P, Jain NK, Stables JP. Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea. Eur J Med Chem 2009; 44(11): 4335-43.
[http://dx.doi.org/10.1016/j.ejmech.2009.05.008] [PMID: 19674817]
[10]
Siddiqui N, Ahsan W. Triazole incorporated thiazoles as a new class of anticonvulsants: Design, synthesis and in vivo screening. Eur J Med Chem 2010; 45(4): 1536-43.
[http://dx.doi.org/10.1016/j.ejmech.2009.12.062] [PMID: 20116140]
[11]
Siddiqui N, Ahsan W, Alam MS, Ali R, Srivastava K. Design, synthesis and evaluation of anticonvulsant activity of pyridinylpyrrolidones: A pharmacophore hybrid approach. Arch Pharm (Weinheim) 2012; 345(3): 185-94.
[http://dx.doi.org/10.1002/ardp.201100140] [PMID: 21997797]
[12]
Amir M, Asif S, Ali I, Hassan Mohd Z. Synthesis of benzothiazole derivatives having acetamido and carbothioamido pharmacophore as anticonvulsant agents. Med Chem Res 2012; 21(9): 2661-70.
[http://dx.doi.org/10.1007/s00044-011-9791-1]
[13]
Hassan MZ, Khan SA, Amir M. Design, synthesis and evaluation of N-(substituted benzothiazol-2-yl)amides as anticonvulsant and neuroprotective. Eur J Med Chem 2012; 58: 206-13.
[http://dx.doi.org/10.1016/j.ejmech.2012.10.002] [PMID: 23124217]
[14]
Prakash CR, Raja S, Saravanan G. Anticonvulsant activity of novel 1-(substituted benzylidene)-4-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl) semicarbazide derivatives in mice and rats acute seizure models. Chem Biol Drug Des 2012; 80(4): 524-32.
[http://dx.doi.org/10.1111/j.1747-0285.2012.01399.x] [PMID: 22540392]
[15]
Malik S, Bahare RS, Khan SA. Design, synthesis and anticonvulsant evaluation of N-(benzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamide derivatives: A hybrid pharmacophore approach. Eur J Med Chem 2013; 67: 1-13.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.026] [PMID: 23831504]
[16]
Nikalje APG, Shaikh AN, Shaikh SI, Kalam Khan FA, Sangshetti JN, Shinde DB. Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted thiazolidin-3ylamino)ethyl)] benzamide derivatives as anticonvulsant agents. Bioorg Med Chem Lett 2014; 24(24): 5558-62.
[http://dx.doi.org/10.1016/j.bmcl.2014.11.016] [PMID: 25466174]
[17]
Ibrahim M-K, El-Adl K, Al-Karmalawy AA. Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo-2-phenyl-3-substituted-quinazolin-4(3h)-ones. Bull Fac Pharm Cairo Univ 2015; 53(2): 101-16.
[http://dx.doi.org/10.1016/j.bfopcu.2015.05.001]
[18]
Dash B, Dash S, Laloo D. Design and synthesis of 4-substituted quinazoline derivatives for their anticonvulsant and CNS depressant activities. Int J Pharm Pharm Sci 2016; 9(1): 165.
[http://dx.doi.org/10.22159/ijpps.2017v9i1.15492]
[19]
Sahu M, Siddiqui N, Naim MJ, et al. Design, synthesis, and docking study of pyrimidine-triazine hybrids for GABA estimation in animal epilepsy models: Pyrimidine-triazine hybrids as anticonvulsants. Arch Pharm (Weinheim) 2017; 350(9): 1700146.
[http://dx.doi.org/10.1002/ardp.201700146] [PMID: 28758238]
[20]
Abuelhassan AH, Badran MM, Hassan HA, Abdelhamed D, Elnabtity S, Aly OM. Design, synthesis, anticonvulsant activity, and pharmacophore study of new 1,5-diaryl-1h-1,2,4-triazole-3-carboxamide derivatives. Med Chem Res 2018; 27(3): 928-38.
[http://dx.doi.org/10.1007/s00044-017-2114-4]
[21]
Noureldin NA, Kothayer H, Lashine EM, Baraka MM, El-Eraky W, Awdan SAE. Synthesis, anticonvulsant activity, and SAR study of novel 4-quinazolinone derivatives: Anticonvulsant quinazolinones. Arch Pharm (Weinheim) 2017; 350(2): 1600332.
[http://dx.doi.org/10.1002/ardp.201600332] [PMID: 28177550]
[22]
Sahu M, Siddiqui N, Sharma V, Wakode S. 5,6-Dihydropyrimidine-1(2H)-carbothioamides: Synthesis, in vitro GABA-AT screening, anticonvulsant activity and molecular modelling study. Bioorg Chem 2018; 77: 56-67.
[http://dx.doi.org/10.1016/j.bioorg.2017.12.031] [PMID: 29331765]
[23]
Jain N, Jaiswal J, Pathak A, Singour PK. Synthesis, molecular docking and evaluation of 3-{4-[2-amino-4-(substitutedphenyl)-2h-[1,3]oxazin/thiazin-6-yl}2-phenyl-3h-quinazolin -4-one derivatives for their anticonvulsant activity. Cent Nerv Syst Agents Med Chem 2018; 18(1): 63-73.
[http://dx.doi.org/10.2174/1871524917666170104142033] [PMID: 28056730]
[24]
Kothayer H, Ibrahim SM, Soltan MK, Rezq S, Mahmoud SS. Synthesis, in vivo and in silico evaluation of novel 2,3-dihydroquinazolin-4(1H)-one derivatives as potential anticonvulsant agents. Drug Dev Res 2019; 80(3): 343-52.
[http://dx.doi.org/10.1002/ddr.21506] [PMID: 30565722]
[25]
Firdaus JU, Habib A, Siddiqui N, et al. Design, synthesis, and molecular docking study of benzothiazolotriazine derivatives for anticonvulsant potential. Arch Pharm (Weinheim) 2018; 351(12): e1800154.
[http://dx.doi.org/10.1002/ardp.201800154] [PMID: 30479053]
[26]
Dehestani L, Ahangar N, Hashemi SM, et al. Design, synthesis, in vivo and in silico evaluation of phenacyl triazole hydrazones as new anticonvulsant agents. Bioorg Chem 2018; 78: 119-29.
[http://dx.doi.org/10.1016/j.bioorg.2018.03.001] [PMID: 29550532]
[27]
Song MX, Huang Y, Wang S, Wang ZT, Deng XQ. Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4-triazolone moiety. Arch Pharm (Weinheim) 2019; 352(8): e1800313.
[http://dx.doi.org/10.1002/ardp.201800313] [PMID: 31330092]
[28]
Aboutabl ME, Hassan RM, El-Azzouny AA-S, Aboul-Enein MN, Abd-Allah WH. Design and synthesis of novel parabanic acid derivatives as anticonvulsants. Bioorg Chem 2020; 94: 103473.
[http://dx.doi.org/10.1016/j.bioorg.2019.103473] [PMID: 31831160]
[29]
Wang S, Liu H, Lei K, et al. Synthesis of 3,4-dihydroquinolin-2(1H)-one derivatives with anticonvulsant activity and their binding to the GABAA receptor. Bioorg Chem 2020; 103: 104182.
[http://dx.doi.org/10.1016/j.bioorg.2020.104182] [PMID: 32890992]
[30]
Abd-Allah WH, Osman EEA, Anwar MA-E-M, Attia HN, El Moghazy SM. Design, synthesis and docking studies of novel benzopyrone derivatives as anticonvulsants. Bioorg Chem 2020; 98: 103738.
[http://dx.doi.org/10.1016/j.bioorg.2020.103738] [PMID: 32179283]
[31]
Nath R, Shahar Yar M, Pathania S, Grover G, Debnath B, Akhtar MJ. Synthesis and anticonvulsant evaluation of indoline derivatives of functionalized aryloxadiazole amine and benzothiazole acetamide. J Mol Struct 2021; 1228: 129742.
[http://dx.doi.org/10.1016/j.molstruc.2020.129742]
[32]
Siddiqui AA, Partap S, Khisal S, Yar MS, Mishra R. Synthesis, anti-convulsant activity and molecular docking study of novel thiazole pyridazinone hybrid analogues. Bioorg Chem 2020; 99: 103584.
[http://dx.doi.org/10.1016/j.bioorg.2020.103584] [PMID: 32229345]

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