Generic placeholder image

Central Nervous System Agents in Medicinal Chemistry


ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

Research Article

Pyrazole based Furanone Hybrids as Novel Antimalarial: A Combined Experimental, Pharmacological and Computational Study

Author(s): Deepika Choudhary, Isha Rani, Jyoti Monga, Rajat Goyal, Asif Husain, Prabha Garg and Sukhbir Lal Khokra*

Volume 22, Issue 1, 2022

Published on: 27 April, 2022

Page: [39 - 56] Pages: 18

DOI: 10.2174/1871524922666220301121811

Price: $65


Background: Malaria parasite strains are resistant to the therapeutic effect of prophylactics medicines presently available. This resistance now poses a significant challenge to researchers to beat malaria parasitic infections. Strategies such as investigating newer hybrid chemical entities and specified drug targets may help us spot new efficient derivatives that bind to the parasites in a more specific manner and inhibit their growth.

Objective: To scientifically perform the experimental, pharmacological, and computational studies of pyrazole-based furanone hybrids as novel antimalarial agents.

Methods: A series of new furanone-based pyrazole derivatives were synthesized and investigated as potential antimalarial agents by performing in vitro antimalarial activity. To get further optimization, these synthesized derivatives were virtually screened based on ADME-T filters, and molecular docking studies were also accomplished on the crystal structures of Plasmodium falciparum lactate dehydrogenase (PfLDH). Furthermore, the in-silico prediction was supported by performing an LDH assay.

Results: The docking data suggested that the designed hybrid of furanone-pyrazole may act as PfLDH inhibitors. It was found that the results of experimental in vitro antimalarial activity and in silico analysis correlate well to each other to a good extent. The compounds (7d), (7g), and (8e) were found to be the most potent derivatives with IC50 values of 1.968, 1.983, and 2.069 μg/ml, respectively.

Conclusion: From the results, it may be concluded that compounds that are active in low doses might be adopted as a lead compound for the development of more active antimalarial agents. The synthesized compounds (7d), (7g), and (8e) exhibited good antimalarial activity with PfLDH inhibition. The best compounds can be explored further in the future for designing the potent inhibitors of PfLDH as new potent antimalarial agents.

Keywords: In-silico, furanones, pyrazole, antimalarial, PfLDH, synthesis, docking studies.

Graphical Abstract
Sato, S. Plasmodium-a brief introduction to the parasites causing human malaria and their basic biology. J. Physiol. Anthropol., 2021, 40(1), 1-13.
[] [PMID: 33413683]
Berwal, R.; Gopalan, N.; Chandel, K.; Prasad, G.B.; Prakash, S. Plasmodium falciparum: enhanced soluble expression, purification and biochemical characterization of lactate dehydrogenase. Exp. Parasitol., 2008, 120(2), 135-141.
[] [PMID: 18619439]
Varo, R.; Balanza, N.; Mayor, A.; Bassat, Q. Diagnosis of clinical malaria in endemic settings. Expert Rev. Anti Infect. Ther., 2021, 19(1), 79-92.
[] [PMID: 32772759]
Manohar, S.; Khan, S.I.; Rawat, D.S. Synthesis, antimalarial activity and cytotoxicity of 4-aminoquinoline-triazine conjugates. Bioorg. Med. Chem. Lett., 2010, 20(1), 322-325.
[] [PMID: 19910192]
Madapa, S.; Tusi, Z.; Sridhar, D.; Kumar, A.; Siddiqi, M.I.; Srivastava, K.; Rizvi, A.; Tripathi, R.; Puri, S.K.; Shiva Keshava, G.B.; Shukla, P.K.; Batra, S. Search for new pharmacophores for antimalarial activity. Part I: Synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides. Bioorg. Med. Chem., 2009, 17(1), 203-221.
[] [PMID: 19058973]
Nguyen, B.; Ma, R.; Tang, W.K.; Shi, D.; Tolia, N.H. Crystal structure of P. falciparum Cpn60 bound to ATP reveals an open dynamic conformation before substrate binding. Sci. Rep., 2021, 11(1), 5930.
[] [PMID: 33723304]
Kaushik, D.; Paliwal, D.; Kumar, A. 2D QSAR and Molecular docking studies of chloroquine-thiazolidinone derivatives as potential pfLDH inhibitors of Plasmodium falciparum. Int. J. Pharm. Pharm. Sci., 2015, 2(5), 42-53.
Saxena, S.; Durgam, L.; Guruprasad, L. Multiple e-pharmacophore modelling pooled with high-throughput virtual screening, docking and molecular dynamics simulations to discover potential inhibitors of Plasmodium falciparum lactate dehydrogenase (PfLDH). J. Biomol. Struct. Dyn., 2019, 37(7), 1783-1799.
[] [PMID: 29718775]
Khokra, S.L.; Monga, J.; Husain, A.; Vij, M.; Saini, R. Docking studies on butenolide derivatives as Cox-II inhibitors. Med. Chem. Res., 2013, 22(11), 5536-5544.
Acharya, B.N.; Saraswat, D.; Tiwari, M.; Shrivastava, A.K.; Ghorpade, R.; Bapna, S.; Kaushik, M.P. Synthesis and antimalarial evaluation of 1, 3, 5-trisubstituted pyrazolines. Eur. J. Med. Chem., 2010, 45(2), 430-438.
[] [PMID: 1992617]
Delarue-Cochin, S.; Grellier, P.; Maes, L.; Mouray, E.; Sergheraert, C.; Melnyk, P. Synthesis and antimalarial activity of carbamate and amide derivatives of 4-anilinoquinoline. Eur. J. Med. Chem., 2008, 43(10), 2045-2055.
[] [PMID: 18226428]
Verhaeghe, P.; Azas, N.; Gasquet, M.; Hutter, S.; Ducros, C.; Laget, M.; Rault, S.; Rathelot, P.; Vanelle, P. Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethylquinazolines. Bioorg. Med. Chem. Lett., 2008, 18(1), 396-401.
[] [PMID: 17981462]
Cortopassi, W.A.; Oliveira, A.A.; Guimarães, A.P.; Rennó, M.N.; Krettli, A.U.; França, T.C. Docking studies on the binding of quinoline derivatives and hematin to Plasmodium falciparum lactate dehydrogenase. J. Biomol. Struct. Dyn., 2011, 29(1), 207-218.
[] [PMID: 21696234]
Thillainayagam, M.; Pandian, L.; Murugan, K.K.; Vijayaparthasarathi, V.; Sundaramoorthy, S.; Anbarasu, A.; Ramaiah, S. In silico analy-sis reveals the anti-malarial potential of quinolinyl chalcone derivatives. J. Biomol. Struct. Dyn., 2015, 33(5), 961-977.
[] [PMID: 24871811]
Haredi Abdelmonsef, A.; Eldeeb Mohamed, M.; El-Naggar, M.; Temairk, H.; Mohamed Mosallam, A. Novel quinazolin-2, 4-dione hybrid molecules as possible inhibitors against Malaria: Synthesis and in silico molecular docking studies. Front. Mol. Biosci., 2020, 7, 105.
[] [PMID: 32582763]
Khokra, S.; Monga, J.; Husain, A. Pharmacophore modeling studies on N-hydroxyphenyl acrylamides and N-hydroxypyridin-2-ylacrylamides as inhibitor of human cancer leukemia K562 cells. Med. Chem. Res., 2013, 22(4), 1837-1845.
Niyibizi, J.B.; Kirira, P.G.; Kimani, F.T.; Oyatsi, F.; Ng’ang’a, J.K. Chemical synthesis, efficacy, and safety of antimalarial hybrid drug comprising of sarcosine and aniline pharmacophores as scaffolds. J. Trop. Med., 2020, 2020, 1-12.
Sabti, A.B.; Al-Fregi, A.A.; Yousif, M.Y. Synthesis and antimicrobial evaluation of some new organic tellurium compounds based on pyrazole derivatives. Molecules, 2020, 25(15), 3439.
[] [PMID: 32751090]
Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y.N.; AlAizari, F.A.; Ansar, M. Synthesis and pharmacological activities of pyra-zole derivatives: A review. Molecules, 2018, 23(1), 134.
[] [PMID: 29329257]
Noedl, H.; Wongsrichanalai, C.; Wernsdorfer, W.H. Malaria drugsensitivity testing: new assays, new perspectives. Trends Parasitol., 2003, 19(4), 175-181.
[] [PMID: 12689648]
Maji, A.K. Drug susceptibility testing methods of antimalarial agents. Trop. Parasitol., 2018, 8(2), 70-76.
[] [PMID: 30693210]
Ioakimidis, L.; Thoukydidis, L.; Mirza, A.; Naeem, S.; Reynisson, J. Benchmarking the reliability of QikProp. Correlation between exper-imental and predicted values. QSAR Comb. Sci., 2008, 27(4), 445-456.
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permea-bility in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[] [PMID: 11259830]
Molegro, ApS, Molegro Virtual Docker; Aarhus, Denmark, 2008. 2.4.
Abou-Elmagd, W.S. EL-Ziaty, A.K.; Elzahar, M.I.; Ramadan, S.K.; Hashem, A.I. Synthesis and antitumor activity evaluation of some N-heterocycles derived from pyrazolyl-substituted2(3H)- furanone. Synth. Commun., 2016, 46(14), 1197-1208.
Rieckmann, K.H.; McNamara, J.V.; Frischer, H.; Stockert, T.A.; Carson, P.E.; Powell, R.D. Gametocytocidal and sporontocidal effects of primaquine and of sulfadiazine with pyrimethamine in a chloroquine-resistant strain of Plasmodium falciparum. Bull. World Health Organ., 1968, 38(4), 625-632.
[PMID: 4876731]
Trager, W.; Jensen, J.B. Human malaria parasites in continuous culture. Science, 1976, 193(4254), 673-675.
[] [PMID: 781840]
Penna-Coutinho, J.; Cortopassi, W.A.; Oliveira, A.A.; França, T.C.; Krettli, A.U. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies. PLoS One, 2011, 6(7), e21237.
[] [PMID: 21779323]
Gehlhaar, D.K.; Verkhivker, G.; Rejto, P.A. Docking conformationally flexible small molecules into a protein binding site through evolu-tionary programming. Lect. Notes Comput. Sci., 1995, 1447, 449-461.
Rosell, M.; Fernández-Recio, J. Docking-based identification of small-molecule binding sites at protein-protein interfaces. Comput. Struct. Biotechnol. J., 2020, 18, 3750-3761.
[] [PMID: 33250973]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy