Skip to content
2000
image of Designing, In-Silico Based Virtual Screening, Synthesis, Biological Evaluation and Molecular Dynamics Simulation of Novel Pyrazoleanalogs for the Treatment of Malaria

Abstract

Malaria, possibly a life-threatening disease, primarily affects the African and South Asian populations worldwide. The development of resistance to current treatment regimens for malaria is a major concern among the medical fraternity. This leads to the need to discover novel antimalarial agents that can attenuate the resistant malarial parasite. To discover novel pyrazole-based molecules that can be used to cure malaria. Initially, a 2D-QSAR-based virtual screening of the 16 pyrazole-based molecules designed for malaria was performed. Further virtual screening was conducted through the molecular docking simulations. Based on the results of the QSAR and molecular docking-based screening, hit compounds were synthesized and evaluated against malaria. Molecular dynamics simulations were performed for the top two molecules obtained from evaluation (Compounds 7b & 7d) to validate our results. From the QSAR-based and molecular docking-based virtual screening, we obtained a total of 6 hit molecules. These 6 hit molecules were synthesized, and their evaluation against malaria was performed. The top two best molecules, namely compounds 7b and 7d, showed EC50 values of 1.98 and 1.95 μg/ml, respectively. We further performed molecular dynamics simulations of these two molecules for 200 ns. From our study, we found that compounds 7b and 7d showed adequate anti-malarial activity. These compounds can be further explored for the development of more potent anti-malarial drugs.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/loc/10.2174/0115701786388937250919055512
2025-09-22
2025-12-15

  • From This Site

    /content/journals/loc/10.2174/0115701786388937250919055512
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Longley R.J. Malinga J. Hesping E. Sutanto E. DonVito S.M. Kucharski M. Oyong D.A. Verhoef J.M.J. Du E. Villasis E. Mwikali K. Trends Parasitol. 2024 40 5 355 361 10.1016/j.pt.2024.03.007 38609740
    [Google Scholar]
  2. World Health OrganizationWorld malaria report 2023 2023 Available from:https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2023
  3. World Health Organization Guidelines for the Treatment of Malaria 2015 Available from:https://www.afro.who.int/publications/guidelines-treatment-malaria-third-edition
    [Google Scholar]
  4. Milner D.A. Cold Spring Harb. Perspect. Med. 2018 8 1 a025569 10.1101/cshperspect.a025569 28533315
    [Google Scholar]
  5. Menard D. Dondorp A. Cold Spring Harb. Perspect. Med. 2017 7 7 a025619 10.1101/cshperspect.a025619 28289248
    [Google Scholar]
  6. Murugan K. Panneerselvam C. Subramaniam J. Paulpandi M. Rajaganesh R. Vasanthakumaran M. Madhavan J. Shafi S.S. Roni M. Portilla-Pulido J.S. Mendez S.C. Duque J.E. Wang L. Aziz A.T. Chandramohan B. Dinesh D. Piramanayagam S. Hwang J.S. Sci. Rep. 2022 12 1 4765 10.1038/s41598‑022‑08397‑5 35306526
    [Google Scholar]
  7. Ravindar L. Hasbullah S.A. Rakesh K.P. Hassan N.I. Eur. J. Med. Chem. 2023 259 115694 10.1016/j.ejmech.2023.115694 37556947
    [Google Scholar]
  8. Mishra I. Sharma V. Kumar N. Krishna G. Sethi V.A. Mittal R. Dhakad P.K. Mishra R. Med. Chem. 2025 21 1 11 31 10.2174/0115734064326879240801043412 39916435
    [Google Scholar]
  9. Chauhan M. Saxena A. Saha B. Eur. J. Med. Chem. 2021 218 113400 10.1016/j.ejmech.2021.113400 33823394
    [Google Scholar]
  10. Redway A. Spry C. Brown A. Wiedemann U. Fathoni I. Garnie L.F. Qiu D. Egan T.J. Lehane A.M. Jackson Y. Saliba K.J. Downer-Riley N. Int. J. Parasitol. Drugs Drug Resist. 2024 25 100536 10.1016/j.ijpddr.2024.100536 38663046
    [Google Scholar]
  11. Akolkar H.N. Dengale S.G. Deshmukh K.K. Karale B.K. Darekar N.R. Khedkar V.M. Shaikh M.H. Polycycl. Aromat. Compd. 2022 42 5 1959 1971 10.1080/10406638.2020.1821231
    [Google Scholar]
  12. Kalita T. Choudhury A. Shakya A. Ghosh S.K. Singh U.P. Bhat H.R. Curr Drug Discov Technol 2024 21 5 e240124226141 10.2174/0115701638276379231223101625 38279721
    [Google Scholar]
  13. Thakur A. Sharma B. Parashar A. Sharma V. Kumar A. Mehta V. J Biomol Struct Dyn 2024 42 1 148 162 10.1080/07391102.2023.2192805 36970779
    [Google Scholar]
  14. Sharma P. Thakur A. Goyal A. Singh Grewal A. Results Chem 2023 6 101105 10.1016/j.rechem.2023.101105
    [Google Scholar]
  15. Thakur A. Mehta V. Nagu P. Goutam K. Computer-Aided Drug Design: QSAR, Molecular Docking, Virtual Screening, Homology and Pharmacophore Modeling. Walter de Gruyter GmbH and Co KG 2024
    [Google Scholar]
  16. Kaushik D. Paliwal D. Kumar A. Int. J. Pharm. Pharm. Sci. 2015 2 5 42 53
    [Google Scholar]
  17. Aggarwal R. Singh G. Kaushik P. Kaushik D. Paliwal D. Kumar A. Eur. J. Med. Chem. 2015 101 326 333 10.1016/j.ejmech.2015.06.011 26160113
    [Google Scholar]
  18. Marinescu M. Antibiotics 2021 10 8 1002 10.3390/antibiotics10081002 34439052
    [Google Scholar]
  19. Ahmed A. Zaib S. Bhat M.A. Saeed A. Altaf M.Z. Zahra F.T. Shabir G. Rana N. Khan I. Front Chem. 2024 12 1380523 10.3389/fchem.2024.1380523 38694406
    [Google Scholar]
  20. Paliwal D Thakur A Sahu R Shah K Rao GSNK Anti-Infective Agent 2025 23 e22113525329311 10.2174/0122113525329311240926041006
    [Google Scholar]
  21. Wiley R.H. Jarboe C.H. Ellert H.G. J. Am. Chem. Soc. 1955 77 19 5102 5105 10.1021/ja01624a045
    [Google Scholar]
  22. Birch A.J. Cameron D.W. Rickards R.W. J. Chem. Society 1960 4395 4400 10.1039/JR9600004395
    [Google Scholar]
  23. Prakash O. Khurana V. Pundeer R. Indian J. Chem. 2016 26 3-4 133 139
    [Google Scholar]
  24. Ioakimidis L. Thoukydidis L. Mirza A. Naeem S. Reynisson J. QSAR Comb. Sci. 2008 27 4 445 456 10.1002/qsar.200730051
    [Google Scholar]
  25. Lipinski C.A. Lombardo F. Dominy B.W. Feeney P.J. Adv. Drug Deliv. Rev. 2012 64 4 17 10.1016/j.addr.2012.09.019 11259830
    [Google Scholar]
  26. Aggarwal S. Paliwal D. Kaushik D. Gupta G.K. Kumar A. Lett. Org. Chem. 2019 16 10 807 817 10.2174/1570178616666190212145754
    [Google Scholar]
  27. Aggarwal S. Paliwal D. Kaushik D. Gupta G.K. Kumar A. Comb. Chem. High Throughput Screen. 2018 21 3 194 203 10.2174/1386207321666180213092911 29436997
    [Google Scholar]
  28. Thakur A. Kumar A. Sharma V. Mehta V. bioRxiv 2022 10.1101/2022.10.15.512366
    [Google Scholar]
  29. Csizmadia P. MarvinSketch and MarvinView: Molecule applets for the World Wide Web Available from:https://chemaxon.com/blog/resentation/marvinsketch-and-marvinview-molecule-applets-for-the-world-wide-web
  30. Chemaxon Marvin 2025 Available from:https://chemaxon.com/marvin
  31. Yap C.W. J. Comput. Chem. 2011 32 7 1466 1474 10.1002/jcc.21707 21425294
    [Google Scholar]
  32. Gramatica P Chirico N Papa E Cassani S Kovarich S J Comput. Chem. 2013 34 24 2121 2132 10.1002/jcc.23361
    [Google Scholar]
  33. Tropsha A. Golbraikh A. Curr. Pharm. Des. 2007 13 34 3494 3504 10.2174/138161207782794257 18220786
    [Google Scholar]
  34. Roy K. Das R.N. Ambure P. Aher R.B. Chemom. Intell. Lab. Syst. 2016 152 18 33 10.1016/j.chemolab.2016.01.008
    [Google Scholar]
  35. Gómez-Jiménez G. Gonzalez-Ponce K. Castillo-Pazos D.J. Madariaga-Mazon A. Barroso-Flores J. Cortes-Guzman F. Martinez-Mayorga K. Adv. Protein Chem. Struct. Biol. 2018 113 85 117 10.1016/bs.apcsb.2018.04.001 30149907
    [Google Scholar]
  36. Gramatica P. QSAR Comb. Sci. 2007 26 5 694 701 10.1002/qsar.200610151
    [Google Scholar]
  37. Kolpakov F.A. Babenko V.N. Mol. Biol. 1997 31 4 540 547
    [Google Scholar]
  38. Trott O. Olson A.J. J. Comput. Chem. 2010 31 2 455 461 10.1002/jcc.21334 19499576
    [Google Scholar]
  39. Pettersen E.F. Goddard T.D. Huang C.C. Couch G.S. Greenblatt D.M. Meng E.C. Ferrin T.E. J. Comput. Chem. 2004 25 13 1605 1612 10.1002/jcc.20084 15264254
    [Google Scholar]
  40. Jejurikar BL Rohane SH Drug designing in discovery studio. Asian J. Res. Chem 2021 14 2 135 138 10.5958/0974‑4150.2021.00025.0
    [Google Scholar]
  41. Trager W. Jensen J.B. Science 1976 193 4254 673 675 10.1126/science.781840 781840
    [Google Scholar]
  42. WHO. In vitro micro-test (MARK III) for the assessment of the response of plasmodium falciparum to chloroquine, mefloquine, quinine, amodiaquine, sulfadoxine/pyrimethamine and artemisinin. 2001 Available from:https://iris.who.int/server/api/core/bitstreams/e47e5353-9069-4320-9f7e-4d6c46d16cc4/content
  43. Duffy E.M. Jorgensen W.L. J. Am. Chem. Soc. 2000 122 12 2878 2888 10.1021/ja993663t
    [Google Scholar]
  44. Berendsen H.J.C. van der Spoel D. van Drunen R. Comput. Phys. Commun. 1995 91 1-3 43 56 10.1016/0010‑4655(95)00042‑E
    [Google Scholar]
  45. Zoete V. Cuendet M.A. Grosdidier A. Michielin O. J. Comput. Chem. 2011 32 11 2359 2368 10.1002/jcc.21816 21541964
    [Google Scholar]
  46. Kumari R. Kumar R. Lynn A. J. Chem. Inf. Model. 2014 54 7 1951 1962 10.1021/ci500020m 24850022
    [Google Scholar]
/content/journals/loc/10.2174/0115701786388937250919055512
Loading
Designing, In-Silico Based Virtual Screening, Synthesis, Biological Evaluation and Molecular Dynamics Simulation of Novel Pyrazoleanalogs for the Treatment of Malaria
Bentham Science Publishers ; https://doi.org/10.2174/0115701786388937250919055512
/content/journals/loc/10.2174/0115701786388937250919055512
/content/journals/loc/10.2174/0115701786388937250919055512
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: virtual screening ; pharmacokinetic properties ; 2D-QSAR ; malaria ; in-silico ; molecular docking ; plasmodium falciparum lactate dehydrogenase ; molecular dynamic simulation ; pyrazole

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test