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Synthesis, Antileishmanial Activity and Molecular Docking Study of New 3,4-Dihydropyrimidinones/Thiones

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Pharmaceutical Chemistry Journal Aims and scope

Appearance of drug-unresponsive strains of Leishmania genus and toxic side effects of current chemotherapies necessitate the search for novel antileishmanial agents. Within present contribution, new dihydropyrimidine/thione-5-carboxylates/carboxamide derivatives were synthesized and biologically assessed against Leishmania major promastigotes. A few derivatives exhibited promising antileishmanial activities (IC50s 24.7 – 2223.9 μM). Results of biological assessment revealed compound 4 as the most potent antileishmanial agent. Compounds 1, 3, 4, 8 and 9 exhibited significant activity with regard to Glucantime (control drug). For both 5-carboxamide and 5-carboxylate series, it was found that steric hindrance of 4-(3-substituted phenyl) position was determinant in antileishmanial effect proposing a hydrophobic pocket near meta position of 4-phenyl moiety. Molecular docking approach vs. pteridine reductase 1 as a validated leishmanial target revealed that 5-carboxylate derivatives made H-bond with enzyme cofactor, i.e., nicotinamide adenine dinucleotide phosphate (NDP602). Interaction pattern was relatively similar to previously reported drugs such as trimethoprim. Binding efficiency indices (BEIs) were in accordance with antileishmanial IC50 values.

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References

  1. WHO (2019): https://www.who.int/csr/resources/publications/CSR_ISR_2000_1leish/en/, visited 20 December 2019.

  2. S. N. Khattab, A. A. Bekhit, A. El-Faham, et al., Chem. Pharm. Bull., 56, 1717 – 1721 (2008).

    Article  CAS  Google Scholar 

  3. D. Mukhopadhyay, J. E. Dalton, P. M. Kaye, et al., Trends Parasitol., 30, 65 – 74 (2014).

    Article  Google Scholar 

  4. P. J. Hotez and B. Pecoul, PLoS Neglected Trop. Dis., 4, e718 (2010).

  5. R. Reithinger., J. Dujardin, H. Louzir, et al., Lancet Infect. Dis., 9, 581 – 596 (2007).

    Article  Google Scholar 

  6. A. Ponte-Sucre, F. Gamarro, J. Dujardin, et al., PLoS Neglected Trop. Dis., 12, 1 – 24 (2017).

    Google Scholar 

  7. P. K. Chaudhari, A. Pandey, and V. H. Shah, Orient. J. Chem., 26(4), 1377 – 1383 (2010).

    CAS  Google Scholar 

  8. V. Virsodia, D. Manvar, R. R. S. Pissurlenkar, et al., Eur. J. Med. Chem., 43(10), 2103 – 2115 (2008).

    Article  CAS  Google Scholar 

  9. N. Foroughifar, S. K. Beromi, H. Pasdar, et al., Iran. J. Pharm. Res., 16(2), 596 – 601 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. T. U. Mayer, T. M. Kapoor, S. J. Haggarty, et al., Science, 268(5441), 971 – 974 (1999).

    Article  Google Scholar 

  11. U. Rashid, R. Sultana, N. Shaheen, et al., Eur. J. Med. Chem., 115, 230 – 244 (2016).

    Article  CAS  Google Scholar 

  12. F. Bohlooli, S. Sepehri, N. Razzaghi-Asl, et al., Comput. Biol. Chem., 67, 158 – 173 (2017).

    Article  CAS  Google Scholar 

  13. C. Abad-Zapatero and J. M. Metz, Drug Discov. Today, 10(7), 464 – 469 (2005).

    Article  Google Scholar 

  14. C. Abad-Zapatero, Expert Opin. Drug Discov., 2(4), 469 – 488 (2007).

    Article  CAS  Google Scholar 

  15. R. Rajasekara and Y.-P. Phoebe Chen, Drug Discov. Today, 20(8), 958 – 968 (2015).

    Article  Google Scholar 

  16. K. F. M Atta, T. M. Ibrahim, O. O. M. Farahat, et al., Future Med. Chem., 9(16), 1913 – 1929 (2017).

    CAS  Google Scholar 

  17. L. B. Tulloch, V. P. Martini, J. Iulek, et al., J. Med. Chem., 53(1), 221 – 229 (2010).

    Article  CAS  Google Scholar 

  18. S. Safari, R. Ghavimi, N. Razzaghi-Asl, et al., J. Heterocycl. Chem., 57(3), 1023 – 1033 (2020).

    Article  CAS  Google Scholar 

  19. A. Niapour, K. Amirshahrokhi, M. Azari Rad, et al., J. Ardabil Univ. Med. Sci., 19(1), 61 – 70 (2019).

  20. M. Heidari-Kharaji, V. Fallah-Omrani, A. Badirzadeh, et al., Parasite Immunol., 41(1), e12605 (2019).

  21. G. M. Morris, R. Huey, W. Lindstrom, et al., J. Comput. Chem., 30, 2785 – 2791, (2009).

    Article  CAS  Google Scholar 

  22. M. Sanner, J. Mol. Graphics Mod., 17(1), 57 – 61 (1999).

    CAS  Google Scholar 

  23. A. W. Schuettelkopf, L. W. Hardy, S. M. Beverley, et al., J. Mol. Biol., 352, 105 – 116 (2005).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and Parasitology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

    Behnam Mohammadi-Ghalehbin, Zahra Hosseinali & Sahar Sabour

  2. Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Saghi Sepehri & Nima Razzaghi-Asl

  3. Students Research Committee, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Negin Nejatkhah & Sahand Safari

Authors
  1. Behnam Mohammadi-Ghalehbin
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  2. Saghi Sepehri
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  3. Negin Nejatkhah
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  4. Sahand Safari
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  5. Zahra Hosseinali
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  6. Sahar Sabour
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  7. Nima Razzaghi-Asl
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Correspondence to Nima Razzaghi-Asl.

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Mohammadi-Ghalehbin, B., Sepehri, S., Nejatkhah, N. et al. Synthesis, Antileishmanial Activity and Molecular Docking Study of New 3,4-Dihydropyrimidinones/Thiones. Pharm Chem J 55, 1050–1056 (2022). https://doi.org/10.1007/s11094-021-02536-4

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  • DOI: https://doi.org/10.1007/s11094-021-02536-4

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