Molecular docking and synthesis of N-alkyl-isatin-3-imino aromatic amine derivatives and their antileishmanial and cytotoxic activities

Farshid Hassanzadeh , Seyed Hossein Hejazi, Elham Jafari , Atefeh Mohammadi fard, Hojjat Sadeghi-aliabadi

Abstract


Background and purpose: Isatin derivatives have excited attention due to their biological attractions, especially, anticancer properties. Isatin analogs such as semaxanib and sunitinib were exposed to tyrosine kinase inhibitory properties. N-substituted isatins were reported to show cytotoxic activity. On the other, the extension of impressive and cost-effective agents against leishmaniasis is necessary in third-world countries. The capability of isatin derivatives to create novel anticancer and anti-leishmanial compounds has been identified in medicinal chemistry research. The current study aimed to synthesize N-alkyl-isatin-3-imino aromatic amine compounds and evaluate their biological effects.

Experimental approach: Synthesis started with the formation of 2-chloro-N-phenylacetamide derivatives                 by the reaction of aniline derivatives with chloroacetyl chloride. N-alkylation of isatin was performed                              in the presence of K2CO3 in N, N-dimethylformamide. Final products were prepared via the condensation                 of N-alkyl isatin derivatives with aromatic amines. Cell viability was checked out by using the MTT                          assay against cancer cells. Final compounds were screened for anti-leishmanial activity. The molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to define the possible interactions.

Findings/Results: Compounds 5c and 4d with IC50 value of 50 µM showed cytotoxic activity on the                            MCF-7 cell line. Compound 5b presented anti-leishmanial activity against promastigote form after 48 h (IC50:59 µM) and 72 h (IC50: 41 µM) incubations. The highest docking score was -7.33 kcal/mol for                  compound 4d.

Conclusions and implications: The nature of substitution in the N1 region of isatin seems to be able to influence the cytotoxic activity. Based on the obtained results of docking and cytotoxic tests, compound 4d seems to be a good compound for further investigations.

 

 


Keywords


Anti-leishmanial activity; Cytotoxicity; Isatin; Schiff base.

Full Text:

PDF PDF

References


Banerjee D, Mittal S, Mandal R, Basu P. Screening technologies for cervical cancer: overview. Cytojournal. 2022;19:23. DOI: 10.25259/CMAS_03_04_2021.

Fisusi FA, Akala EO. Drug combinations in breast cancer therapy. Pharm Nanotechnol. 2019;7(1):3-23.DOI: 10.2174/2211738507666190122111224.

Dantas LLSFR, Fonseca AG, Pereira JR, Furtado AA, Gomes PATM, Fernandes-Pedrosa MF, et al. Anti-inflammatory and antinociceptive effects of the isatin derivative (Z)-2-(5-chloro-2-oxoindolin-3-ylidene)-N-phenyl-hydrazinecarbothioamide in mice. Braz J Med Biol Res. 2020;53(10):e10204.DOI: 10.1590/1414-431X202010204.

Hassanzadeh F, Jafari E, Khayambashi N, Hajhashemi V. Synthesis and anti-inflammatory effects evaluation of 1, 3 substituted isatin derivatives. Thai J Pharm Sci. 2021;45(4):248-252.

Sabet R, Mohammadpour M, Sadeghi A, Fassihi A. QSAR study of isatin analogues as in vitro anti-cancer agents. Eur J Med Chem. 2010; 45(3):1113-1118.DOI: 10.1016/j.ejmech.2009.12.010.

Matesic L, Locke JM, Bremner JB, Pyne SG, Skropeta D, Ranson M, et al. N-phenethyl and N-naphthylmethyl isatins and analogues as in vitro cytotoxic agents. Bioorg Med Chem. 2008;16(6):3118-3124.DOI: 10.1016/j.bmc.2007.12.026.

Taher AT, Khalil NA, Ahmed EM. Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents. Arch Pharm Res. 2011;34(10):1615-1621.DOI: 10.1007/s12272-011-1005-3.

Khan KM, Mughal UR, Samreen S, Perveen S, Choudhary MI. Schiff bases of istain: Potential anti-leishmanial agents. Lett Drug Des Discov. 2008;5(4):243-249.DOI: 10.2174/157018008784619915.

Pervez H, Manzoor N, Yaqub M, Khan KM. 5-Nitroisatin-derived thiosemicarbazones: potential antileishmanial agents. J Enzyme Inhib Med Chem. 2014;29(5):628-632. DOI: 10.3109/14756366.2013.836641.

Alkahtani HM, Alanazi MM, Aleanizy FS, Alqahtani FY, Alhoshani A, Alanazi FE, et al. Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5, 5-diphenylimidazolidine-2, 4-dione derivatives: molecular docking studies. Saudi Pharm J. 2019;27(5):682-693. DOI: 10.1016/j.jsps.2019.04.003.

Khaldoun K, Safer A, Boukabcha N, Dege N, Ruchaud S, Souab M, et al. Synthesis and evaluation of new isatin-aminorhodanine hybrids as PIM1 and CLK1 kinase inhibitors. J Mol Struct. 2019;1192: 82-90.DOI: 10.1016/j.molstruc.2019.04.122.

Ibrahim NW, Mahdi M, Raauf AMR. Design, molecular docking, synthesis and evaluation of new isatin derivatives bearing pyridine moiety as potential tyrosine kinase inhibitors. Egypt J Chem. 2022;65(2):9-18. DOI: 10.21608/EJCHEM.2021.72747.3607.

Al-Salem HS, Arifuzzaman M, Issa IS, Rahman AFMM. Isatin-hydrazones with multiple receptor tyrosine kinases (RTKs) inhibitory activity and in-silico binding mechanism. Appl Sci (Basel). 2021;11(9):3746,1-12. DOI: 10.3390/app11093746.

Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, et al. Discovery of 5-[5-fluoro-2-oxo-1, 2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2003;46(7):1116-1119.DOI: 10.1021/jm0204183.

Eldehna WM, Abo-Ashour MF, Nocentini A, El-Haggar RS, Bua S, Bonardi A, et al. Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents. Eur J Med Chem. 2019;162:147-160.DOI: 10.1016/j.ejmech.2018.10.068.

Farooq M, Al Marhoon ZM, Taha NA, Baabbad AA, Al-Wadaan MA, El-Faham A. Synthesis of novel class of N-alkyl-isatin-3-iminobenzoic acid derivatives and their biological activity in zebrafish embryos and human cancer cell lines. Biol Pharm Bull. 2018;41(3):350-359.DOI: 10.1248/bpb.b17-00674.

Vine KL, Matesic L, Locke JM, Ranson M, Skropeta D. Cytotoxic and anticancer activities of isatin and its derivatives: a comprehensive review from 2000-2008. Anticancer Agents Med Chem. 2009;9(4):397-414.DOI: 10.2174/1871520610909040397.

Modi NR, Shah RJ, Patel MJ, Suthar M, Chauhan BF, Patel LJ. Design, synthesis, and QSAR study of novel 2-(2, 3-dioxo-2, 3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents. Med Chem Res. 2011;20:615-625.DOI: 10.1007/s00044-010-9361-y.

Pakravan P, Kashanian S, Khodaei MM, Harding FJ. Biochemical and pharmacological characterization of isatin and its derivatives: from structure to activity. Pharmacol Rep. 2013;65(2):313-335.DOI: 10.1016/s1734-1140(13)71007-7.

Medvedev A, Buneeva O, Glover V. Biological targets for isatin and its analogues: implications for therapy. Biologics. 2007;1(2):151-162.PMID: 19707325.

Krishnegowda G, Prakasha Gowda AS, Tagaram HRS, Staveley-O’Carroll KF, Irby RB, Sharma AK, et al. Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway. Bioorg Med Chem. 2011;19(20):6006-6014.DOI: 10.1016/j.bmc.2011.08.044.

Igosheva N, Lorz C, O’conner E, Glover V, Mehmet H. Isatin, an endogenous monoamine oxidase inhibitor, triggers a dose-and time-dependent switch from apoptosis to necrosis in human neuroblastoma cells. Neurochem Int. 2005;47(3):216-224.DOI: 10.1016/j.neuint.2005.02.011.

Al-Salem HS, Arifuzzaman M, Alkahtani HM, Abdalla AN, Issa IS, Alqathama A, et al. A series of isatin-hydrazones with cytotoxic activity and CDK2 kinase inhibitory activity: a potential type II ATP competitive inhibitor. Molecules. 2020;25(19):4400,1-16.DOI: 10.3390/molecules25194400.

Gangarapu K, Thumma G, Manda S, Jallapally A, Jarapula R, Rekulapally S. Design, synthesis and molecular docking of novel structural hybrids of substituted isatin based pyrazoline and thiadiazoline as antitumor agents. Med Chem Res. 2017;26:819-829. DOI: 10.1007/s00044-017-1781-5.

Hassanzadeh F, Jafari E, Saeedi M, Saberi S. Synthesis and evaluation of thiadiazole-based antileishmanial agents. J Rep Pharma Sci. 2020;9:189-195. DOI: 10.4103/jrptps.JRPTPS_3_20.

Mohammadpour M, Sadeghi A, Fassihi A, Saghaei L, Movahedian A, Rostami M. Synthesis and antioxidant evaluation of some novel ortho-hydroxypyridine-4-one iron chelators. Res Pharm Sci. 2012;7(3):171-179.PMID: 23181095.

Hassanzadeh F, Jafari E, Zarabi M, Khodarahmi G, Vaseghi G. Synthesis, cytotoxic evaluation, and molecular docking studies of some new 1, 3, 4-oxadiazole-based compounds. Res Pharm Sci. 2020;15(5):454-462.DOI: 10.4103/1735-5362.297848.

Hassanzadeh F, Sadeghi-Aliabadi H, Jafari E, Sharifzadeh A, Dana N. Synthesis and cytotoxic evaluation of some quinazolinone-5-(4-chlorophenyl) 1, 3, 4-oxadiazole conjugates. Res Pharm Sci. 2019;14(5):408-413.DOI: 10.4103/1735-5362.268201.

Ramezani P, Hejazi SH, Narimani M, Soleimanifard S. In vitro antileishmanial activity and apoptosis induction of Pleurotus ostreatus alcoholic extract on Leishmania major. Res J Pharmacogn. 2017;4(3):51-58.

Hassanzadeh F, Jafari E, Zarei S, Sadeghi-Aliabadi H. Synthesis, cytotoxic effect assessment and molecular docking studies of disubstituted thiadiazole including oxadiazole as hybrid component. Hacet Univ J Fac Pharm. 2022;42(4):228-237.DOI: 10.52794/hujpharm.1069664.

Orlova DD, Novikova DS, Garabadzhiu AV, Tribulovich VG. A study on hydrolytic stability of isatin N-Mannich bases. Russ J Gen Chem. 2018; 88(1):52-60. DOI: 10.1134/S1070363218010085.

Vine KL, Locke JM, Ranson M, Pyne SG, Bremner JB. An investigation into the cytotoxicity and mode of action of some novel N-alky l-substituted isatins. J Med Chem. 2007;50(21): 5109-5117.DOI: 10.1021/jm0704189.

Ganguly S, Debnath B. Molecular docking studies and ADME prediction of novel isatin analogs with potent anti-EGFR activity. Med Chem (Los Angeles). 2014;4(8):558-568. DOI: 10.4172/2161-0444.1000194.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.