Email this article Synthesis and antileishmanial effect of a few cyclic and non-cyclic n-aryl enamino amide derivatives
, Sima Najafi, Nima Razzaghi-Asl Abstract
Background and purpose: The prevalence of leishmaniasis is reported in more than 98 countries and Iran is one of the endemic areas. There is no vaccine for this disease and few effective drugs are available to treat it. Moreover, drug resistance to the disease is increasing. During the past decade, several in vitro and in vivo studies have been performed on dihydropyrimidine derivatives as antileishmanial agents.
Experimental approach: In the present project, a few 6-methyl-4-aryl-N-aryl dihydropyrimidinone/thiones (A7-A11) and N-heteroaryl-3-(para-methoxy benzyl) amino but-enamides (A1-A6) were synthesized, structurally characterized, and finally subjected to in vitro anti-leishmanial effect against Leishmania major promastigotes.
Findings / Results: Results of the study showed that compound A10, 4-(3-chlorophenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, exhibited superior anti-leishmanial effect with IC50 value of 52.67 µg/mL (more active than standard drug Glucantim® with IC50 71000 ± 390 µg/mL).
Conclusion and implications: It was demonstrated that some dihydropyrimidine thiones were able to inhibit Leishmania major promastigotes. Structure-activity relationship evaluations indicated that more electron-poor rings such as isoxazole afforded higher activity within A1-A6 series and in these derivatives, N-benzothiazole rings reinforced anti-leishmanial activity concerning thiazole. It was also observed that higher anti-parasite activities of A10 and A11 concerning A7-A9 might be related to the incorporation of the sulfur atom into C2 position, replacement of N-thiazole carboxamide by N-phenyl carboxamide on C5 position of dihydropyrimidine ring, and also replacement of para with meta-substituted phenyls within C4 of dihydropyrimidine ring. The results may help unveil new 4-aryl-5-carboxamide dihydropyrimidines as potential anti-leishmanial agents and their further structural modification toward more potent derivatives.
Keywords
Full Text:
PDFReferences
World Health Organization, WHO report on global surveillance of epidemic-prone infectious diseases-leishmaniasis. https://www.who.int/csr/resources/publications/CSR_ISR_2000_1leish/en/, visited 20 Dece1. World Health Organization, WHO report on global surveillance of epidemic-prone infectious diseases-leishmaniasis. https://www.who.int/csr/resources/publications/CSR_ISR_2000_1leish/en/, visited 20 December 2019.
Shirzadi MR, Esfahania SB, Mohebalia M, Ershadia MR, Gharachorlo F, Razavia MR, et al. Epidemiological status of leishmaniasis in the Islamic Republic of Iran, 1983-2012. East Mediterr Health J. 2015;21(10):736-742.
DOI: 10.26719/2015.21.10.736.
Sajjadi SE, Eskandarian AA, Shokoohinia Y, Yousefi HA, Mansourian M, Asgarian-Nasab H, et al. Antileishmanial activity of prenylated coumarins isolated from Ferulago angulata and Prangos asperula. Res Pharm Sci. 2016;11(4):324-331.
DOI: 10.4103/1735-5362.189314.
Savoia D. Recent updates and perspectives on leishmaniasis. J Infect Dev Ctries. 2015;9(6):588-596.
DOI: 10.3855/jidc.6833.
Ortalli M, Ilari A, Colotti G, De Ionna I, Battista T, Bisi A, et al. Identification of chalcone-based antileishmanial agents targeting trypanothione reductase. Eur J Med Chem. 2018;152:527-541.
DOI: 10.1016/j.ejmech.2018.04.057.
Mendoza-Martínez C, Correa-Basurto J, Nieto-Meneses R, Marquez-Navarro A, Aguilar-Suarez R, Montero-Cortes MD, et al. Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents. Eur J Med Chem. 2015;96:296-307.
DOI: 10.1016/j.ejmech.2015.04.028.
Vijayakumar S, Das P. Recent progress in drug targets and inhibitors towards combating leishmaniasis. Acta Trop. 2018;181:95-104.
DOI: 10.1016/j.actatropica.2018.02.010.
Sheikhmoradi V, Saberi S, Saghaei L, Pestehchian N, Fassihi A. Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands. Res Pharm Sci. 2018;13(2):111-120.
DOI: 10.4103/1735-5362.223793.
Ponte-Sucre A, Gamarro F, Dujardin J, Barret MP, Lopez-Velez R, García-Hernandez R, et al. Drug resistance and treatment failure in leishmaniasis: a 21st century challenge. PLoS Negl Trop Dis. 2017;11(12):e0006052,1-24.
DOI: 10.1371/journal.pntd.0006052.
Bhattacharya SK, Dash AP. Elimination of Kala-Azar from the southeast Asia region. Am J Trop Med Hyg. 2017;96(4):802-804.
DOI: 10.4269/ajtmh.16-0279.
Rezaee Nasab R, Hassanzadeh F, Mansourian M. Synthesis, antimicrobial evaluation and docking studies of some novel quinazolinone Schiff base derivatives. Res Pharm Sci. 2018;13(3):213-221.
DOI: 10.4103/1735-5362.228942.
Singh N, Kaur J, Kumar P, Gupta S, Singh N, Ghosal A, et al. An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1. Parasitol Res. 2009;105(5):1317-1325.
DOI: 10.1007/s00436-009-1557-z.
Saudi MNS, El-Semary MMA, Elbayaa RY, Jaeda MI, Eissa MM, Amer EI, et al. Synthesis and biological evaluation of a novel class as antileishmanial agent. Med Chem Res. 2012;21:257-267.
DOI: 10.1007/s00044-010-9532-x.
Rashid U, Sultana R, Shaheen N, Hassan SF, Yaqoob F, Ahmad MJ, et al. Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents. Eur J Med Chem. 2016;115:230-244.
DOI: 10.1016/j.ejmech.2016.03.022.
Mishra R, Mishra B, Hari Narayana Moorthy NS. Synthesis and anti-microbial evaluation of some 3,4-dihydro pyrimidine-2-one derivatives. Trends Appl Sci Res. 2008;3(20):203-208.
DOI: 10.3923/tasr.2008.203.208.
Razzaghi-Asl N,Omidreza F, Hemmateenejad B, Javidnia K, Edraki N, Miri R. Design and synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors. Bioorg Med Chem. 2013;21(22): 6893-6909.
DOI: 10.1016/j.bmc.2013.09.033.
Tavangar S, Bohlooli S, Razzaghi-Asl N. Synthesis and cytotoxic effect of a few N-heteroaryl enamino amides and dihydropyrimidinethiones on AGS & MCF-7 human cancer cell lines. Res Pharm Sci. 2020;15(2):154-163.
DOI: 10.4103/1735-5362.283815.
Memarian HR, Ranjbar M. Synthesis of Biginelli compounds using Cobalt Hydrogen sulfate. J Chin Chem Soc. 2011;58(4):522-527.
DOI: 10.1002/jccs.201190016.
Jalali M, Mahdavi M, Memarian HR, Ranjbar M, Soleymani M, Fassihi A, et al. Antimicrobial evaluation of some novel derivatives of 3,4-dihydropyrimidine-2(1H)-one. Res Pharm Sci. 2012;7(4):243-247.
Niapour A, Bohlooli S, Sharifi Pasandi M, Mohammadi-ghalehbin B. In vitro anti leishmanial effect of Agrostemma githago extract on Leishmania major promastigotes by cell count and MTT assay. J Mazandaran Univ Med Sci. 2018;28(165):13-23.
Heidari-Kharaji M, Fallah-Omrani V, Badirzadeh A, Mohammadi-Ghalehbin B, Nilforoushzadeh MA, Masoori L, et al. Sambucus ebulus extract stimulates cellular responses in cutaneous leishmaniasis. Parasite Immunol. 2019;41(1) :e12605,1-37.
DOI: 10.1111/pim.12605.
das Neves AR, Trefzger OS, Barbosa NV, Honorato AM, Carvalho DB, Moslaves IS, et al. Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania (Leishmania) amazonensis: a structure-activity relationship comparative study with triazole‐neolignan‐based compounds. Chem Biol Drug Des. 2019;94(6):2004-2012.
DOI: 10.1111/cbdd.13609.
Liu M, Wilairat P, Croft SL, Tan AL, Go ML. Structure-activity relationships of antileishmanial and antimalarial chalcones. Bioorg Med Chem. 2003;11(13):2729-2738.
DOI: 10.1016/s0968-0896(03)00233-5.
Ashok P, Chander S, Smith TK, Prakash Singh R, Jha PN, Sankaranarayanan M. Biological evaluation and structure activity relationship of 9-methyl-1-phenyl-9H-pyrido [3, 4-b] indole derivatives as anti-leishmanial agents. Bioorg Chem. 2019;84: 98-105.
DOI: 10.1016/j.bioorg.2018.11.037.
mber 2019.
Shirzadi MR, Esfahania SB, Mohebalia M, Ershadia MR, Gharachorlo F, Razavia MR, et al. Epidemiological status of leishmaniasis in the Islamic Republic of Iran, 1983-2012. East Mediterr Health J. 2015;21(10):736-742.
DOI: 10.26719/2015.21.10.736.
Sajjadi SE, Eskandarian AA, Shokoohinia Y, Yousefi HA, Mansourian M, Asgarian-Nasab H, et al. Antileishmanial activity of prenylated coumarins isolated from Ferulago angulata and Prangos asperula. Res Pharm Sci. 2016;11(4):324-331.
DOI: 10.4103/1735-5362.189314.
Savoia D. Recent updates and perspectives on leishmaniasis. J Infect Dev Ctries. 2015;9(6):588-596.
DOI: 10.3855/jidc.6833.
Ortalli M, Ilari A, Colotti G, De Ionna I, Battista T, Bisi A, et al. Identification of chalcone-based antileishmanial agents targeting trypanothione reductase. Eur J Med Chem. 2018;152:527-541.
DOI: 10.1016/j.ejmech.2018.04.057.
Mendoza-Martínez C, Correa-Basurto J, Nieto-Meneses R, Marquez-Navarro A, Aguilar-Suarez R, Montero-Cortes MD, et al. Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents. Eur J Med Chem. 2015;96:296-307.
DOI: 10.1016/j.ejmech.2015.04.028.
Vijayakumar S, Das P. Recent progress in drug targets and inhibitors towards combating leishmaniasis. Acta Trop. 2018;181:95-104.
DOI: 10.1016/j.actatropica.2018.02.010.
Sheikhmoradi V, Saberi S, Saghaei L, Pestehchian N, Fassihi A. Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands. Res Pharm Sci. 2018;13(2):111-120.
DOI: 10.4103/1735-5362.223793.
Ponte-Sucre A, Gamarro F, Dujardin J, Barret MP, Lopez-Velez R, García-Hernandez R, et al. Drug resistance and treatment failure in leishmaniasis: a 21st century challenge. PLoS Negl Trop Dis. 2017;11(12):e0006052,1-24.
DOI: 10.1371/journal.pntd.0006052.
Bhattacharya SK, Dash AP. Elimination of Kala-Azar from the southeast Asia region. Am J Trop Med Hyg. 2017;96(4):802-804.
DOI: 10.4269/ajtmh.16-0279.
Rezaee Nasab R, Hassanzadeh F, Mansourian M. Synthesis, antimicrobial evaluation and docking studies of some novel quinazolinone Schiff base derivatives. Res Pharm Sci. 2018;13(3):213-221.
DOI: 10.4103/1735-5362.228942.
Singh N, Kaur J, Kumar P, Gupta S, Singh N, Ghosal A, et al. An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1. Parasitol Res. 2009;105(5):1317-1325.
DOI: 10.1007/s00436-009-1557-z.
Saudi MNS, El-Semary MMA, Elbayaa RY, Jaeda MI, Eissa MM, Amer EI, et al. Synthesis and biological evaluation of a novel class as antileishmanial agent. Med Chem Res. 2012;21:257-267.
DOI: 10.1007/s00044-010-9532-x.
Rashid U, Sultana R, Shaheen N, Hassan SF, Yaqoob F, Ahmad MJ, et al. Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents. Eur J Med Chem. 2016;115:230-244.
DOI: 10.1016/j.ejmech.2016.03.022.
Mishra R, Mishra B, Hari Narayana Moorthy NS. Synthesis and anti-microbial evaluation of some 3,4-dihydro pyrimidine-2-one derivatives. Trends Appl Sci Res. 2008;3(20):203-208.
DOI: 10.3923/tasr.2008.203.208.
Razzaghi-Asl N,Omidreza F, Hemmateenejad B, Javidnia K, Edraki N, Miri R. Design and synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors. Bioorg Med Chem. 2013;21(22): 6893-6909.
DOI: 10.1016/j.bmc.2013.09.033.
Tavangar S, Bohlooli S, Razzaghi-Asl N. Synthesis and cytotoxic effect of a few N-heteroaryl enamino amides and dihydropyrimidinethiones on AGS & MCF-7 human cancer cell lines. Res Pharm Sci. 2020;15(2):154-163.
DOI: 10.4103/1735-5362.283815.
Memarian HR, Ranjbar M. Synthesis of Biginelli compounds using Cobalt Hydrogen sulfate. J Chin Chem Soc. 2011;58(4):522-527.
DOI: 10.1002/jccs.201190016.
Jalali M, Mahdavi M, Memarian HR, Ranjbar M, Soleymani M, Fassihi A, et al. Antimicrobial evaluation of some novel derivatives of 3,4-dihydropyrimidine-2(1H)-one. Res Pharm Sci. 2012;7(4):243-247.
Niapour A, Bohlooli S, Sharifi Pasandi M, Mohammadi-ghalehbin B. In vitro anti leishmanial effect of Agrostemma githago extract on Leishmania major promastigotes by cell count and MTT assay. J Mazandaran Univ Med Sci. 2018;28(165):13-23.
Heidari-Kharaji M, Fallah-Omrani V, Badirzadeh A, Mohammadi-Ghalehbin B, Nilforoushzadeh MA, Masoori L, et al. Sambucus ebulus extract stimulates cellular responses in cutaneous leishmaniasis. Parasite Immunol. 2019;41(1) :e12605,1-37.
DOI: 10.1111/pim.12605.
das Neves AR, Trefzger OS, Barbosa NV, Honorato AM, Carvalho DB, Moslaves IS, et al. Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania (Leishmania) amazonensis: a structure-activity relationship comparative study with triazole‐neolignan‐based compounds. Chem Biol Drug Des. 2019;94(6):2004-2012.
DOI: 10.1111/cbdd.13609.
Liu M, Wilairat P, Croft SL, Tan AL, Go ML. Structure-activity relationships of antileishmanial and antimalarial chalcones. Bioorg Med Chem. 2003;11(13):2729-2738.
DOI: 10.1016/s0968-0896(03)00233-5.
Ashok P, Chander S, Smith TK, Prakash Singh R, Jha PN, Sankaranarayanan M. Biological evaluation and structure activity relationship of 9-methyl-1-phenyl-9H-pyrido [3, 4-b] indole derivatives as anti-leishmanial agents. Bioorg Chem. 2019;84: 98-105.
DOI: 10.1016/j.bioorg.2018.11.037.
Refbacks
- There are currently no refbacks.
This 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.