Synthesis, Cytotoxic Effect Assessment and Molecular Docking Studies of Disubstituted Thiadiazole Including Oxadiazole as Hybrid Component
Yıl 2022,
, 228 - 237, 01.12.2022
Farshid Hassanzadeh
Elham Jafari
,
Sara Zareı
Hojjat Sadeghı-alıabadı
Öz
Cancer is the second leading cause of death in the world. Due to toxicity and resistance to common therapies, the attempt to develop new anticancer agents has become a major challenge. Oxadiazole and thiadiazole are of interest building blocks used in drug design. Hybrids of thiadiazole- oxadiazole have been synthesized with significant cytotoxic effects. Considering importance of mentioned scaffolds some of the thiadiazole-oxadiazole derivatives were synthesized by three steps in this study. Firstly, thiol function of 2-amino-5-mercapto-1, 3, 4-thiadiazole was alkylated by benzyl chloride derivatives to give compounds (1a-c). The reaction of chloroacetyl chloride with amine group of compounds (1a–c) terminates to amide derivatives (2a-c). Definitive products were produced by treatment of corresponding amide derivatives with 5-(4-chlorophenyl)-1, 3, 4-oxadiazole-2-thiol. Synthesized compounds were evaluated by MTT assay against three cell lines. The final molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to assay the possible interactions. Final products showed range of cytotoxic activity of moderate to good against tested cell lines. Compound (3a) demonstrated a higher cytotoxic activity against MCF-7 (IC50: 26 μM) and Lncap (IC50: 37 μM) cell lines in comparison with other compounds. The highest docking score was -10.55 kcal/mol for compound 3a.
Kaynakça
- 1. Aliabadi A, Eghbalian E, Kiani A. Synthesis and evaluation of the cytotoxicity of a series of 1, 3, 4-thiadiazole based compounds as anticancer agents. Iran. J. Basic. Med. Sic. 2013; 16(11):1133-38.
- 2. Gomha S.M, Kheder NA, Abdelaziz MR, Mabkhot YN, Alhajoj AM. A facile synthesis and anticancer activity of some novel thiazoles carrying 1, 3, 4-thiadiazole moiety. Chem. Cent .J. 2017;11(1):1-9.
- 3.Kaur H, Kaur H, Chawla P, Chawla A, Baghel US, Dhawan RK. Thiadiazole: an amazing anticancer moiety. Int J Pharm Chem2014;4:1-5.
- 4.Zhang K, Wang P, Xuan LN, Fu XY, Jing F, Li S, Liu M. Synthesis and antitumor activities of novel hybrid molecules containing 1, 3, 4-oxadiazole and 1, 3, 4-thiadiazole bearing Schiff base moiety. Bioorg Med ChemLett.2014;24(22):5154-6.
- 5 .Radi M, Crespan E, Botta G, Falchi F, Maga G, ManettiF,Corradi V . Discovery and SAR of 1, 3, 4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents. Bioorg.Med.Chem .Lett . 2008;1;18(3):1207-11.
- 6. Jain A.K, Sharma S, Vaidya A, Ravichandran V, Agrawal RK. 1, 3, 4‐Thiadiazole and its derivatives: A review on recent progress in biological activities. Chem.Biol.Drug .Des2013;81(5):557-76.
- 7 .Asif M. A mini review on pharmacological activities of oxadiazole and thiadiazole compounds. Mor. J Chem. 2014;(2):70-84.
- 8. YangXH, Wen Q, Zhao TT, Sun J, Li X, Xing M, Lu X, Zhu HL. Synthesis, biological evaluation, and molecular docking studies of cinnamic acyl 1, 3, 4-thiadiazole amide derivatives as novel antitubulin agents. Bioorg.Med.Chem. 2012;20(3):.1181-87.
- 9.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):408-13.
- 10.Jafari E, Mohammadi T, Jahanian-Najafabadi A, Hassanzadeh F. Synthesis and antimicrobial evaluation of some 2, 5 disubstituted 1, 3, 4-oxadiazole derivatives. Res Pharm Sci.2017;12(4):330-36.
- 11.Hassanzadeh F , Jafari E, Zarabi M, Khodarahmi GA, Vaseghi G. Synthesis, cytotoxic evaluation, and molecular docking studies of some new 1, 3, 4-oxadiazole-based compounds. Res PharmSci .2020;15(5): 454-62
- 12.Rezki N, Al-Yahyawi AM, Bardaweel SK, Al-Blewi FF, Aouad MR. Synthesis of novel 2, 5-disubstituted-1, 3, 4-thiadiazoles clubbed 1, 2, 4-triazole, 1, 3, 4-thiadiazole, 1, 3, 4-oxadiazole and/or schiff base as potential antimicrobial and antiproliferative agents. Molecules;2015;20(9):16048-67.
- 13. Hassanzadeh F, Jafari .E, Saeedi M, Saberi S.Synthesis and evaluation of thiadiazole-based antileishmanial agents. J .Rep. Pharm .Sci.2020;9(2):189-195.
- 14. Hassanzadeh F, Sadeghi-Aliabadi H, Nikooei S, Jafari E, Vaseghi G. Synthesis and cytotoxic evaluation of some derivatives of triazole-quinazolinone hybrids. Res. Pharm. Sci. 2019 ;14(2):130-137.
- 15.Hassanzadeh F, Jafari E, Hakimelahi GH, RahmaniKhajouei M, Jalali M, Khodarahmi GA.Antibacterial, antifungal and cytotoxic evaluation of some new quinazolinone derivatives. Res .Pharm .Sci2012 ;7(2): 87-94.
- 16. Joseph A, Shah CS, Kumar SS, Alex AT, Maliyakkal N, Moorkoth S, Mathew JE. Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones. Acta.Pharmaceutica1.2013;63(3):397-408.
- 17. Kumar N, Sharma CS, Singh HP, Chauhan LS. Synthesis and in vitro evaluation of novel isatinincorporatedthiadiazole hybrids as potential anti-breast cancer agents. Trop. J .Pharm. Res.2017;16(8):1957-63.
Synthesis, Cytotoxic Effect Assessment and Molecular Docking Studies of Disubstituted Thiadiazole Including Oxadiazole as Hybrid Component
Yıl 2022,
, 228 - 237, 01.12.2022
Farshid Hassanzadeh
Elham Jafari
,
Sara Zareı
Hojjat Sadeghı-alıabadı
Öz
Cancer is the second leading cause of death in the world. Due to toxicity and resistance to common therapies, the attempt to develop new anticancer agents has become a major challenge. Oxadiazole and thiadiazole are of interest building blocks used in drug design. Hybrids of thiadiazole- oxadiazole have been synthesized with significant cytotoxic effects. Considering importance of mentioned scaffolds some of the thiadiazole-oxadiazole derivatives were synthesized by three steps in this study.
Firstly, thiol function of 2-amino-5-mercapto-1, 3, 4-thiadiazole was alkylated by benzyl chloride derivatives to give compounds (1a-c). The reaction of chloroacetyl chloride with amine group of compounds (1a–c) terminates to amide derivatives (2a-c). Definitive products were produced by treatment of corresponding amide derivatives with 5-(4-chlorophenyl)-1, 3, 4-oxadiazole-2-thiol. Synthesized compounds were evaluated by MTT assay against three cell lines. The final molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to assay the possible interactions. Final products showed range of cytotoxic activity of moderate to good against tested cell lines. Compound (3a) demonstrated a higher cytotoxic activity against MCF-7 (IC50: 26 μM) and Lncap (IC50: 37 μM) cell lines in comparison with other compounds. The highest docking score was -10.55 kcal/mol for compound 3a.
Kaynakça
- 1. Aliabadi A, Eghbalian E, Kiani A. Synthesis and evaluation of the cytotoxicity of a series of 1, 3, 4-thiadiazole based compounds as anticancer agents. Iran. J. Basic. Med. Sic. 2013; 16(11):1133-38.
- 2. Gomha S.M, Kheder NA, Abdelaziz MR, Mabkhot YN, Alhajoj AM. A facile synthesis and anticancer activity of some novel thiazoles carrying 1, 3, 4-thiadiazole moiety. Chem. Cent .J. 2017;11(1):1-9.
- 3.Kaur H, Kaur H, Chawla P, Chawla A, Baghel US, Dhawan RK. Thiadiazole: an amazing anticancer moiety. Int J Pharm Chem2014;4:1-5.
- 4.Zhang K, Wang P, Xuan LN, Fu XY, Jing F, Li S, Liu M. Synthesis and antitumor activities of novel hybrid molecules containing 1, 3, 4-oxadiazole and 1, 3, 4-thiadiazole bearing Schiff base moiety. Bioorg Med ChemLett.2014;24(22):5154-6.
- 5 .Radi M, Crespan E, Botta G, Falchi F, Maga G, ManettiF,Corradi V . Discovery and SAR of 1, 3, 4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents. Bioorg.Med.Chem .Lett . 2008;1;18(3):1207-11.
- 6. Jain A.K, Sharma S, Vaidya A, Ravichandran V, Agrawal RK. 1, 3, 4‐Thiadiazole and its derivatives: A review on recent progress in biological activities. Chem.Biol.Drug .Des2013;81(5):557-76.
- 7 .Asif M. A mini review on pharmacological activities of oxadiazole and thiadiazole compounds. Mor. J Chem. 2014;(2):70-84.
- 8. YangXH, Wen Q, Zhao TT, Sun J, Li X, Xing M, Lu X, Zhu HL. Synthesis, biological evaluation, and molecular docking studies of cinnamic acyl 1, 3, 4-thiadiazole amide derivatives as novel antitubulin agents. Bioorg.Med.Chem. 2012;20(3):.1181-87.
- 9.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):408-13.
- 10.Jafari E, Mohammadi T, Jahanian-Najafabadi A, Hassanzadeh F. Synthesis and antimicrobial evaluation of some 2, 5 disubstituted 1, 3, 4-oxadiazole derivatives. Res Pharm Sci.2017;12(4):330-36.
- 11.Hassanzadeh F , Jafari E, Zarabi M, Khodarahmi GA, Vaseghi G. Synthesis, cytotoxic evaluation, and molecular docking studies of some new 1, 3, 4-oxadiazole-based compounds. Res PharmSci .2020;15(5): 454-62
- 12.Rezki N, Al-Yahyawi AM, Bardaweel SK, Al-Blewi FF, Aouad MR. Synthesis of novel 2, 5-disubstituted-1, 3, 4-thiadiazoles clubbed 1, 2, 4-triazole, 1, 3, 4-thiadiazole, 1, 3, 4-oxadiazole and/or schiff base as potential antimicrobial and antiproliferative agents. Molecules;2015;20(9):16048-67.
- 13. Hassanzadeh F, Jafari .E, Saeedi M, Saberi S.Synthesis and evaluation of thiadiazole-based antileishmanial agents. J .Rep. Pharm .Sci.2020;9(2):189-195.
- 14. Hassanzadeh F, Sadeghi-Aliabadi H, Nikooei S, Jafari E, Vaseghi G. Synthesis and cytotoxic evaluation of some derivatives of triazole-quinazolinone hybrids. Res. Pharm. Sci. 2019 ;14(2):130-137.
- 15.Hassanzadeh F, Jafari E, Hakimelahi GH, RahmaniKhajouei M, Jalali M, Khodarahmi GA.Antibacterial, antifungal and cytotoxic evaluation of some new quinazolinone derivatives. Res .Pharm .Sci2012 ;7(2): 87-94.
- 16. Joseph A, Shah CS, Kumar SS, Alex AT, Maliyakkal N, Moorkoth S, Mathew JE. Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones. Acta.Pharmaceutica1.2013;63(3):397-408.
- 17. Kumar N, Sharma CS, Singh HP, Chauhan LS. Synthesis and in vitro evaluation of novel isatinincorporatedthiadiazole hybrids as potential anti-breast cancer agents. Trop. J .Pharm. Res.2017;16(8):1957-63.