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How to cite this paper
APA: Atif, A., Ameur, S & Sir, H. (2025). Synthesis, characterization and in silico evaluation of 2,5-bis(2-(trifluoromethyl)-1H-benzimidazol-5-yl)-1,3,4-oxadiazole: Reactivity, ADME/toxicity, and docking against therapeutic targets. Current Chemistry Letters, 14(4), 793-804.
Chicago/Turabian: Atif, A., Ameur, S & Sir, H. 2025. "Synthesis, characterization and in silico evaluation of 2,5-bis(2-(trifluoromethyl)-1H-benzimidazol-5-yl)-1,3,4-oxadiazole: Reactivity, ADME/toxicity, and docking against therapeutic targets." Current Chemistry Letters 14, no. 4 (2025): 793-804.
AMA: Atif, A., Ameur, S & Sir, H. Synthesis, characterization and in silico evaluation of 2,5-bis(2-(trifluoromethyl)-1H-benzimidazol-5-yl)-1,3,4-oxadiazole: Reactivity, ADME/toxicity, and docking against therapeutic targets. Current Chemistry Letters. 2025;14(4):793-804.
References
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2. Pace A., and Pierro P. (2009) The new era of 1, 2, 4-oxadiazoles. Org. Biomol. Chem., 7(21) 4337-4348.
3. Boström J., Hogner A., Llinàs A., Wellner E., and Plowright, A. T. (2012) Oxadiazoles in medicinal chemistry. J. Med. Chem., 55(5) 1817-1830.
4. Delaugerre C. (2010) Genetic barrier to antiretroviral drug-resistance. Focus on raltegravir, the first integrase inhibitor. MMI Formation, 4(1) 1-10.
5. Sultana R., Ali A., Rana M., Ahmad I., Kamthan M., Almuqdadi H. T. A., Mehandi R., Abid M., and El-Bahy Z. M. (2024) Synthesis of oxadiazole derivatives: Anti-bacterial, DNA binding and in silico molecular modelling approaches. J. Mol. Struct., 131(2) 139350.
6. James N. D., and Growcott J. W. (2009) Zibotentan. Drugs Future., 34(8) ) 624-633.
7. Banerjee A. G., Das N., Shengule S. A., Srivastava R. S., and Shrivastava S. K. (2015) Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6–diphenyl–1, 2, 4–triazin–3 (2H)–one derivatives bearing 5–substituted 1, 3, 4–oxadiazole as potential anti–inflammatory and analgesic agents. Eur. J. Med. Chem., 101(2015) 81-95.
8. Gulnaz A. R., Mohammed Y. H. E., and Khanum S. A. (2019) Design, synthesis and molecular docking of benzophenone conjugated with oxadiazole sulphur bridge pyrazole pharmacophores as anti inflammatory and analgesic agents. Bioorg. Chem., 92(2019) 103220.
9. Abd-Ellah H. S., Abdel-Aziz M., Shoman M. E., Beshr E. A., Kaoud T., and Ahmed A. S. F. (2017) New 1, 3, 4-oxadiazole/oxime hybrids: Design, synthesis, anti-inflammatory, COX inhibitory activities and ulcerogenic liability. Bioorg. Chem., 74(2017) 15-29.
10. Jayashankar B., Rai K. L., Baskaran N., and Sathish H. S. (2009) Synthesis and pharmacological evaluation of 1, 3, 4-oxadiazole bearing bis (heterocycle) derivatives as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 44(10) 3898-3902.
11. Kaur J., Soto-Velasquez M., Ding Z., Ghanbarpour A., Lill M. A., van Rijn R. M., Watts V, J., and Flaherty D. P. (2019) Optimization of a 1, 3, 4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain. Eur. J. Med. Chem., 162(2019) 568-585.
12. Tantray M. A., Khan I., Hamid H., Alam M. S., Dhulap A., and Kalam A. (2018) Synthesis of benzimidazole-linked-1, 3, 4-oxadiazole carboxamides as GSK-3β inhibitors with in vivo antidepressant activity. Bioorg. Chem., 77(2018) 393-401.
13. Singh P., Sharma P. K., Sharma J. K., Upadhyay A., and Kumar N. (2012) Synthesis and evaluation of substituted diphenyl-1, 3, 4-oxadiazole derivatives for central nervous system depressant activity. Bioorg. Med. Chem. Lett., 2(8) 1-10.
14. Yadagiri B., Gurrala S., Bantu R., Nagarapu L., Polepalli S., Srujana G., and Jain N. (2015) Synthesis and evaluation of benzosuberone embedded with 1, 3, 4-oxadiazole, 1, 3, 4-thiadiazole and 1, 2, 4-triazole moieties as new potential anti proliferative agents. Bioorg. Med. Chem. Lett., 25(10) 2220-2224.
15. Glomb T., Szymankiewicz K., and Świątek P. (2018) Anti-cancer activity of derivatives of 1, 3, 4-oxadiazole. mol., 23(12) 3361.
16. Shyma P. C., Balakrishna K., Peethambar K. S., and Vijesh M. A. (2015) Synthesis, characterization, antidiabetic and antioxidant activity of 1, 3, 4-oxadiazole derivatives bearing 6-methyl pyridine moiety. Der Pharma Chem, 7(12) 137-45.
17. Nazreen S., Alam M. S., Hamid H., Yar M. S., Shafi S., Dhulap A., Alam P., Pasha M. A. Q., Bano S., Alam M. M., Haider S., Ali Y., Kharbanda C., and Pillai K. K. (2014) Design, synthesis, in silico molecular docking and biological evaluation of novel oxadiazole based thiazolidine-2, 4-diones bis-heterocycles as PPAR-γ agonists. Eur. J. Med. Chem., 87(2014) 175-185.
18. Şahin G., Palaska E., Ekizoğlu M., and Özalp M. (2002) Synthesis and antimicrobial activity of some 1, 3, 4-oxadiazole derivatives. Il Farmaco, 57(7) 539-542.
19. Ali M. A., and Shaharyar M. (2007) Oxadiazole mannich bases: Synthesis and antimycobacterial activity. Bioorg. Med. Chem. Lett., 17(12) 3314-3316.
20. Rane R. A., Bangalore P., Borhade S. D., and Khandare P. K. (2013) Synthesis and evaluation of novel 4-nitropyrrole-based 1, 3, 4-oxadiazole derivatives as antimicrobial and anti-tubercular agents. Eur. J. Med. Chem., 70(2013) 49-58.
21. Zoumpoulakis P., Camoutsis C., Pairas G., Soković M., Glamočlija J., Potamitis C., and Pitsas A. (2012) Synthesis of novel sulfonamide-1, 2, 4-triazoles, 1, 3, 4-thiadiazoles and 1, 3, 4-oxadiazoles, as potential antibacterial and antifungal agents. Biological evaluation and conformational analysis studies. Bioorg. Med. Chem., 20(4) 1569-1583.
22. Xu W., He J., He M., Han F., Chen X., Pan Z., Wang X and Tong, M. (2011). Synthesis and antifungal activity of novel sulfone derivatives containing 1, 3, 4-oxadiazole moieties. mol., 16(11) 9129-9141.
23. Johns B. A., Weatherhead J. G., Allen S. H., Thompson J. B., Garvey E. P., Foster S. A., Jeffrey J. L., and Miller W. H. (2009) 1, 3, 4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position. Bioorg. Med. Chem. Lett., 19(6) 1807-1810.
24. El-Sayed W. A., El-Essawy F. A., Ali O. M., Nasr B. S., Abdalla M. M., and Abdel-Rahman A. A. H. (2009) Anti-HIV activity of new substituted 1, 3, 4-oxadiazole derivatives and their acyclic nucleoside analogues. Z. Naturforsch. C, 64(11-12) 773-778.
25. Hanson M. D. (2024) Visualizing the Hydrogen Atomic Orbitals: A Tool for Undergraduate Physical Chemistry. J. Chem. Educ., 101(8) 3539-3546
26. Gokcan H., and Isayev O. (2022) Learning molecular potentials with neural networks. Wiley Interdiscip. Rev. Comput. Mol. Sci., 12(2) e1564.
27. Daina A., Michielin O., and Zoete V. (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7(1) 42717.
28. Morris G. M., Huey R., Lindstrom W., Sanner M. F., Belew R. K., Goodsell D. S., and Olson A. J. (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 30(16) 2785-2791.
29. Kerraj S., Al-Zaydi K. M., Moussaoui M., Salah, M., and Belaaouad S. (2024) Functionalized η 6-Arene Chromium Half-Sandwich Complexes in DSSC Performance: A Theoretical Perspective. Sci. Afr.
30. Sliwoski G., Kothiwale S., Meiler J., and Lowe Jr, E. W. (2014) Computational methods in drug discovery. Pharmacol. Rev., 66(1) 334-395.
31. Trott O., and Olson A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 31(2) 455-461.
32. Dhannur S. H., Shridhar A. H., Suresh S., Al-Asbahi B. A., Al-Hada N. M., Shelar V. M., and Naik, L. (2024) DFT studies on D–π–A substituted bis-1, 3, 4-oxadiazole for nonlinear optical application. J. Opt., 53(5) 5079-5089.
33. Yurovskaya M. A., and Afanas' ev A. Z. (1991) Methods for the synthesis of 3-nitropyridines. Chem. Heterocycl. Compd., 27(7) 681-707.
34. Sadowski M., and Kula K. (2024) Unexpected course of reaction between (1E,3E)-1,4-Dinitro-1,3-butadiene and n-methyl azomethine ylide—a comprehensive experimental and quantum-chemical study. molecules., 29(21) 5066.
35. « Protein Data Bank | Nucleic Acids Research | Oxford Academic ». Consulté le: 22 avril 2025. [En ligne]. Disponible sur: https://academic.oup.com/nar/article/28/1/235/2384399
36. Kim S., Chen J., Cheng T., Gindulyte A., He J., He S., Li Q., Shoemaker A. B., Thiessen A. P., Yu B., Zaslavsky L., Zhang J., and Bolton, E. E. (2021) PubChem in 2021: new data content and improved web interfaces. Nucleic. Acids. Res., 49(D1) D1388-D1395.
37. Navarrete-Vázquez G., Cedillo R., Hernández-Campos A., Yépez L., Hernández-Luis F., Valdez J., Morales R., Cortes R., Hernandez M., and Castillo R. (2001) Synthesis and antiparasitic activity of 2-(trifluoromethyl) benzimidazole derivatives. Bioorg. Med. Chem. Lett., 11(2) 187-190.
38. Al-Zobaydi S. F., Karim B., Al-Sahib S. A., and Ismael B. D. (2016) Synthesis, Characterization of some New 1, 3, 4-Oxadiazole derivatives based on 4-amino benzoic acid. Baghdad Sci. J., 13(2.2 NCC) 0289-0289.
39. Luiksaar S. I., Belen'kii L. I., and Krayushkin M. M. (1998) An efficient synthesis of symmetrical 2, 5-diaryl-1, 3, 4-oxadiazoles. Mendeleev Commun., 8(4) 136-137.
40. Al-Zobaydi S. F., Karim B., Al-Sahib S. A., and Ismael B. D. (2016) Synthesis, Characterization of some New 1, 3, 4-Oxadiazole derivatives based on 4-amino benzoic acid. Baghdad Sci. J., 13(2.2 NCC) 0289-0289.
41. Hendrickson J. B., and Hussoin M. S. (1989) Reactions of carboxylic acids with phosphonium anhydrides. J. Org. Chem., 54(5) 1144-1149.
42. Kaul S., Kumar A., Sain B., and Bhatnagar A. K. (2007) Simple and convenient one‐pot synthesis of benzimidazoles and benzoxazoles using N, N‐Dimethylchlorosulfitemethaniminium chloride as condensing agent. Synth. Commun., 37(15) 2457-2460.
43. Phillips M. A. (1928) CCCXVII.—The formation of 2-substituted benziminazoles. J. Chem. Soc., 0, 2393-2399.
44. MoloU K. Y., and SISSoUMa D. (2010) Synthèse de 2-hétéroarylbenzimidazoles à visée anti-infectieuse par application de la réaction de phillips. J. sci, 11(2) 40-51.
2. Pace A., and Pierro P. (2009) The new era of 1, 2, 4-oxadiazoles. Org. Biomol. Chem., 7(21) 4337-4348.
3. Boström J., Hogner A., Llinàs A., Wellner E., and Plowright, A. T. (2012) Oxadiazoles in medicinal chemistry. J. Med. Chem., 55(5) 1817-1830.
4. Delaugerre C. (2010) Genetic barrier to antiretroviral drug-resistance. Focus on raltegravir, the first integrase inhibitor. MMI Formation, 4(1) 1-10.
5. Sultana R., Ali A., Rana M., Ahmad I., Kamthan M., Almuqdadi H. T. A., Mehandi R., Abid M., and El-Bahy Z. M. (2024) Synthesis of oxadiazole derivatives: Anti-bacterial, DNA binding and in silico molecular modelling approaches. J. Mol. Struct., 131(2) 139350.
6. James N. D., and Growcott J. W. (2009) Zibotentan. Drugs Future., 34(8) ) 624-633.
7. Banerjee A. G., Das N., Shengule S. A., Srivastava R. S., and Shrivastava S. K. (2015) Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6–diphenyl–1, 2, 4–triazin–3 (2H)–one derivatives bearing 5–substituted 1, 3, 4–oxadiazole as potential anti–inflammatory and analgesic agents. Eur. J. Med. Chem., 101(2015) 81-95.
8. Gulnaz A. R., Mohammed Y. H. E., and Khanum S. A. (2019) Design, synthesis and molecular docking of benzophenone conjugated with oxadiazole sulphur bridge pyrazole pharmacophores as anti inflammatory and analgesic agents. Bioorg. Chem., 92(2019) 103220.
9. Abd-Ellah H. S., Abdel-Aziz M., Shoman M. E., Beshr E. A., Kaoud T., and Ahmed A. S. F. (2017) New 1, 3, 4-oxadiazole/oxime hybrids: Design, synthesis, anti-inflammatory, COX inhibitory activities and ulcerogenic liability. Bioorg. Chem., 74(2017) 15-29.
10. Jayashankar B., Rai K. L., Baskaran N., and Sathish H. S. (2009) Synthesis and pharmacological evaluation of 1, 3, 4-oxadiazole bearing bis (heterocycle) derivatives as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 44(10) 3898-3902.
11. Kaur J., Soto-Velasquez M., Ding Z., Ghanbarpour A., Lill M. A., van Rijn R. M., Watts V, J., and Flaherty D. P. (2019) Optimization of a 1, 3, 4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain. Eur. J. Med. Chem., 162(2019) 568-585.
12. Tantray M. A., Khan I., Hamid H., Alam M. S., Dhulap A., and Kalam A. (2018) Synthesis of benzimidazole-linked-1, 3, 4-oxadiazole carboxamides as GSK-3β inhibitors with in vivo antidepressant activity. Bioorg. Chem., 77(2018) 393-401.
13. Singh P., Sharma P. K., Sharma J. K., Upadhyay A., and Kumar N. (2012) Synthesis and evaluation of substituted diphenyl-1, 3, 4-oxadiazole derivatives for central nervous system depressant activity. Bioorg. Med. Chem. Lett., 2(8) 1-10.
14. Yadagiri B., Gurrala S., Bantu R., Nagarapu L., Polepalli S., Srujana G., and Jain N. (2015) Synthesis and evaluation of benzosuberone embedded with 1, 3, 4-oxadiazole, 1, 3, 4-thiadiazole and 1, 2, 4-triazole moieties as new potential anti proliferative agents. Bioorg. Med. Chem. Lett., 25(10) 2220-2224.
15. Glomb T., Szymankiewicz K., and Świątek P. (2018) Anti-cancer activity of derivatives of 1, 3, 4-oxadiazole. mol., 23(12) 3361.
16. Shyma P. C., Balakrishna K., Peethambar K. S., and Vijesh M. A. (2015) Synthesis, characterization, antidiabetic and antioxidant activity of 1, 3, 4-oxadiazole derivatives bearing 6-methyl pyridine moiety. Der Pharma Chem, 7(12) 137-45.
17. Nazreen S., Alam M. S., Hamid H., Yar M. S., Shafi S., Dhulap A., Alam P., Pasha M. A. Q., Bano S., Alam M. M., Haider S., Ali Y., Kharbanda C., and Pillai K. K. (2014) Design, synthesis, in silico molecular docking and biological evaluation of novel oxadiazole based thiazolidine-2, 4-diones bis-heterocycles as PPAR-γ agonists. Eur. J. Med. Chem., 87(2014) 175-185.
18. Şahin G., Palaska E., Ekizoğlu M., and Özalp M. (2002) Synthesis and antimicrobial activity of some 1, 3, 4-oxadiazole derivatives. Il Farmaco, 57(7) 539-542.
19. Ali M. A., and Shaharyar M. (2007) Oxadiazole mannich bases: Synthesis and antimycobacterial activity. Bioorg. Med. Chem. Lett., 17(12) 3314-3316.
20. Rane R. A., Bangalore P., Borhade S. D., and Khandare P. K. (2013) Synthesis and evaluation of novel 4-nitropyrrole-based 1, 3, 4-oxadiazole derivatives as antimicrobial and anti-tubercular agents. Eur. J. Med. Chem., 70(2013) 49-58.
21. Zoumpoulakis P., Camoutsis C., Pairas G., Soković M., Glamočlija J., Potamitis C., and Pitsas A. (2012) Synthesis of novel sulfonamide-1, 2, 4-triazoles, 1, 3, 4-thiadiazoles and 1, 3, 4-oxadiazoles, as potential antibacterial and antifungal agents. Biological evaluation and conformational analysis studies. Bioorg. Med. Chem., 20(4) 1569-1583.
22. Xu W., He J., He M., Han F., Chen X., Pan Z., Wang X and Tong, M. (2011). Synthesis and antifungal activity of novel sulfone derivatives containing 1, 3, 4-oxadiazole moieties. mol., 16(11) 9129-9141.
23. Johns B. A., Weatherhead J. G., Allen S. H., Thompson J. B., Garvey E. P., Foster S. A., Jeffrey J. L., and Miller W. H. (2009) 1, 3, 4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position. Bioorg. Med. Chem. Lett., 19(6) 1807-1810.
24. El-Sayed W. A., El-Essawy F. A., Ali O. M., Nasr B. S., Abdalla M. M., and Abdel-Rahman A. A. H. (2009) Anti-HIV activity of new substituted 1, 3, 4-oxadiazole derivatives and their acyclic nucleoside analogues. Z. Naturforsch. C, 64(11-12) 773-778.
25. Hanson M. D. (2024) Visualizing the Hydrogen Atomic Orbitals: A Tool for Undergraduate Physical Chemistry. J. Chem. Educ., 101(8) 3539-3546
26. Gokcan H., and Isayev O. (2022) Learning molecular potentials with neural networks. Wiley Interdiscip. Rev. Comput. Mol. Sci., 12(2) e1564.
27. Daina A., Michielin O., and Zoete V. (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7(1) 42717.
28. Morris G. M., Huey R., Lindstrom W., Sanner M. F., Belew R. K., Goodsell D. S., and Olson A. J. (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 30(16) 2785-2791.
29. Kerraj S., Al-Zaydi K. M., Moussaoui M., Salah, M., and Belaaouad S. (2024) Functionalized η 6-Arene Chromium Half-Sandwich Complexes in DSSC Performance: A Theoretical Perspective. Sci. Afr.
30. Sliwoski G., Kothiwale S., Meiler J., and Lowe Jr, E. W. (2014) Computational methods in drug discovery. Pharmacol. Rev., 66(1) 334-395.
31. Trott O., and Olson A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 31(2) 455-461.
32. Dhannur S. H., Shridhar A. H., Suresh S., Al-Asbahi B. A., Al-Hada N. M., Shelar V. M., and Naik, L. (2024) DFT studies on D–π–A substituted bis-1, 3, 4-oxadiazole for nonlinear optical application. J. Opt., 53(5) 5079-5089.
33. Yurovskaya M. A., and Afanas' ev A. Z. (1991) Methods for the synthesis of 3-nitropyridines. Chem. Heterocycl. Compd., 27(7) 681-707.
34. Sadowski M., and Kula K. (2024) Unexpected course of reaction between (1E,3E)-1,4-Dinitro-1,3-butadiene and n-methyl azomethine ylide—a comprehensive experimental and quantum-chemical study. molecules., 29(21) 5066.
35. « Protein Data Bank | Nucleic Acids Research | Oxford Academic ». Consulté le: 22 avril 2025. [En ligne]. Disponible sur: https://academic.oup.com/nar/article/28/1/235/2384399
36. Kim S., Chen J., Cheng T., Gindulyte A., He J., He S., Li Q., Shoemaker A. B., Thiessen A. P., Yu B., Zaslavsky L., Zhang J., and Bolton, E. E. (2021) PubChem in 2021: new data content and improved web interfaces. Nucleic. Acids. Res., 49(D1) D1388-D1395.
37. Navarrete-Vázquez G., Cedillo R., Hernández-Campos A., Yépez L., Hernández-Luis F., Valdez J., Morales R., Cortes R., Hernandez M., and Castillo R. (2001) Synthesis and antiparasitic activity of 2-(trifluoromethyl) benzimidazole derivatives. Bioorg. Med. Chem. Lett., 11(2) 187-190.
38. Al-Zobaydi S. F., Karim B., Al-Sahib S. A., and Ismael B. D. (2016) Synthesis, Characterization of some New 1, 3, 4-Oxadiazole derivatives based on 4-amino benzoic acid. Baghdad Sci. J., 13(2.2 NCC) 0289-0289.
39. Luiksaar S. I., Belen'kii L. I., and Krayushkin M. M. (1998) An efficient synthesis of symmetrical 2, 5-diaryl-1, 3, 4-oxadiazoles. Mendeleev Commun., 8(4) 136-137.
40. Al-Zobaydi S. F., Karim B., Al-Sahib S. A., and Ismael B. D. (2016) Synthesis, Characterization of some New 1, 3, 4-Oxadiazole derivatives based on 4-amino benzoic acid. Baghdad Sci. J., 13(2.2 NCC) 0289-0289.
41. Hendrickson J. B., and Hussoin M. S. (1989) Reactions of carboxylic acids with phosphonium anhydrides. J. Org. Chem., 54(5) 1144-1149.
42. Kaul S., Kumar A., Sain B., and Bhatnagar A. K. (2007) Simple and convenient one‐pot synthesis of benzimidazoles and benzoxazoles using N, N‐Dimethylchlorosulfitemethaniminium chloride as condensing agent. Synth. Commun., 37(15) 2457-2460.
43. Phillips M. A. (1928) CCCXVII.—The formation of 2-substituted benziminazoles. J. Chem. Soc., 0, 2393-2399.
44. MoloU K. Y., and SISSoUMa D. (2010) Synthèse de 2-hétéroarylbenzimidazoles à visée anti-infectieuse par application de la réaction de phillips. J. sci, 11(2) 40-51.