Bis(Benzofuran–1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus
Abstract
:1. Introduction
2. Results and Discussion
2.1. Syntheses of Bis(Benzofuran–Imidazolidinone) Conjugates 2 (Scheme 1) and Their Structural Identification
2.2. Synthesis of Bis(Benzofuran–Benzimidazole) Conjugates 3 (Scheme 2) and Their Structural Identification
2.3. Biological Activities of the New Bis-Conjugated Compounds and Their Lipophilicity
2.4. Essential Moieties and Substituents for Anti-YFV Activity
3. Materials and Methods
3.1. General Information
3.2. Synthesis of Bis(Benzofuran–Imidazolidinone)s 2 (Standard Procedure 1)
3.2.1. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis[2-(N-methyl-3″-phenyl-4″-oxo-1″,3″-imidazolidin-2″-yl)benzofuran] (2a)
3.2.2. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(4-methylphenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2b)
3.2.3. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(2,3-dimethylphenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2c)
3.2.4. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(2,5-dimethylphenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2d)
3.2.5. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis[2-(N-methyl-3″-(3,5-dimethylphenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl)benzofuran] (2e)
3.2.6. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(2-ethylphenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2f)
3.2.7. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(4-methoxyphenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2g)
3.2.8. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebi(2-[N-methyl-3″-(4-fluorophenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2h)
3.2.9. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(4-chlorophenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2i)
3.2.10. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(4-bromophenyl)-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2j)
3.2.11. (2″R,2‴R)-, (2″S,2‴S)-, and meso-(2″R,2‴S)-5,5′-Methylenebis(2-[N-methyl-3″-(3-trifluoromethyl)phenyl-4″-oxo-1″,3″-imidazolidin-2″-yl]benzofuran) (2k)
3.3. Synthesis of Bis(Benzofuran–Benzimidazole)s 3 (Standard Procedure 2)
3.3.1. 5,5′-Methylenebis[2-(1-benzylbenzimidazol-2-yl)benzofuran] (3a)
3.3.2. 5,5′-Methylenebis(2-[1-(p-methylbenzyl)benzimidazol-2-yl]benzofuran) (3b)
3.3.3. 5,5′-Methylenebis(2-[1-(m-methoxybenzyl)benzimidazol-2-yl]benzofuran) (3c)
3.3.4. 5,5′-Methylenebis(2-[1-(p-methoxybenzyl)benzimidazol-2-yl]benzofuran) (3d)
3.3.5. 5,5′-Methylenebis(2-[1-(o-fluorobenzyl)benzimidazol-2-yl]benzofuran) (3e)
3.3.6. 5,5′-Methylenebis(2-[1-(p-fluorobenzyl)benzimidazol-2-yl]benzofuran) (3f)
3.3.7. 5,5′-Methylenebis(2-[1-(o-chlorobenzyl)benzimidazol-2-yl]benzofuran) (3g)
3.3.8. 5,5′-Methylenebis(2-[1-(p-chlorobenzyl)benzimidazol-2-yl]benzofuran) (3h)
3.3.9. 5,5′-Methylenebis(2-[1-(m-bromobenzyl)benzimidazol-2-yl]benzofuran) (3i)
3.3.10. 5,5′-Methylenebis[2-(1-isopropylbenzimidazol-2-yl)benzofuran] (3j)
3.3.11. 5,5′-Methylenebis[2-(1-cyclopentylbenzimidazol-2-yl)benzofuran] (3k)
3.3.12. 5,5′-Methylenebis[2-(1-cyclohexylbenzimidazol-2-yl)benzofuran] (3l)
3.4. Biological Evaluation
3.5. Study Plans of QSAR
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Bis-Conjugate | CC50 (μM) | EC50 (μM) | SI | log p |
---|---|---|---|---|
2a | – | >133 | – | 4.75 |
2b | − | >160 | − | − |
2c | 41.0 | 6.75 | 6.07 | 3.77 |
2d | 18.5 | 7.7 | 2.40 | 4.38 |
2e | 54.1 | 3.54 | 15.3 | 4.15 |
2f | 28.5 | 8.51 | 3.35 | 4.68 |
2g | – | >152 | – | 4.25 |
2h | 38.5 | 23.5 | 1.63 | 4.60 |
2i | 12.3 | 14.4 | 0.85 | – |
2j | – | >133 | − | – |
2k | 75.0 | 8.89 | 8.43 | 5.16 |
3a | – | >114 | – | – |
3b | – | >145 | – | – |
3c | – | >139 | – | – |
3d | – | 27.7 | – | – |
3e | – | >21.5 | – | 4.65 |
3f | – | 28.7 | – | – |
3g | – | >137 | – | – |
3h | – | >103 | – | – |
3i | – | 91.6 | – | – |
3j | 69.3 | 6.14 | 11.3 | 3.71 |
3k | – | >162 | – | – |
3l | – | >28.7 | – | – |
7 | – | >329 | – | 3.75 |
10 | – | >255 | – | – |
11 | – | >297 | – | – |
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Gupta, N.K.; Jayakumar, S.; Huang, W.-C.; Leyssen, P.; Neyts, J.; Bachurin, S.O.; Hwu, J.R.; Tsay, S.-C. Bis(Benzofuran–1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus. Int. J. Mol. Sci. 2022, 23, 12675. https://doi.org/10.3390/ijms232012675
Gupta NK, Jayakumar S, Huang W-C, Leyssen P, Neyts J, Bachurin SO, Hwu JR, Tsay S-C. Bis(Benzofuran–1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus. International Journal of Molecular Sciences. 2022; 23(20):12675. https://doi.org/10.3390/ijms232012675
Chicago/Turabian StyleGupta, Nitesh K., Srinivasan Jayakumar, Wen-Chieh Huang, Pieter Leyssen, Johan Neyts, Sergey O. Bachurin, Jih Ru Hwu, and Shwu-Chen Tsay. 2022. "Bis(Benzofuran–1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus" International Journal of Molecular Sciences 23, no. 20: 12675. https://doi.org/10.3390/ijms232012675