The effect of position or nature of substituents on the antioxidant activity of the chalcone and Mannich base derivatives can be further studied by synthesizing chalcones with different acetophenone or benzaldehyde starting materials or synthesizing the Mannich bases using different secondary amines.
Furthermore, the Claisen-Schmidt condensation reaction can be carried out using the green synthesis methods, such as microwave-assisted or grinding methods, in order to achieve better yield with shorter reaction time and a more environmentally friendly approach.
Last but not least, the synthesized compounds can be tested for different biological activities, such as cytotoxicity and antibacterial activity.
89 REFERENCES
Aksöz, B.E. and Ertan, R., 2012. Spectral properties of chalcones II.
FABAD Journal of Pharmaceutical Sciences, pp. 37(4), pp. 205-216.
Amole, L.K., Bello, I.A. and Oyewale, A.O., 2019. Synthesis, characterization and biological evaluation of three derivatives of 2- hydroxychalcones. Journal of Applied Sciences and Environmental Management, 23(4), pp. 647-653.
Anwar, C., Prasetyo, Y.D., Matsjeh, S., Haryadi, W., Sholikhah, E.N. and Nendrowati, 2018. Synthesis of chalcone derivatives and their in vitro anticancer test against breast (T47D) and colon (WiDr) cancer cell line.
Indonesian Journal of Chemistry, 18(7), pp. 102-107.
Attarde, M., Vora, A., Varghese, A. and Kachwala, Y., 2014. Synthesis and evaluation of chalcone derivatives for its alpha amylase inhibitory activity.
Organic Chemistry An Indian Journal, 10(5), pp. 192-204.
Bala, S., Sharma, N., Kajal, A., Kamboj, S. and Saini, V., 2014. Mannich bases: an important pharmacophore in present scenario. International Journal of Medicinal Chemistry, 14, pp. 1-15.
Behrendorff, J., Vickers, C.E., Chrysanthopoulos, P. and Nielsen, L.K., 2013. 2,2-Diphenyl-1-picrylhydrazyl as a screening tool for recombinant monoterpene biosynthesis. Microbial Cell Factories, 12(1), pp. 76-87.
Bernades, A., Pérez, C.N., Mayer, M., da Silva, C.C., Martins, F.T. and Perjési, P., 2017. Study of reactions of two Mannich bases derived of 4’- hydroxychalcones with glutathione by RP-TLC, RP-HPLC and RP-HPLC- ESI-MS analysis. Journal of the Brazilian Chemical Society, 28(6), pp.
1048-1062.
Hieu, B.T., Thuy, L.T., Thuy, V.T., Tien, H.X., Chinh, L.V., Hoang, V.D.
and Vu, T.K., 2012. Bulletin of the Korean Chemical Society, 33(5), pp.
1586-1592.
Koçyiğit, Ü.M., Gezegen, H. and Taslimi, P., 2020. Synthesis, characterization, and biological studies of chalcone derivatives containing Schiff bases: Synthetic derivatives for the treatment of epilepsy and Alzheimer's disease. Archiv der Pharmazie, 353(12), pp. 1-11.
Kostopoulou, I., Tzani, A., Polyzos, N., Karadendrou, M., Kritsi, E., Pontiki, E., Liargkova, T., Hadjipavlou-Litina, D., Zoumpoulakis, P. and Detsi, A., 2021. Exploring the 2’-hydroxy-chalcone framework for the development of dual antioxidant and soybean lipoxygenase inhibitory agents. Molecules, 26, pp. 2777-2801.
90 Kristanti, A.N., Suwito, H., Aminah, N.S., Haq, K.U., Hardiyanti, H.D., Anggraeni, H., Faiza, N., Anto, R.S. and Muharromah, S., 2020. Synthesis of some chalcone derivatives, in vitro and in silico toxicity evaluation.
Rasayan Journal of Chemistry, 13(1), pp. 654-662.
Leopoldini, M., Marino, T., Russo, N. and Toscano, M., 2004. Antioxidant properties of phenolic compounds: H-atom versus electron transfer mechanism. The Journal of Physical Chemistry, 108(22), pp. 4916-4922.
Marinescu, M., Cinteză, L.O., Marton, G.L., Chifiriuc, M., Popa, M., Stănculescu, L., Zălaru, C. and Stavarache, C., 2020. Synthesis, density functional theory study and in vitro antimicrobial evaluation of new benzimidazole Mannich bases. BMC Chemistry, 14(1):45.
Merck, 2022. 1-(4-Hydroxyphenyl)-3-phenyl-prop-2-en-1-one. [online]
Available at:
<https://www.sigmaaldrich.com/MY/en/product/ambeedinc/ambh2d6f6d8 a?context=bbe> [Accessed 15 April 2022].
Minatel, I.O., Borges, C.V., Ferreira, M.I., Gomez, H.A., Chen, C.O. and Lima, G.P., 2017. Phenolic compounds: functional properties, impact of processing and bioavailability. In: M. Soto-Hernandez, M. Palma-Tenango and M.R. Garcia-Mateos, eds. Phenolic Compounds – Biological Activity.
London: IntechOpen.
Prabhakar, V., Iqbal, H. and Balasubramanian, R., 2019. Antioxidant studies on monosubstituted chalcone derivatives – understanding substituent effects. Pakistan Journal of Pharmaceutical Sciences, 29(1), pp.
165-171.
Rammohan, A., Reddy, J.S., Sravya, G., Rao, C.N. and Zyryanov, G.V., 2020. Chalcone synthesis, properties and medicinal applications: a review.
Environmental Chemistry Letter, 18, pp. 433-458.
Rashdan, S.A., Hassan, A.M., Mandeel, Q.A., Alasfoor, N.M. and Dawood, Z.H., 2018. Synthesis of substituted chalcones and investigation of their biological activities. Journal of Chemistry and Biochemistry, 6(1), pp. 1-8.
Reddy, M.V.B., Su, C., Chiou, W., Liu, Y, Chen, R.Y., Bastow, K.F., Lee, K. and Wu, T., 2008. Design, synthesis, and biological evaluation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents.
Bioorganic & Medicinal Chemistry, 16, pp. 7358-7370.
Rozmer, Z. Bernades, A., Pérez, C.N. and Perjési, P. Study on the interaction of 4’-hydroxychalcones and their Mannich derivatives with calf thymus DNA by TLC and spectroscopic methods, a DNA cleavage study.
The Open Medicinal Chemistry Journal, 14, pp. 122-131.
91 Sökmen, M. and Khan, M.A., 2017. The antioxidant activity of some curcuminoids and chalcones. Inflammopharmacology, 24, pp. 81-86.
Sreedhar, N.Y., Jayapal, M.R., Prasad, K.S. and Prasad, P.R., 2010.
Synthesis and characterization of 4-hydroxy chalcones using PEG-400 as a recyclable solvent. Research Journal of Pharmaceutical, Biological and Chemical Sciences, 1(4), pp. 480-485.
Susanti, V.H.E. and Setyowati, W.A.E., 2019. Synthesis and characterization of some bromochalcones derivatives. In: 3rd International Conference on Advanced Materials for Better Future 2018. Indonesia, 15- 16 October 2018. Bristol, United Kingdom: IOP Publishing. Available at:
<https://iopscience.iop.org/article/10.1088/1757-
899X/578/1/012002/pdf#:~:text=Chalcone%20synthesis%20can%20be%2 0carried,an%20acidic%20or%20alkaline%20atmosphere.> [Accessed 15 April 2022].
Syahri, J., Nasution, H., Nurohmah, B.A., Purwono, B., Yuanita, E., Zakaria, N.H. and Hassan, N.I., 2020. Design, synthesis and biological evaluation of aminoalkylated chalcones as antimalarial agent. Sains Malaysiana, 49(11), pp. 2667-2677.
The Royal Society of Chemistry, 2017. Solvent-free aldol condensation reactions: synthesis of chalcone derivatives. [online] Available at:
<http://www.rsc.org/suppdata/books/184973/9781849739634/bk9781849 739634-chapter%204.2.2.pdf> [Accessed 15 April 2022].
Vutturi, A.V., 2011. Mannich reaction. [online] Available at:
<https://www.adichemistry.com/organic/namedreactions/mannich/mannic h-reaction-1.html> [Accessed 15 April 2022].
Xue, Y., Zheng, Y., Zhang, L., Wu, W., Yu, D. and Liu, Y., 2013.
Theoretical study on the antioxidant properties of 2’-hydroxychalcones: H- atom vs. electron transfer mechanism. Journal of Molecular Modeling, 19, pp. 3851-3862.
Zhang, X., Song, Q., Cao, Z., Li, Y., Tian, C., Yang, Z., Zhang, H. and Deng, Y., 2019. Design, synthesis and evaluation of chalcone Mannich base derivatives as multifunctional agents for the potential treatment of Alzheimer’s disease. Bioorganic Chemistry, 87, pp. 395-408.
92 APPENDICES
APPENDIX A
Appendix A1: FTIR spectrum ofDA2(KBr)..
93
Appendix A2: FTIR spectrum ofPY2(KBr)..
94
Appendix A3: FTIR spectrum ofPI2(KBr)..
95 APPENDIX B
Figure B1: LC-MS spectrum and spectrum identification of CA2.
96 Figure B2: LC-MS spectrum and spectrum identification of DA2.
97 Figure B3: LC-MS spectrum and spectrum identification of PI2.
98 APPENDIX C
Table C1: 1H, 13C and DEPT NMR spectral data of CA2.
Atom Number 1H (δH, ppm)
13C (δC, ppm)
DEPT
C=O - 187.8 C
α 7.86 (d, J =
15.6 Hz)
122.6 CH
β 7.64 (d, J =
15.6 Hz)
143.3 CH
1 - 135.4 C
2 & 6 7.81 (m) 129.4 CH
3 & 5 7.40 (m) 129.2 CH
4 7.40 (m) 130.9 CH
1’ - 129.6 C
2’ & 6’ 8.03 (d, J = 8.24 Hz)
131.7 CH
3’ & 5’ 6.87 (d, J = 8.72 Hz)
116.0 CH
4’ - 162.7 C
99 Table C2: 1H – 13C correlations in CA2.
Carbon Number
Proton Number
HMQC HMBC
1J 2J 3J 4J
C=O - Hα Hβ, H2’,
H6’
-
Cα Hα - - -
Cβ Hβ Hα H2, H6 H3, H5
C1 - Hβ, H2, H6 Hα, H3, H5 -
C2 H2 Hβ - -
C3 H3 H2 - -
C4 H4 - H2, H6 -
C5 H5 H6 - -
C6 H6 - Hβ -
C1’ - - - -
C2’ H2’ - - -
C3’ H3’ H2’ H5’ -
C4’ - H3’, H5’ H2’, H6’ -
C5’ H5’ H6’ H3’ -
C6’ H6’ - - -
100 Figure C1: Expanded (downfield region) 1H NMR spectrum of 4’-
hydroxychalcone (CA2) (400 MHz, DMSO-d6).
101 Figure C2: 13C NMR spectrum of 4’-hydroxychalcone (CA2) (100 MHz,
DMSO-d6).
102 Figure C3: DEPT NMR spectrum of 4’-hydroxychalcone (CA2).
103 Figure C4: HMQC NMR spectrum of 4’-hydroxychalcone (CA2).
104 Figure C5: Expanded (downfield region) HMBC NMR spectrum of 4’-
hydroxychalcone (CA2).
105 APPENDIX D
Table D1: 1H, 13C and DEPT NMR spectral data of DA2.
Atom Number 1H (δH, ppm)
13C (δC, ppm)
DEPT
C=O - 188.7 C
α 7.54 (d, J =
15.88)
121.9 CH
β 7.78 (t, J =
15.88)
143.8 CH
1 - 135.3 C
2 & 6 7.63 (m) 128.4 CH
3 & 5 7.40 (m) 129.0 CH
4 7.40 (m) 129.6 CH
1’ - 130.4 C
2’ 7.78 (t, J = 15.88)
130.4 CH
3’ - 116.1 CH
4’ - 163.5 C
5’ 6.88 (d, J = 8.56)
116.1 CH
6’ 7.92 (dd, J = 2.44, 8.56)
130.4 CH
7’ 3.74 (s) 62.6 CH2
9’ & 10’ 2.36 (s) 44.5 CH3
106 Table D2: 1H – 13C correlations in DA2.
Carbon Number
Proton Number
HMQC HMBC
1J 2J 3J 4J
C=O - Hα Hβ, H2’,
H6’
-
Cα Hα - - -
Cβ Hβ Hα H2, H6 -
C1 - Hβ Hα, H3, H5 -
C2 H2 H3 Hβ, H4 -
C3 H3 - - -
C4 H4 - H2, H6 -
C5 H5 - - Hβ
C6 H6 H5 Hβ, H4 -
C1’ - H2’, H6’ H5’ -
C2’ H2’ - - -
C3’ - - - -
C4’ - H5’ H2’, H6’,
H7’
-
C5’ H5’ - - -
C6’ H6’ - - -
C7’ H7’ - H2’, H9’,
H10’
-
C9’ & C10’ H9’ or H10’ - H7’ -
107 Figure D1: 1H NMR spectrum of 4’-hydroxy-3’-
dimethylaminomethylchalcone (DA2) (400 MHz, CDCl3).
108 Figure D2: 13C NMR spectrum of 4’-hydroxy-3’-
dimethylaminomethylchalcone (DA2) (100 MHz, CDCl3).
109 Figure D3: DEPT NMR spectrum of 4’-hydroxy-3’-
dimethylaminomethylchalcone (DA2).
110 Figure D4: HMQC NMR spectrum of 4’-hydroxy-3’-
dimethylaminomethylchalcone (DA2).
111 Figure D5: HMBC NMR spectrum of 4’-hydroxy-3’-
dimethylaminomethylchalcone (DA2).
112 APPENDIX E
Table E1: 1H, 13C and DEPT NMR spectral data of PY2.
Atom Number 1H (δH, ppm)
13C (δC, ppm)
DEPT
C=O - 188.7 C
α 7.55 (d, J =
15.88)
122.0 CH
β 7.78 (q, J =
15.88)
143.7 CH
1 - 135.3 C
2 & 6 7.64 (m) 128.4 CH
3 & 5 7.40 (m) 129.0 CH
4 7.40 (m) 129.2 CH
1’ - 129.4 C
2’ 7.78 (q, J = 15.88)
130.3 CH
3’ - 116.1 C
4’ - 163.6 C
5’ 6.87 (d, J = 8.56)
116.1 CH
6’ 7.91 (dd, J = 8.56)
130.3 CH
7’ 3.92 (s) 58.6 CH2
9’ & 12’ 2.68 (s) 53.6 CH2
10’ & 11’ 1.88 (s) 23.7 CH2
113 Table E2: 1H – 13C correlations in PY2.
Carbon Number
Proton Number
HMQC HMBC
1J 2J 3J 4J
C=O - Hα Hβ, H2’,
H6’
-
Cα Hα Hβ - -
Cβ Hβ Hα H2, H6 -
C1 - Hβ Hα, H3, H5 -
C2 H2 - - -
C3 H3 H4 - -
C4 H4 H3, H5 - -
C5 H5 H4 - Hβ
C6 H6 - - -
C1’ - H2’, H6’ H5’ -
C2’ H2’ - - -
C3’ - - - -
C4’ - H5’ H2’, H6’ -
C5’ H5’ - - -
C6’ H6’ - - -
C7’ H7’ - H2’ -
C9’ & C12’ H9’ or H12’ H10’or H11’
H7’ -
C10’ &
C11’
H10’ or H11’
- - -
114 Figure E1: 1H NMR spectrum of 4’-hydroxy-3’-
pyrrolidinomethylchalcone (PY2) (400 MHz, CDCl3).
115 Figure E2: 13C NMR spectrum of 4’-hydroxy-3’-
pyrrolidinomethylchalcone (PY2) (100 MHz, CDCl3).
116 Figure E3: DEPT NMR spectrum of 4’-hydroxy-3’-
pyrrolidinomethylchalcone (PY2)
117 Figure E4: HMQC NMR spectrum of 4’-hydroxy-3’-
pyrrolidinomethylchalcone (PY2).
118 Figure E5: HMBC NMR spectrum of 4’-hydroxy-3’-
pyrrolidinomethylchalcone (PY2).
119 APPENDIX F
Table F1: 1H, 13C and DEPT NMR spectral data of PI2.
Atom Number
1H (δH, ppm)
13C (δC, ppm)
C=O - 188.7
α 7.54 (d, J = 15.24 Hz) 122.0
β 7.78 (d, J = 15.88 Hz) 143.7
1 - 135.3
2 & 6 7.64 (m) 128.4
3 & 5 7.40 (t, J = 4.88 Hz) 129.0
4 7.40 (t, J = 4.88 Hz) 129.4
1’ - 129.8
2’ 7.78 (d, J = 15.88 Hz) 130.3
3’ - 116.2
4’ - 163.6
5’ 6.86 (d, J = 8.52 Hz) 116.2
6’ 7.90 (dd, J = 1.84 Hz, 8.56 Hz) 130.3
7’ 3.75 (s) 61.9
9’ & 13’ 1.98 (t) 23.8
10’ & 12’ 1.64 (t, J = 4.88 Hz) 25.7
11’ 1.24 (m) 29.8
120 Figure F1: 1H NMR spectrum of 4’-hydroxy-3’-
piperidinomethylchalcone (PI2) (400 MHz, CDCl3).