Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents Ehtesham Jameel a , Poonam Meena b , Mudasir Maqbool a , Jitendra Kumar a , Waqar Ahmed a , Syed Mumtazuddin c , Manisha Tiwari b *, Nasimul Hoda a * and B. Jayaram d,e,f a Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi 110025, India b Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India c Department of Chemistry, B. R. Ambedkar Bihar University, Muzaffarpur 842001, Bihar, India d Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India e Kusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, India f Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi 110016, India. * Corresponding authors. # Nasimul Hoda, Ph.D. $ Manisha Tiwari, Ph.D. Professor Assistant Professor
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ars.els-cdn.com · Web viewbDr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India cDepartment of Chemistry, B. R. Ambedkar Bihar University,
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Rational design, synthesis and biological screening of
triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents
Mumtazuddinc, Manisha Tiwarib*, Nasimul Hodaa* and B. Jayaramd,e,f
aDepartment of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi
110025, IndiabDr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007,
IndiacDepartment of Chemistry, B. R. Ambedkar Bihar University, Muzaffarpur 842001, Bihar, IndiadDepartment of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016,
IndiaeKusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, IndiafSupercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi
110016, India.
* Corresponding authors.
#Nasimul Hoda, Ph.D. $Manisha Tiwari, Ph.D.Professor Assistant ProfessorDepartment of Chemistry Dr. B. R. Ambedkar Jamia Millia Islamia, Centre for Biomedical Research, Jamia Nagar, New Delhi- 110025, University of Delhi, New Delhi- 110007, India India Email: [email protected] Email: [email protected]
Mass spectra of 4-chloro-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine 9 (a).
1H-NMR of 4-chloro-N-(4-methoxyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (b).
-7-6-5-4-3-2-101234567891011121314151617f1 (ppm)
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
3.02
8.00
3.02
1.00
2.01
2.01
1.01
1.00
2.46
0
3.69
63.
894
6.61
36.
877
6.89
97.
521
7.54
28.
445
10.0
27
Mass spectra of 4-chloro-N-(4-methoxyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (b).
1H-NMR of 4-chloro-N-(4-fluoroyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (c).
Mass spectra of N2-cyclopropyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (a).
1H NMR of 6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N2-(p-tolyl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (b).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
3.05
3.00
8.00
1.05
2.02
1.07
1.02
2.04
1.01
1.04
1.05
1.02
1.00
2.30
2
3.10
93.
742
3.78
4
6.42
66.
882
6.90
97.
072
7.09
87.
305
7.38
57.
411
7.80
97.
830
8.00
38.
256
8.99
89.
335
13C NMR of 6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N2-(p-tolyl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (b).
Mass spectra of 6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N2-(p-tolyl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (b).
1H NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (c).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
3.00
8.00
1.00
2.02
1.01
1.00
2.02
1.00
1.00
1.03
1.02
2.50
7
3.95
73.
990
6.65
07.
303
7.32
97.
536
7.68
27.
992
8.00
78.
158
8.47
59.
512
9.67
1
13C NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (c).
Mass spectra of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (c).
1H NMR of N2-(4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (d).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
3.01
8.00
1.03
2.06
1.08
1.01
2.04
1.01
1.03
1.02
1.02
1.03
2.27
8
3.72
53.
763
6.39
06.
888
7.05
27.
077
7.28
67.
501
7.52
37.
761
7.78
27.
974
8.22
29.
073
9.31
3
13C NMR of N2-(4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (d).
Mass spectra of N2-(4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (d).
1H NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(p-tolyl)-1,3,5-triazine-2,4diamine 10 (e).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
3.09
3.17
8.00
1.02
2.11
1.07
2.12
2.03
1.10
1.08
1.01
2.26
82.
507
3.31
33.
942
3.97
5
6.62
47.
100
7.12
77.
310
7.56
27.
588
8.04
88.
070
8.45
19.
196
9.37
4
13C NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(p-tolyl)-1,3,5-triazine-2,4diamine 10 (e).
Mass spectra of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(p-tolyl)-1,3,5-triazine-2,4diamine 10 (e).
1H NMR of N2-cyclopropyl-6-(piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (f).
-7-6-5-4-3-2-101234567891011121314151617f1 (ppm)
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
3.2
4.96
7.97
2.00
1.98
1.06
1.00
1.00
2.73
23.
400
3.76
1
7.17
07.
188
7.40
27.
780
8.68
69.
497
13C NMR of N2-cyclopropyl-6-(piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (f).
Abbreviations: US FDA, United States Food and Drug administration; NTP, National toxicity program; EC50, effective concentration 50%; LD50, lethal dose 50%; LOAEL, lowest observed adverse effect level.
Probability values:Low probability- 0.0-0.3High probability-0.7-1.0Indeterminate- 0.3-0.7