Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
2.1.1. 2-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines 1
2.1.2. 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines 2
2.2. In Vitro Biological Evaluation
2.3. Electrochemical Behavior
3. Conclusions
4. Materials and Methods
4.1. General Experimental
4.2. Synthetic Organic Chemistry
4.2.1. Preparation of 2,4-bis(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidine (4)
4.2.2. General Procedure 2 (GP2) for the Preparation of Compounds 1a-d, 1f-l and 1n-s
2-((2-(3-Nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)amino)ethan-1-ol (1a)
N,N-Dimethyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1b)
N-Methyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1c)
N-Benzyl-N-methyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1d)
3-((2-(3-Nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)amino)propan-1-ol (1f)
N-Ethyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1g)
4-(2-(3-Nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)morpholine (1h)
4-(4-Methylpiperazin-1-yl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidine (1i)
N-Benzyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1j)
N-Isobutyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1k)
2,2′-((2-(3-Nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)azanediyl)bis(ethan-1-ol) (1l)
N-Cyclopropyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1n)
N-Isopropyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1o)
N-(3-(1H-Imidazol-1-yl)propyl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1p)
2-(3-Nitro-1H-1,2,4-triazol-1-yl)-4-(pyrrolidin-1-yl)pyrimidine (1q)
2-(3-Nitro-1H-1,2,4-triazol-1-yl)-N-propylpyrimidin-4-amine (1r)
N-(4-Methoxybenzyl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1s)
N-(4-Methoxyphenyl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1e)
2-(3-Nitro-1H-1,2,4-triazol-1-yl)-N-(p-tolyl)pyrimidin-4-amine (1m)
4.2.3. Preparation of 2-chloro-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidine (5)
4.2.4. General Procedure 1 (GP1) for Preparation of Compounds 1a-d, 1f-l and 1n-s
2-((4-(3-Nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)amino)ethan-1-ol (2a)
N,N-Dimethyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2b)
N-Methyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2c)
N-Benzyl-N-methyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2d)
3-((4-(3-Nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)amino)propan-1-ol (2f)
N-Ethyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2g)
4-(4-(3-Nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)morpholine (2h)
2-(4-Methylpiperazin-1-yl)-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidine (2i)
N-Benzyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2j)
N-Isobutyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2k)
2,2′-((4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)azanediyl)bis(ethan-1-ol) (2l)
N-cyclopropyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2n)
N-Isopropyl-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2o)
N-(3-(1H-Imidazol-1-yl)propyl)-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2p)
4-(3-Nitro-1H-1,2,4-triazol-1-yl)-2-(pyrrolidin-1-yl)pyrimidine (2q)
4-(3-Nitro-1H-1,2,4-triazol-1-yl)-N-propylpyrimidin-2-amine (2r)
N-(4-Methoxybenzyl)-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2s)
N-(4-Methoxyphenyl)-4-(3-nitro-1H-1,2,4-triazol-1-yl)pyrimidin-2-amine (2e)
4-(3-Nitro-1H-1,2,4-triazol-1-yl)-N-(p-tolyl)pyrimidin-2-amine (2m)
4.3. Evaluation of Antimycobacterial Activity
4.4. Screening against ESKAPE Pathogens
4.5. Cyclic Voltammetry
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Entry | Compound | Product | Ratio 1:2 | Isolated Yield of 1 (%) |
---|---|---|---|---|
1 | 1a | | 4.6:1 | 65 |
2 | 1b | | 2.5:1 | 48 |
3 | 1c | | 3.2:1 | 61 |
4 | 1d | | 4:1 | 68 |
5 | 1e | | 11.2:1 a | 45 |
6 | 1f | | 4.6:1 | 35 |
7 | 1g | | 2.2:1 | 46 |
8 | 1h | | 3.5:1 | 38 |
9 | 1i | | 22:1 | 66 |
10 | 1j | | 3.5:1 | 39 |
11 | 1k | | 1.4:1 | 32 |
12 | 1l | | 1.2:1 | 28 |
13 | 1m | | 1.6:1 a | 35 |
14 | 1n | | 3.5:1 | 47 |
15 | 1o | | 2.4:1 | 43 |
16 | 1p | | 7.2:1 | 66 |
17 | 1q | | 4:1 | 44 |
18 | 1r | | - b | 61 |
19 | 1s | | - b | 19 |
Entry | Compound | Product | Yield (%) |
---|---|---|---|
1 | 2a | | 39 |
2 | 2b | | 54 |
3 | 2c | | 62 |
4 | 2d | | 23 |
5 | 2e | | 41 a |
6 | 2f | | 58 |
7 | 2g | | 75 |
8 | 2h | | 83 |
9 | 2i | | 76 |
10 | 2j | | 81 |
11 | 2k | | 44 |
12 | 2l | | 71 |
13 | 2m | | 62 a |
14 | 2n | | 49 |
15 | 2o | | 59 |
16 | 2p | | 26 |
17 | 2q | | 40 |
18 | 2r | | 49 |
19 | 2s | | 46 |
Entry | Compound | R1NR2 Side Chain | MIC, μg/mL | |||||
---|---|---|---|---|---|---|---|---|
E1 | S | K | A | P | E2 | |||
1 | 1a | | 16 | >100 | >100 | 16 | >100 | >100 |
2 | 2a | 8 | 63 | 8 | >100 | >100 | 63 | |
3 | 1b | | 8 | >100 | >100 | 4 | >100 | >100 |
4 | 2b | 8 | >100 | 2 | 2 | >100 | 8 | |
5 | 1c | | 16 | >100 | >100 | 4 | >100 | >100 |
6 | 2c | 63 | >100 | >100 | 8 | >100 | >100 | |
7 | 1d | | 8 | 16 | 32 | >100 | >100 | 63 |
8 | 2d | 8 | 63 | 16 | >100 | >100 | 63 | |
9 | 1e | | 4 | >100 | 63 | >100 | >100 | >100 |
10 | 2e | 8 | 8 | >100 | 4 | >100 | 63 | |
11 | 1f | | 4 | >100 | >100 | 8 | >100 | >100 |
12 | 2f | 8 | 63 | 8 | 32 | >100 | 16 | |
13 | 1g | | 4 | >100 | >100 | 32 | >100 | >100 |
14 | 2g | 32 | >100 | >100 | 8 | >100 | 63 | |
15 | 1h | | 16 | >100 | >100 | 32 | >100 | >100 |
16 | 2h | 4 | 16 | >100 | 63 | >100 | >100 | |
17 | 1i | | 2 | 4 | 32 | 32 | >100 | 32 |
18 | 2i | 2 | >100 | >100 | >100 | >100 | >100 | |
19 | 1j | | 4 | >100 | >100 | 4 | >100 | >100 |
20 | 2j | 8 | >100 | >100 | 63 | >100 | >100 | |
21 | 1k | | 2 | 63 | >100 | >100 | >100 | >100 |
22 | 2k | >100 | >100 | >100 | 4 | >100 | >100 | |
23 | 1l | | 63 | >100 | >100 | 4 | >100 | >100 |
24 | 2l | 16 | 16 | >100 | 8 | >100 | >100 | |
25 | 1m | | 8 | 8 | 32 | 2 | >100 | 16 |
26 | 2m | 16 | >100 | >100 | 8 | >100 | >100 | |
27 | 1n | | >100 | >100 | >100 | >100 | >100 | >100 |
28 | 2n | 4 | 32 | >100 | 63 | >100 | >100 | |
29 | 1o | | 2 | 4 | 16 | 32 | >100 | 32 |
30 | 2o | >100 | >100 | >100 | 8 | >100 | >100 | |
31 | 1p | | 32 | >100 | >100 | 8 | >100 | >100 |
32 | 2p | 4 | >100 | >100 | 8 | >100 | >100 | |
33 | 1q | | 16 | >100 | >100 | 4 | >100 | >100 |
34 | 2q | 32 | 63 | >100 | 16 | >100 | >100 | |
35 | 1r | | 16 | >100 | >100 | 8 | >100 | 63 |
36 | 2r | 16 | 63 | >100 | >100 | >100 | >100 | |
37 | 1s | | 16 | 63 | 63 | >100 | >100 | >100 |
38 | 2s | 2 | >100 | >100 | 4 | >100 | >100 | |
39 | 4 | | 32 | >100 | >100 | >100 | >100 | >100 |
40 | ciprofloxacin | 0.3 | 1.25 | 0.6 | 2.5 | 0.6 | 1.25 |
Entry | Compound | E1/2 (V vs. Ag/Ag+) | E1/2 (V vs. Fc/Fc+) | E. faecium MIC (μg/mL) |
---|---|---|---|---|
1 | 1i | −1.253 | −1.439 | 2 |
2 | 1j | −1.262 | −1.447 | 4 |
3 | 1m | −1.246 | −1.432 | 8 |
4 | 1n | −1.255 | −1.441 | >100 |
5 | 2b | −1.195 | 1.381 | 8 |
6 | 2e | −1.178 | −1.364 | 8 |
7 | 2i | −1.192 | −1.378 | 2 |
8 | 2r | −1.196 | −1.382 | 16 |
9 | ferrocene | 0.186 | 0.000 | – |
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Chuprun, S.; Dar’in, D.; Rogacheva, E.; Kraeva, L.; Levin, O.; Manicheva, O.; Dogonadze, M.; Vinogradova, T.; Bakulina, O.; Krasavin, M. Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens. Antibiotics 2020, 9, 666. https://doi.org/10.3390/antibiotics9100666
Chuprun S, Dar’in D, Rogacheva E, Kraeva L, Levin O, Manicheva O, Dogonadze M, Vinogradova T, Bakulina O, Krasavin M. Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens. Antibiotics. 2020; 9(10):666. https://doi.org/10.3390/antibiotics9100666
Chicago/Turabian StyleChuprun, Sergey, Dmitry Dar’in, Elizaveta Rogacheva, Liudmila Kraeva, Oleg Levin, Olga Manicheva, Marine Dogonadze, Tatiana Vinogradova, Olga Bakulina, and Mikhail Krasavin. 2020. "Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens" Antibiotics 9, no. 10: 666. https://doi.org/10.3390/antibiotics9100666