New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies
Abstract
1. Introduction
2. Experimental
2.1. Synthesis
2.1.1. General Procedure for the Synthesis of Carboxylic Acid Hydrazides (Series A)
2.1.2. General Procedure for the Synthesis of Thiosemicarbazides (Series B)
B13. 4-(2,4-Dichlorophenyl)-1-(pyridin-3-yl)acetylthiosemicarbazide
B14. 4-(3,4-Dichlorophenyl)-1-(pyridin-4-yl)acetylothiosemicarbazide
2.1.3. General Procedure for the Synthesis of 1,2,4-triazole Derivatives (Series C)
C1. 4-(2-Fluorphfenyl)-3-(pyridin-2-yl)-1,2,4-triazoline-5-thione
C2. 4-(2-Chlorophenyl)-3-(pyridin-2-yl)-1,2,4-triazoline-5-thione
C3. 4-(2,4-Dichlorofenylo)-3-(pyridin-2-yl)-1,2,4-triazoline-5-thione
C4. 4-(3,4-Dichlorofenylo)-3-(pyridin-2-yl)-1,2,4-triazoline-5-thione
C5. 4-(2-Chlorofenylo)-3-(pyridin-3-yl)-1,2,4-triazoline-5-thione
C6. 4-(4-Nitrofenylo)-3-(pyridin-3-yl)-1,2,4-triazoline-5-thione
C7. 4-(2,4-Dichlorofenylo)-3-(pyridin-3-yl)-1,2,4-triazoline-5-thione
C8. 4-(3,4-Dichlorofenylo)-3-(pyridin-3-yl)-1,2,4-triazoline-5-htione
C9. 4-(2-Fluorofenylo)-3-(pyridin-4-yl)-1,2,4-triazoline-5-thione
C10. 4-(2,4-Dichlorophenyl)-3-(pyridin-4-yl)-1,2,4-triazoline-5-thione
C11. 4-Phenyl-3-(pyridin-2-yl)-1,2,4-triazoline-5-thione
C12. 4-(4-Methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-triazoline-5-thione
C13. 4-(2,4-Dichlorophenyl)-3-(pyridin-3-ylmethyl)-1,2,4-triazoline-5-thione
C14. 4-(3,4-Dichlorophenyl)-3-(pyridin-4-ylmethyl)-1,2,4-triazoline-5-thione
2.2. X-ray Structure Determination
2.3. Theoretical Calculations
2.4. Antimycobacterial Assay
2.5. Molecular Docking
3. Results and Discussion
3.1. Chemistry
3.2. X-ray Analysis
3.3. Theoretical Calculations
3.4. Antimycobacterial Activity
3.5. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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D–H…A | D–H | H…A | D…A | D–H…A |
---|---|---|---|---|
C1 | ||||
N1–H1…S5i | 0.89(3) | 2.37(4) | 3.261(2) | 175(3) |
i = −x, 2 − y, −z | ||||
C12 | ||||
N1–H1…N63i | 0.92(3) | 1.88(3) | 2.789(3) | 171(2) |
i = x, 3/2 − y, −1/2 + z | ||||
C13 | ||||
N1–H1…N63i | 0.99(3) | 1.83(3) | 2.815(4) | 170(3) |
C43–H43…N2ii | 0.93 | 2.53 | 3.435(4) | 164 |
C46–H46…S5iii | 0.93 | 2.84 | 3.675(4) | 150 |
C65–H65…S5iv | 0.93 | 2.87 | 3.714(4) | 152 |
C31–H312…Sv | 0.97 | 2.87 | 3.552(4) | 129 |
i = −1 + x, 1 + y, z; ii = x, −1+y, z; iii = −x, 1 − y, 1 − z; iv = −x, 1 − y, −z; v = 1 + x, y, z |
Compound | Dm | NBO Charge | EHOMO | ELUMO | ΔE | logP | ||||
---|---|---|---|---|---|---|---|---|---|---|
N1 | N2 | N4 | Npyridil | S | ||||||
C1 | 5.631 | −0.381 | −0.274 | −0.455 | −0.455 | −0.207 | −134.17 | −45.45 | 88.68 | 4.95 |
C2 | 5.736 | −0.381 | −0.276 | −0.462 | −0.451 | −0.205 | −133.80 | −45.42 | 88.38 | 5.33 |
C3 | 6.001 | −0.389 | −0.273 | −0.460 | −0.451 | −0.200 | −136.58 | −48.19 | 88.39 | 5.85 |
C4 | 6.262 | −0.382 | −0.274 | −0.462 | −0.451 | −0.202 | −137.66 | −49.22 | 88.44 | 5.85 |
C5 | 3.265 | −0.384 | −0.277 | −0.471 | −0.444 | −0.206 | −136.88 | −43.70 | 93.18 | 5.40 |
C6 | 6.515 | −0.382 | −0.270 | −0.471 | −0.440 | −0.193 | −144.86 | −73.52 | 77.33 | 0.97 |
C7 | 3.502 | −0.384 | −0.276 | −0.474 | −0.443 | −0.202 | −139.61 | −46.19 | 93.42 | 5.81 |
C8 | 3.901 | −0.384 | −0.275 | −0.465 | −0.441 | −0.206 | −140.92 | −47.72 | 93.20 | 5.91 |
C9 | 2.870 | −0.382 | −0.258 | −0.455 | −0.442 | −0.196 | −138.88 | −49.32 | 89.55 | 5.02 |
C10 | 1.587 | −0.381 | −0.265 | −0.472 | −0.439 | −0.206 | −141.92 | −51.26 | 90.65 | 5.91 |
C11 | 4.538 | −0.394 | −0.308 | −0.476 | −0.469 | −0.222 | −132.84 | −32.45 | 100.39 | 4.75 |
C12 | 3.208 | −0.384 | −0.281 | −0.461 | −0.444 | −0.217 | −133.86 | −42.17 | 91.68 | 4.63 |
C13 | 3.694 | −0.393 | −0.294 | −0.482 | −0.444 | −0.205 | −138.47 | −38.39 | 99.94 | 5.85 |
C14 | 4.688 | −0.392 | −0.291 | −0.480 | −0.448 | −0.205 | −140.64 | −39.24 | 101.40 | 5.85 |
Inhibition Zone (mm) 250 μg of Compound PerWell | ||||||
---|---|---|---|---|---|---|
Ar | R | Mycobacterium H37Ra | Mycobacterium Phlei | Mycobacterium Smegmatis | Mycobacterium Timereck | |
C1 | pyridin-2-yl | 2-FC6H4 | 15.1 ± 0.61 | 15.1 ± 0.53 | 16.0 ± 0.81 | 15.1 ± 0.67 |
C2 | pyridin-2-yl | 2-ClC6H4 | 19.6 ± 0.43 | 21.5 ± 1.12 | 17.2 ± 0.98 | 15.3 ± 0.84 |
C3 | pyridin-2-yl | 2,4-Cl2C6H3 | 10.2 ± 0.8 | 17.0 ± 0.78 | 17.9 ± 0.77 | 20.1 ± 1.15 |
C4 | pyridin-2-yl | 3,4-Cl2C6H3 | 26.9 ± 0.78 | 22.7 ± 0.91 | 22.3 ± 1.05 | 21.5 ± 0.9 |
C5 | pyridin-3-yl | 2-ClC6H4 | 12.3 ± 0.78 | 0.0 | 10.2 ± 0.86 | 16.5 ± 0.41 |
C6 | pyridin-3-yl | 4-NO2C6H4 | 0.0 | 0.0 | 0.0 | 10.6 ± 0.53 |
C7 | pyridin-3-yl | 2,4-Cl2C6H3 | 0.0 | 8.9 ± 0.66 | 0.0 | 0.0 |
C8 | pyridin-3-yl | 3,4-Cl2C6H3 | 22.2 ± 0.72 | 21.9 ± 0.29 | 23.1 ± 0.6 | 24.7 ± 0.87 |
C9 | pyridin-4-yl | 2-FC6H4 | 10.6 ± 0.53 | 10.9 ± 0.66 | 12.3 ± 0.92 | 19.6 ± 0.53 |
C10 | pyridin-4-yl | 2,4-Cl2C6H3 | 0.0 | 0.0 | 0.0 | 0.0 |
C11 | pyridin-2-yl | C6H5 | 35.9 ± 0.49 | 34.0 ± 0.93 | 35.3 ± 0.7 | 35.1 ± 0.58 |
C12 | pyridin-3-yl | 4-CH3OC6H4 | 10.6 ± 0.85 | 0.0 | 0.0 | 0.0 |
C13 | pyridin-3-ylmethyl | 2,4-Cl2C6H3 | 12.0 ± 0.67 | 0.0 | 0.0 | 0.0 |
C14 | pyridin-4-ylmethyl | 3,4-Cl2C6H3 | 20.7 ± 0.29 | 0.0 | 18.2 ± 0.53 | 18.6 ± 0.98 |
MIC (µg/mL) | ||||||
---|---|---|---|---|---|---|
Ar | R | Mycobacterium H37Ra | Mycobacterium Phlei | Mycobacterium Smegmatis | Mycobacterium Timereck | |
C1 | pyridin-2-yl | 2-FC6H4 | 62.5 | 500 | >500 | >500 |
C4 | pyridin-2-yl | 3,4-Cl2C6H3 | 0.976 | 7.81 | 125 | 62.5 |
C8 | pyridin-3-yl | 3,4-Cl2C6H3 | 62.5 | 31.25 | 125 | 62.5 |
C11 | pyridin-2-yl | C6H5 | 62.5 | 31.25 | 250 | 62.5 |
C14 | pyridin-2-ylmethyl | 3,4-Cl2C6H3 | 62.5 | 125 | >500 | 125 |
Compound | fCHEMPLP | Ligand—Amino Acids Interactions |
---|---|---|
C1 | 56.67 | F42…C(HEME); S5…C(MET62); N1…O(HEME); N2…C(HEME) |
C2 | 57.79 | N1…O(HEME); N2…C(HEME); S5…C(MET62) |
C3 | 54.59 | S5…C(HEME); N1…O(VAL82) |
C4 | 57.68 | N2…C(PHE280); S5…C(HEME); C45…O(HEME); C46…O(HEME); Cl44…(MET62) |
C5 | 57.04 | S5…C(MET62); N2…C(PHE280) |
C6 | 67.83 | S5…C(MET62) × 2; N63…N(ARG386); O…O(SER237) |
C7 | 55.14 | S5…C(MET62); N63…C(PHE280); Cl44…(C(PHE280); Cl42…O(HEME) |
C8 | 53.67 | N63…N(ARG386); Cl43…C(VAL78) |
C9 | 58.71 | S5…C((MET62); N64…O(SER237) |
C10 | 60.20 | N2…C(HEME); N64…N(ARG386); C63…O(SER237); C43…O(HEME) |
C11 | 65.77 | S5…C(MET62) × 2; S5…C(HEME) |
C12 | 55.89 | N1…O(VAL82) |
C13 | 66.94 | S5…N(ASN85); S5…C(ASN85); N64…C(MET62); N1…O(VAL82); N2…C(MET62) |
C14 | 68.29 | N1…O(VAL82); S5…N(ASN85); S5…C(ASN85); Cl43…C(HEME) |
Sample Availability: Samples of the compounds B13, B14, C1–C14 are available from the authors. |
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Karczmarzyk, Z.; Swatko-Ossor, M.; Wysocki, W.; Drozd, M.; Ginalska, G.; Pachuta-Stec, A.; Pitucha, M. New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies. Molecules 2020, 25, 6033. https://doi.org/10.3390/molecules25246033
Karczmarzyk Z, Swatko-Ossor M, Wysocki W, Drozd M, Ginalska G, Pachuta-Stec A, Pitucha M. New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies. Molecules. 2020; 25(24):6033. https://doi.org/10.3390/molecules25246033
Chicago/Turabian StyleKarczmarzyk, Zbigniew, Marta Swatko-Ossor, Waldemar Wysocki, Monika Drozd, Grazyna Ginalska, Anna Pachuta-Stec, and Monika Pitucha. 2020. "New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies" Molecules 25, no. 24: 6033. https://doi.org/10.3390/molecules25246033
APA StyleKarczmarzyk, Z., Swatko-Ossor, M., Wysocki, W., Drozd, M., Ginalska, G., Pachuta-Stec, A., & Pitucha, M. (2020). New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies. Molecules, 25(24), 6033. https://doi.org/10.3390/molecules25246033