Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activity
2.2.1. Antimicrobial Activity
2.2.2. TEM Analysis of Microorganisms in Response to the Tested Compounds
2.2.3. Cytotoxicity Analysis
Cytotoxicity Assay
2.3. Molecular Docking Study
2.4. Pharmacokinetics and ADME Activity
2.5. Computational Details
2.5.1. Structural Parameters and Models
6-Amino-5-(4-benzylidene-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-1-ethylpyrimidine-2,4(1H,3H)-dione, compound 12
6-Amino-5-(4-benzylidene-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-1-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one, compound 13
6-Amino-5-((4-(dimethylamino)benzylidene)amino)-1-ethylpyrimidine-2,4(1H,3H)-dione, compound (16)
2.5.2. Charge Distribution Analysis
2.5.3. Molecular Orbitals and Frontier
2.5.4. Excited State
3. Material and Methods
3.1. Chemistry
3.1.1. Materials and Instruments
3.1.2. Synthetic Procedures
3.1.3. N-Substituted-8-purinyl-2-(arylvinyl)acetamides 3-5
3.1.4. N-(1-(3-Benzyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(4-chlorophenyl)vinyl) acetamide (3)
3.1.5. N-(2-(4-Chlorophenyl)-1-(3-methyl-6-oxo-2-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl) acetamide (4)
3.1.6. N-(1-(3-(2-Chlorobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(4-chlorophenyl) vinyl)acetamide (5)
3.1.7. 1-Substituted-6-amino-5-(4-arylidene-2-methyl)imidazolylpyrimidinediones 6-13
3.1.8. 6-Amino-5-(4-(4-chlorobenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione (6)
3.1.9. 6-Amino-1-(2-chlorobenzyl)-5-(2-methyl-4-(3-nitrobenzylidene)-5-oxo-4,5-dihydro-1H-imidazol-1-yl)pyrimidine-2,4(1H,3H)-dione (7)
3.1.10. 6-Amino-1-benzyl-5-(2-methyl-4-(3-nitrobenzylidene)-5-oxo-4,5-dihydro-1H-imidazol-1-yl)pyrimidine-2,4(1H,3H)-dione (8)
3.1.11. 6-Amino-1-ethyl-5-(2-methyl-4-(3-nitrobenzylidene)-5-oxo-4,5-dihydro-1H-imidazol-1-yl) pyrimidine-2,4(1H,3H)-dione (9)
3.1.12. 6-Amino-1-benzyl-5-(4-benzylidene-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)pyrimidine-2,4(1H,3H)-dione (10)
3.1.13. 6-Amino-5-(4-benzylidene-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-1-(2-chlorobenzyl)pyrimidine-2,4(1H,3H)-dione (11)
3.1.14. 6-Amino-5-(4-benzylidene-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-1-ethylpyrimidine-2,4(1H,3H)-dione (12)
3.1.15. 6-Amino-5-(4-benzylidene-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-1-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (13)
3.1.16. 1-Substituted-6-amino-5-((4-(dimethylamino)benzylidene)aminopyrimidindiones 14-16
3.1.17. 6-Amino-5-((4-(dimethylamino)benzylidene)amino)-1-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one [44] (14)
3.1.18. 6-Amino-1-benzyl-5-((4-(dimethylamino)benzylidene)amino)pyrimidine-2,4(1H,3H)-dione (15)
3.1.19. 6-Amino-5-((4-(dimethylamino)benzylidene)amino)-1-ethylpyrimidine-2,4(1H,3H)-dione (16)
3.2. Biological Activity
3.2.1. Antibacterial and Antifungal Activity
3.2.2. Transmission Electron Microscopic Analysis
3.2.3. Cytotoxicity Assay
3.3. Molecular Docking Study
3.4. Pharmacokinetics and ADME Activity
3.5. Computational Method
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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Diameter of Inhibition Zone (mm) | |||||||
---|---|---|---|---|---|---|---|
Fungi | Gram Negative Bacteria | Gram Positive Bacteria | |||||
Cpd | C. albicans | A. flavus | E. coli | Salmonella sp. | Pseudomonas sp. | S. aureus | Bacillus sp. |
10% DMSO | - | - | - | - | - | - | - |
3 | 10 ± 0.8 | 2 | 4 ± 0.2 | 0.2 ± 0.01 | 0 | 2 ± 0.01 | 0.7 ± 0.01 |
4 | 2 | 0 | 2 | 0.1 | 0 | 1 ± 0.01 | 0.1 |
5 | 2 | 0 | 2 | 0 | 0 | 0.8 ± 0.01 | 0.8 ± 0.04 |
6 | 10 ± 0.6 | 2 | 4 ± 0.1 | 0 | 0 | 1 ± 0.01 | 0.9 ± 0.01 |
7 | 2 | 0 | 2 | 0 | 0 | 0 | 0 |
8 | 2 | 3 | 2 | 0 | 1.8 ± 0.01 | 0.2 | 0 |
9 | 5 ± 0.2 | 2 | 3± 0.3 | 0 | 0.9 ± 0.05 | 0 | 0.8 ± 0.03 |
10 | 4 ± 0.2 | 0 | 4 ± 0.23 | 0 | 0 | 0 | 0 |
11 | 6 ± 0.3 | 3 | 3 ± 0.3 | 0 | 0 | 0 | 0 |
12 | 8 ± 0.4 | 4 | 5 ± 0.22 | 0 | 1.5 ± 0.01 | 0.3 | 0 |
13 | 6 ± 0.2 | 3 | 4 ± 0.23 | 0 | 0 | 0.4 | 0.9 ± 0.01 |
14 | 2 | 2 | 2 | 0 | 1.9 ± 0.03 | 0 | 0 |
15 | 7 ± 0.5 | 3 | 3 ± 0.1 | 0.1 ± 0.01 | 1.8 ± 0.03 | 0 | 0.8 ± 0.03 |
16 | 12 ±0.3 | 10 | 7 ± 0.2 | 0.2 ± 0.01 | 1.9 ± 0.04 | 0.7 | 1.2 ± 0.04 |
Fluconazole | 2.1 ± 0.1 | 2.9 ± 0.1 | 0 | 0 | 0 | 0 | 0 |
Bacimethrin | 0.9 ± 0.2 | 0.6 ± 0.2 | 0.8 ± 0.2 | 0.9 ± 0.2 | 0.7 ± 0.2 | ||
Primsol | 0.6 ± 0.09 | 0.5 ± 0.02 | 0.4 ± 0.02 | 0.3 ± 0.01 | 0.4 ± 0.3 |
IC50 Values of the Synthesized Compounds | |||||||
---|---|---|---|---|---|---|---|
Fungi | Gram Negative Bacteria | Gram Positive Bacteria | |||||
Cpd | C. albicans | A. flavus | E. coli | Salmonella sp. | Pseudomonas sp. | S. aureus | Bacillus sp. |
3 | 1.07 | 4.9 | 1.8 | 3.9 | 5.2 | 2.8 | 2.4 |
4 | 5.0 | 6.0 | 4.8 | 2.1 | 5.7 | 2.1 | 3.2 |
5 | 6.0 | 7.5 | 4.5 | 5.0 | 6.1 | 2.9 | 2.8 |
6 | 1.02 | 4.2 | 1.9 | 4.9 | 5.1 | 2.9 | 2.2 |
7 | 5.3 | 8.0 | 5.1 | 6.2 | 7.1 | 5.2 | 5.2 |
8 | 5.1 | 7.5 | 4.9 | 7.9 | 1.9 | 5.4 | 5.5 |
9 | 4.9 | 3.8 | 4.1 | 8.0 | 4.2 | 6.0 | 3.8 |
10 | 4.2 | 8.0 | 2.1 | 7.9 | 2.9 | 6.2 | 4.9 |
11 | 3.2 | 3.2 | 2.2 | 7.0 | 3.9 | 6.3 | 5.5 |
12 | 1.46 | 2.9 | 2.11 | 7.2 | 2.2 | 3.1 | 6.9 |
13 | 3.3 | 3.9 | 1.9 | 2.3 | 6.9 | 3.2 | 2.8 |
14 | 4.2 | 3.9 | 5.1 | 8.1 | 2.8 | 4.0 | 4.9 |
15 | 4.1 | 4.2 | 4.9 | 7.2 | 2.9 | 5.1 | 5.3 |
16 | 0.82 | 1.2 | 1.98 | 1.5 | 2.1 | 2.67 | 2.1 |
Fluconazole | 0.6 ± 0.1 | 6.0 ± 0.1 | 0 | 0 | 0 | 0 | 0 |
Bacimethrin | 0 | 0 | 3.9 ± 0.6 | 4.8 ± 0.1 | 5.1 ± 0.1 | 4.2 ± 0.1 | 3.9 ± 0.1 |
Primsol | 0 | 0 | 4.3 ± 0.4 | 4.8 ± 0.1 | 4.6 ± 0.1 | 5.0 ± 0.1 | 4.3 ± 0.1 |
Compounds | APC Protein (PDB: 2KR5) | |||
---|---|---|---|---|
Free Binding of Energy (Kcal/mol) | H-Bond | |||
No of H-Bond | Amino Acid Residues | Length Å | ||
3 | −5.1 | 1 | GLU65 | 2.261 |
12 | −5.1 | 1 | GLU65 | 2.348 |
13 | −5.2 | 1 | GLU65 | 2.358 |
16 | −4.5 | 1 | GLU65 | 1.984 |
PNS | −4.5 | 2 | GLU65 | 2.265 |
ASP71 | 2.559 | |||
Compounds | DNAg Protein (PDB: 1KZN) | |||
Free Binding of Energy (Kcal/mol) | H-Bond | |||
No of H-Bond | Amino Acid Residues | Length Å | ||
3 | −8.2 | 1 | THR165 | 3.074 |
12 | −7.2 | 2 | ASP49 | 2.576 |
ASN46 | 3.395 | |||
13 | −7.4 | 2 | ASP49 | 2.573 |
ASN46 | 3.368 | |||
16 | −7.1 | 2 | ASP73 | 2.276 |
ASN46 | 2.392 | |||
CBN | −9.3 | 4 | ASN46 | 3.142 |
ARG136 | 2.930 | |||
ARG136 | 2.923 | |||
ARG136 | 3.244 | |||
Compounds | PBP Protein (PDB: 3UDI) | |||
Free Binding of Energy (Kcal/mol) | H-Bond | |||
No of H-Bond | Amino Acid Residues | Length Å | ||
3 | −8.7 | 1 | ASN674 | 2.006 |
12 | −8.2 | 2 | SER470 | 2.118 |
THR672 | 2.797 | |||
13 | −7.6 | 2 | SER470 | 2.458 |
THR672 | 3.040 | |||
16 | −7.3 | 3 | SER470 | 2.697 |
SER487 | 3.278 | |||
THR672 | 2.916 | |||
PNS | −7.2 | 5 | TYR670 | 3.006 |
TYR670 | 3.035 | |||
SER434 | 3.078 | |||
THR672 | 3.128 | |||
THR672 | 2.310 |
Properties | Compound 12 |
---|---|
Formula | C17H17N5O3 |
Molecular weight | 339.35 |
Num. of heavy atoms | 25 |
Num. of aromatic heavy atoms | 12 |
Num. of rotatable bonds | 3 |
Num. H-bond donors (HBD) | 2 |
Num. H-bond acceptor (HBA) | 4 |
Molar reactivity | 103.26 |
Topological Polar Surface area (TPSA) | 113.55 |
Lipophilicity (Log P) | 2.04 |
Water solubility (Log S) | −2.39 |
Bond Length (Å) | |||||
C1-C2 C2-C3 C3-C4 C4-C6 C5-C6 C1-C5 C1-Cl7 C4-C8 C8-C9 C9-C10 C9-N12 | 1.346 1.345 1.348 1.354 1.343 1.341 1.726 1.351 1.353 1.346 1.354 | C13-N12 C13-O14 C13-C15 C10-N11 N11-C16 C16-C18 N17-C18 C10-N17 C16-C19 C19-N20 C19-O23 | 1.384 1.209 1.521 1.339 1.334 1.338 1.348 1.269 1.349 1.377 1.210 | N20-C21 C21-N22 C21-O24 C18-N22 N22-C25 C25-C26 C26-C27 C27-C28 C28-C29 C29-C31 C30-C31 C26-C30 | 1.389 1.395 1.208 1.351 1.453 1.556 1.346 1.342 1.341 1.342 1.342 1.346 |
Bond Angle (°) | |||||
C3C4C8 C6C4C8 C4C8C9 C8C9N12 C8C9C10 | 124.63 118.83 131.89 113.55 126.94 | C9N12C13 N12C13C15 N12C13O14 O14C13C15 C9C10N17 | 124.18 122.51 118.39 119.04 125.31 | C9C10N11 C18N22C25 C25N22C21 C26C25N22 C25C26C27 C25C26C30 | 123.47 120.23 120.71 113.98 119.35 122.79 |
Dihedral Angles (°) | |||||
C3C4C8C9 C6C4C8C9 C4C8C9N12 C4C8C9C10 C8C9N12C13 O23C19N20C21 | 18.74 −165.54 −179.95 20.23 −105.95 178.85 | C10C9N12C13 C9N12C13C15 N12C9C10N11 N12C9C10N17 C10N17C18N22 O24C21N20C19 | 82.58 −19.77 23.75 −154.23 178.05 179.53 | C26C25N22C18 C26C25N22C21 N22C25C26C20 N22C25C26C27 C8C9N10N17 | −84.71 87.88 −4.19 175.85 102.31 |
Mulliken charges | |||||
C1 Cl7 N12 C13 C9 O14 | 0.237 −0.295 −0.284 0.424 0.114 −0.488 | C10 N11 N17 C16 C18 N22 | 0.217 −0.107 −0.334 −0.111 0.246 −0.198 | C21 N20 O24 C19 O23 | 0.501 −0.324 −0.432 0.425 −0.446 |
Total energy/k cal/mol Heat of formation k cal/mol Total dipole moment/D | −172,059.722 −10,607.049 3.078 |
Parameters | Compound 3 | Compound 12 | Compound 13 | Compound 16 |
---|---|---|---|---|
HOMO, H | −0.319 | −0.321 | −0.315 | −0.309 |
LUMO, L | −0.237 | −0.245 | −0.254 | −0.237 |
I = −H | 0.319 | 0.321 | 0.315 | 0.309 |
A = −L | 0.237 | 0.245 | 0.254 | 0.237 |
∆E = L − H | 0.082 | 0.067 | 0.061 | 0.072 |
η = (I − A)/2 | 0.041 | 0.034 | 0.031 | 0.036 |
χ = −(H − L/2) | 0.278 | 0.283 | 0.285 | 0.237 |
σ = 1/η | 24.390 | 29.412 | 32.258 | 27.778 |
S = 1/2 η | 12.195 | 14.706 | 16.129 | 13.889 |
Pi = −χ | −0.278 | −0.283 | −0.285 | −0.237 |
ω = (Pi)2/2 η | 0.942 | 1.178 | 1.310 | 0.780 |
∆Nmax = χ/η | 6.780 | 8.324 | 9.194 | 6.583 |
Compound 3 | Compound 12 | ||||
---|---|---|---|---|---|
H | L | H | L | ||
2,6-dioxopurine ring C10, N11, C16-O24 | 55.5% | 53.7% | 2,4-dioxo-6-aminopyrimidine ring C1-O8, N12 | 25.6% | 0.0% |
Chlorophenyl ring C1-Cl7 | 15.4% | 21.8% | 2-methyl-5-oxoimidazol ring N13-C19 | 61.2% | 51.9% |
Vinyl group C8-C9 | 7.9% | 15.9% | Benzylidene ring C20-C26 | 13.2% | 48.1% |
acetamide group N12-C15 | 20.2% | 8.6% | Ethyl group C9, C11 | 0.0% | 0.0% |
Benzyl group C25-C31 | 1% | 0.0% | |||
Compound 13 | Compound 16 | ||||
H | L | H | L | ||
2-thio-4-oxo-6-aminopyrimidine ring C1-S8, N11 | 56.3% | 0.0% | 2,4-dioxo-6-aminopyrimidine ring C13-O19, N23 | 41.3% | 19.5% |
2-methyl-5-oxoimidazol ring N12-C18 | 41.9% | 52.7% | dimethylaminobenzylidene ring C1-N9, C33-C34 | 33.6% | 58.7% |
Benzylidene ring C19-C25 | 1.8% | 31.4% | Amino group N24-C25 | 25.1% | 21.8% |
Methyl group C9 | 0.0% | 15.9% | Ethyl group C20, C22 | 0.0% | 0.0% |
Compound | eV | nm | Major Contributions | Assignment | λmax, nm |
---|---|---|---|---|---|
3 | 4.9546 | 250.24 | H-11 → L(4.5%), H-11 → L + 6(2.9%), H → L(4.9%), H-7 → L(3.2%), H-5→L(34.5%), H-3 → L(3.7%), H-1 → L(14.7%), H → L(4.4%) | π-π * | 265 |
4.7874 | 258.98 | H-11 → L (7.8%), H-10 → L (2.5%), H-5 → L (2.8%), H-1→L (78.4%), H → L(4,6%), H → L + 1(3.6%) | π-π * | 275 | |
4.4144 | 280.86 | H-11 → L + 7 (4.9%), H-10 → L + 6 (14.1%), H-10 → L + 7 (41.8%), H-7 → L + 7 (6.7%), H-6 → L + 6 (9.6%), H-6 → L + 7 (26.7%) | n-π * | 290 | |
4.0996 | 302.43 | H-9 → L (5.2%), H-9 → L + 5 (61.6%), H-9 → L + 6 (21.3%), H-9 → L + 7 (2.7%), H-8 → L + 5(6.3%), H-8 → L + 6 (2.8%) | π-π * | 305 | |
3.4797 | 356.3 | H-11 → L + 2 (5.3%), H-10 → L (6.3%), H-10 → L + 1 (10.4%), H-6 → L (22.9%), H-6 → L + 1 (38.3%), H-6 → L + 7 (8.8%), H-6 → L + 10 (7.8%) | n-π * | 368 | |
3.2847 | 377.47 | H-1 → L (4.5%), H → L(93.4%) | π-π * | 383 | |
12 | 4.7935 | 258.65 | H-8 → L + 1 (2.4%), H-1 → L + 1 (54.4%), H → L + 1 (43%) | π-π * | 269 |
4.4183 | 280.61 | H-6 → L (5.8%), H-4 → L (9.8%), H-3 → L (8.6%), H-2 → L(2.7%), H-1 → L(72.8%) | π-π * | 278 | |
4.3485 | 285.12 | H-9 → L + 3 (20.5%), H-9 → L + 4 (12.4%), H-8 → L + 3 (7.6%), H-8 → L + 4 (4%), H-7 → L + 3 (27.3%), H-3 → L + 4 (16.6%), H-5 → L + 3 (7%), H-5 → L + 4 (4.2%) | n-π * | 300 | |
4.0172 | 308.64 | H-10 → L (5%), H-8 → L (35.2%), H-8 → L + 3 (3.3%), H-8 → L + 4 (7.3%), H-3 → L (15.4%), H-3 → L + 3 (8.5%), H-3 → L + 4 (8.2%), H-3 → L + 5 (7%) | n-π * | 315 | |
3.8482 | 322.23 | H-6 → L + 1 (6.1%), H-5 → L + 1 (35.8%), H-5 → L + 3 (13.5%), H-5 → L + 6 (13.6%), H-4 → L + 1 (18.3%), H-4 → L + 3 (6.3%), H-4 → L + 6 (6%) | n-π * | 322 | |
3.7319 | 332.23 | H → L (100%) | π-π * | 338 | |
3.6207 | 342.43 | H-8 → L (14.5%), H-8 → L + 5 (8.9%), H-6 → L (3.3%), H-5 → L(11.7%), H-5 → L + 5 (3%), H-4 → L (5.7%), H-3 → L (36.7%), H-3 → L + 5 (3.5%) | n-π * | 350 |
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El-Kalyoubi, S.; Agili, F.; Zordok, W.A.; El-Sayed, A.S.A. Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives. Int. J. Mol. Sci. 2021, 22, 10979. https://doi.org/10.3390/ijms222010979
El-Kalyoubi S, Agili F, Zordok WA, El-Sayed ASA. Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives. International Journal of Molecular Sciences. 2021; 22(20):10979. https://doi.org/10.3390/ijms222010979
Chicago/Turabian StyleEl-Kalyoubi, Samar, Fatimah Agili, Wael A. Zordok, and Ashraf S. A. El-Sayed. 2021. "Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives" International Journal of Molecular Sciences 22, no. 20: 10979. https://doi.org/10.3390/ijms222010979