Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthetic Chemistry
2.1.1. Spectroscopic and Crystallographic Characterization of Cycloadducts 4 and 9
2.1.2. DFT Mechanistic Studies
2.2. Biological Evaluation of the Synthesized Compounds
2.2.1. Antimicrobial Activity
2.2.2. Structure-Activity Relationship (SAR)
2.3. DFT Computational Studies
2.3.1. Optimized Molecular Structures and HOMO-LUMO Energies
2.3.2. Molecular Electrostatic Potential (MEP)
2.4. Drug-Likeness Analysis
3. Materials and Methods
3.1. Apparatus and General Information
3.2. General Procedure for Preparation of Cycloadducts 4 and 9
3.2.1. (2S*,3R*,4*S,5S*)-Spiro[2,3′]-oxindole-spiro[3,3″]thiochroman-4″-one-4-phenyl-5-carboxyethoxypyrrolidine (4a)
3.2.2. (2S*,3R*,4*S,5S*)-Spiro[2,3′]-oxindole-spiro[3,3″]thiochroman-4″-one-4-(p-methyl phenyl)-5-carboxyethoxypyrrolidine (4b)
3.2.3. (2S*,3R*,4*S,5S*)-[2,3′]-oxindole-spiro[3,3″]thiochroman-4″-one-4-(p-methoxyphenyl)-5-carboxyethoxypyrrolidine (4c)
3.2.4. (2S*,3R*,4*S,5S*)-[2,3′]-oxindole-spiro[3,3″]thiochroman-4″-one-4-(p-bromophenyl)-5-carboxyethoxypyrrolidine (4d)
3.2.5. (2S*,3R*,4*S,5S*)-Spiro[2,2′]-acenaphthene-1′-one-spiro[3,3′]thiochroman-4″-one-4-(p-methylphenyl)-5-carboxyethoxypyrrolidine (4e)
3.2.6. (2S*,3R*,4*S,5S*)-Spiro[2,2′]-acenaphthene-1′-one-spiro[3,3″]thiochroman-4″-one-4-(p-methoxyphenyl)-5-arboxyethoxypyrrolidine (4f)
3.2.7. (2S*,3R*,4*S,5S*)-Spiro[2,3′]-oxindole-spiro[3,3″]chroman-4″-one-4-phenyl-5-carboxyethoxypyrrolidine (9a)
3.2.8. (2S*,3R*,4*S,5S*)-Spiro[2,3′]-oxindole-spiro[3,3″]chroman-4″-one-4-(p-methylphenyl)-5-carboxyethoxypyrrolidine (9b)
3.2.9. (2S*,3R*,4*S,5S*)-Spiro[2,3′]-oxindole-spiro[3,3″]chroman-4″-one-4-(p-methoxyphenyl)-5-carboxyethoxypyrrolidine (9c)
3.2.10. (2S*,3R*,4*S,5S*)-Spiro[2,3′]-oxindole-spiro[3,3″]chroman-4″-one-4-(p-bromophenyl)-5-carboxyethoxypyrrolidine (9d)
3.2.11. (2S*,3R*,4*S,5S*)-Spiro[2,2′]-acenaphthene-1′-one-spiro[3,3″]chroman-4″-one-4-phenyl-5-carboxyethoxypyrrolidine (9e)
3.2.12. (2S*,3R*,4*S,5S*)-Spiro[2,2′]-acenaphthene-1′-one-spiro[3,3″]chroman-4″-one-4-(p-methylphenyl)-5-carboxyethoxypyrrolidine (9f)
3.2.13. (2S*,3R*,4*S,5S*)-Spiro[2,2′]-acenaphthene-1′-one-spiro[3,3″]chroman-4″-one-4-(p-methoxyphenyl)-5-carboxyethoxypyrrolidine (9g)
3.2.14. (2S*,3R*,4*S,5S*)-Spiro[2,2′]-acenaphthene-1′-one-spiro[3,3″]chroman-4″-one-4-(p-bromophenyl)-5-carboxyethoxypyrrolidine (9h)
3.3. Crystal Structure Determinations
3.4. Antimicrobial Activity
3.4.1. Determination of the Antibacterial and Antifungal Activity
3.4.2. Microorganisms
3.5. Computational Methods
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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ΔG | ΔH | ΔS | ΔU | |
---|---|---|---|---|
TS-exo-4d | 0.4 | −17.6 | −50.9 | −16.9 |
TS-endo-4d | 2.0 | 15.4 | −48.9 | −14.7 |
TS-exo-5d | 15.1 | −3.6 | −52.7 | −2.9 |
TS-endo-5d | 14.9 | −0.3 | −42.7 | 0.4 |
exo-4d | −21.8 | −42.4 | −58.1 | −41.7 |
endo-4d | −14.6 | −34.8 | 57.0 | −34.2 |
exo-5d | −16.8 | −37.9 | −59.5 | −37.2 |
endo-5d | −16.3 | −36.2 | −56.3 | −35.5 |
Gram Positive Bacteria | Gram Negative Bacteria | ||||||||
---|---|---|---|---|---|---|---|---|---|
Comp. | B. subtilis ATCC 6633 | S. epidermidis CI1232 | S. aureus ATCC 29213 | S. aureus ATCC 25923 | E. faecalis ATCC 29212 | E. coli ATCC 25922 | K. pneumoniae ATCC 4352 | S. enterica 800390 | P. aeruginosa ATCC 9023 |
4a | 32 | 32 | 64 | 32 | 32 | 125 | 64 | 64 | 64 |
4b | 32 | 32 | 64 | 32 | 32 | 125 | 64 | 64 | 125 |
4c | 32 | 32 | 64 | 64 | 32 | 125 | 64 | 64 | 64 |
4d | 32 | 32 | 64 | 64 | 32 | 125 | 64 | 64 | 64 |
4e | 32 | 32 | 64 | 32 | 64 | 250 | 64 | 125 | 64 |
9a | 125 | 250 | 125 | 125 | 125 | 250 | 250 | 550 | 250 |
9b | 125 | 250 | 250 | 250 | 125 | 125 | 125 | 550 | 125 |
9c | 125 | 125 | 125 | 250 | 64 | 250 | 64 | 550 | 125 |
9d | 64 | 64 | 500 | 125 | 64 | 125 | 64 | 550 | 125 |
9e | 125 | 250 | 125 | 125 | 64 | 250 | 64 | 550 | 125 |
9f | 64 | 64 | 125 | 125 | 125 | 125 | 250 | 550 | 250 |
9g | 64 | 64 | 125 | 125 | 125 | 125 | 500 | 500 | 500 |
9h | 64 | 64 | 125 | 125 | 250 | 250 | 500 | 500 | 500 |
AMXa | 64 | - | - | - | 1 | 256 | 256 | - | 256 |
AMPa | - | 78 | 50 | 50 | - | - | - | 100 | - |
Compound | Candida albicans ATCC 90028 | Candida glabrata ATCC 90030 | Candida krusei ATCC 6258 |
---|---|---|---|
4a | 64 | 64 | 64 |
4b | 64 | 64 | 64 |
4c | 64 | 64 | 64 |
4d | 64 | 32 | 32 |
4e | 64 | 64 | 64 |
9a | 250 | 250 | 250 |
9b | 250 | 125 | 125 |
9c | 125 | 125 | 125 |
9d | 125 | 125 | 250 |
9e | 500 | 500 | 500 |
9f | 125 | 250 | 125 |
9g | 250 | 125 | 250 |
9h | 125 | 250 | 250 |
Amphotericin Ba | 500 | 500 | 500 |
Compound | EHOMO | ELUMO | ΔEgap | ղ | μ | ω |
---|---|---|---|---|---|---|
(eV) | (eV) | |||||
4a | −7.463 | −5.502 | 1.961 | 0.981 | −6.483 | 21.422 |
4b | −7.462 | −5.501 | 1.961 | 0.981 | −6.482 | 21.415 |
4c | −7.459 | −5.494 | 1.965 | 0.983 | −6.477 | 21.338 |
4d | −7.462 | −5.507 | 1.955 | 0.978 | −6.485 | 21.501 |
4e | −7.497 | −5.860 | 1.637 | 0.819 | −6.679 | 27.234 |
4f | −7.496 | −5.860 | 1.636 | 0.818 | −6.678 | 27.259 |
Compound | EHOMO | ELUMO | ΔEgap | ղ | μ | ω |
---|---|---|---|---|---|---|
(eV) | (eV) | |||||
9a | −8.386 | −5.499 | 2.887 | 1.444 | −6.943 | 16.692 |
9b | −8.387 | −5.497 | 2.890 | 1.445 | −6.942 | 16.675 |
9c | −8.380 | −5.492 | 2.888 | 1.444 | −6.936 | 16.658 |
9d | −8.387 | −5.499 | 2.888 | 1.444 | −6.943 | 16.692 |
9e | −8.449 | −5.875 | 2.574 | 1.287 | −7.162 | 19.928 |
9f | −8.447 | −5.874 | 2.573 | 1.287 | −7.161 | 19.922 |
9g | −8.426 | −5.874 | 2.552 | 1.276 | −7.150 | 20.032 |
9h | −8.448 | −5.878 | 2.570 | 1.285 | −7.163 | 19.964 |
Compound | 4d | 9d | 9e | 9c | 4a | 4e |
---|---|---|---|---|---|---|
lip_acc | 6 | 7 | 6 | 8 | 6 | 5 |
lip_don | 3 | 3 | 2 | 3 | 3 | 2 |
lip_druglike | 1 | 1 | 1 | 1 | 1 | 0 |
lip_violation | 1 | 1 | 1 | 0 | 0 | 2 |
logP(o/w) | 4.46 | 3.83 | 4.81 | 2.99 | 3.67 | 5.75 |
Weight | 564.48 | 548.41 | 504.56 | 499.54 | 485.58 | 534.66 |
TPSA | 89.08 | 98.31 | 86.28 | 107.54 | 89.08 | 77.05 |
logS | −8.03 | −7.06 | −7.95 | −6.02 | −6.94 | −9.4 |
vol | 478.5 | 464.88 | 476 | 464.88 | 451.25 | 507.5 |
b_rotN | 4 | 4 | 4 | 5 | 4 | 4 |
mr | 14.37 | 13.8 | 14.32 | 13.68 | 13.61 | 15.34 |
a_hyd | 27 | 26 | 29 | 26 | 26 | 31 |
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Chouchène, N.; Toumi, A.; Boudriga, S.; Edziri, H.; Sobeh, M.; Abdelfattah, M.A.O.; Askri, M.; Knorr, M.; Strohmann, C.; Brieger, L.; et al. Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds. Molecules 2022, 27, 582. https://doi.org/10.3390/molecules27030582
Chouchène N, Toumi A, Boudriga S, Edziri H, Sobeh M, Abdelfattah MAO, Askri M, Knorr M, Strohmann C, Brieger L, et al. Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds. Molecules. 2022; 27(3):582. https://doi.org/10.3390/molecules27030582
Chicago/Turabian StyleChouchène, Nourhène, Amani Toumi, Sarra Boudriga, Hayet Edziri, Mansour Sobeh, Mohamed A. O. Abdelfattah, Moheddine Askri, Michael Knorr, Carsten Strohmann, Lukas Brieger, and et al. 2022. "Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds" Molecules 27, no. 3: 582. https://doi.org/10.3390/molecules27030582