Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Antimicrobial Activity
2.2.1. Determination of Minimum Inhibitory Concentrations (MIC)
2.2.2. Structure-Activity Relationships (SARs) Study for Biological Evaluation
2.2.3. Time-Kill Kinetic Study
2.2.4. Evaluation of the In Vitro Antibiofilm Activity
2.2.5. In Silico Molecular Interaction Studies
3. Experimental
3.1. Chemicals and Apparatus
3.2. X-ray Diffraction Analysis
3.3. Procedure for the Synthesis of the Methyl Quinolinequinone (QQ)
6,7-Dichloro-2-methyl-5,8-quinolinequinone (QQ)
3.4. General Procedure for the Synthesis of the Aminated Quinolinequinones (AQQ1–16)
3.4.1. 7-Chloro-2-methyl-6-((2-(trifluoromethyl)phenyl)amino)-5,8-quinolinequinone (AQQ1)
3.4.2. 7-Chloro-2-methyl-6-((3-(trifluoromethyl)phenyl)amino)-5,8-quinolinequinone (AQQ2)
3.4.3. 7-Chloro-2-methyl-6-((4-(trifluoromethyl)phenyl)amino)-5,8-quinolinequinone (AQQ3)
3.4.4. 7-Chloro-6-((4-(cyano)phenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ4)
3.4.5. 6-((3,5-Bis(trifluoromethyl)phenyl)amino)-7-chloro-2-methyl-5,8-quinolinequinone (AQQ5)
3.4.6. 7-Chloro-2-methyl-6-(m-tolylamino)-5,8-quinolinequinone (AQQ6)
3.4.7. 7-Chloro-2-methyl-6-(p-tolylamino)-5,8-quinolinequinone (AQQ7)
3.4.8. 7-Chloro-6-((2-isopropylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ8)
3.4.9. 7-Chloro-6-((3-isopropylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ9)
3.4.10. 7-Chloro-6-((4-isopropylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ10)
3.4.11. 7-Chloro-6-((4-(diethylamino)phenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ11)
3.4.12. 7-Chloro-6-((2,3-dimethylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ12)
3.4.13. 7-Chloro-6-((2,4-dimethylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ13)
3.4.14. 7-Chloro-6-((2,5-dimethylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ14)
3.4.15. 7-Chloro-6-((3,4-dimethylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ15)
3.4.16. 7-Chloro-6-((3,5-dimethylphenyl)amino)-2-methyl-5,8-quinolinequinone (AQQ16)
3.5. Biological Evaluation
3.5.1. MIC Determinations
3.5.2. Determination of Time-Kill Curves
3.5.3. Biofilm Attachment and Inhibition of Biofilm Formation Assays
3.5.4. Molecular Docking
3.5.5. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ATCC | American Type Culture Collection |
CCDC | Cambridge Crystallographic Data Center |
CLSI | Clinical and Laboratory Institute |
EDG | Electron-donating group |
EWG | Electron-withdrawing group |
HPC | High-performance computing |
HPLC | High-performance liquid chromatography |
MIC | Minimum inhibitory concentration |
NMR | Nuclear magnetic resonance |
PBS | Phosphate-buffered saline |
SAR | Structure-activity relationship |
TKC | Time-kill curve |
TKS | Time-kill kinetic studies |
TLC | Thin-layer chromatography |
References
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Identification Code | AQQ7 | AQQ10 |
---|---|---|
Chemical formula | C17H13ClN2O2 | C19H17ClN2O2 |
Formula weight (g mol−1) | 312.74 | 340.79 |
Temperature (K) | 292(2) | 299(2) |
Radiation λ (Å) | 0.71073 | 0.71073 |
Crystal system | Monoclinic | Trigonal |
Space groups, Z | P 1 21/c 1, 4 | R 3 c, 18 |
Unit cell dimensions (Å) | a = 4.8838 (5) | a = 28.573 (6) |
b = 25.878 (3) | b = 28.573 (6) | |
c = 11.6611 (12) | c = 10.771 (3) | |
α, γ = 90° | α, β = 90° | |
β = 98.331 (2)° | γ = 120° | |
Volume (Å3) | 1458.2 (3) | 7615.(4) |
Crystal sizes (mm) | 0.068 × 0.146 × 0.500 | 0.038 × 0.070 × 0.434 |
dcalc (g cm−3) | 1.425 | 1.338 |
Absorption coefficient (mm−1) | 0.270 | 0.239 |
Tmin, Tmax | 0.8770, 0.9820 | 0.9030, 0.9910 |
θmax, deg | 27.48 | 25.02 |
Goodness-of-fit on F2 | 1.014 | 1.041 |
Index ranges | −6 ≤ h ≤ 6 | −33 ≤ h ≤ 34 |
−33 ≤ k ≤ 33 | −33 ≤ k ≤ 34 | |
−15 ≤ l ≤ 15 | −12 ≤ l ≤ 12 | |
Reflections collected | 21278 | 54427 |
Independent reflections | 3346 [R(int) = 0.0599] | 2980 [R(int) = 0.0831] |
Final R indices [I > 2σ(I)] | 2635 data | 1930 data |
R1 = 0.0446 | R1 = 0.0526 | |
wR2 = 0.1219 | wR2 = 0.1344 | |
R indices (all data) | R1 = 0.0579 | R1 = 0.0919 |
wR2 = 0.1305 | wR2 = 0.1589 | |
Refinement method | Full-matrix least-squares on F2 | Full-matrix least-squares on F2 |
Data/restraints/parameters | 3346/0/202 | 2980/1/220 |
Largest diff. peak and hole (eÅ−3) | 0.446 and −0.277 | 0.189 and −0.144 |
AQQs | Subseries (X) | Substituent(s) | Gram-Negative Bacteria (MIC, μg/mL) | Gram-Positive Bacteria (MIC, μg/mL) | ||||||
---|---|---|---|---|---|---|---|---|---|---|
General Formula | ID | P. aeruginosa | E. coli | K. pneumoniae | P. mirabilis | S. aureus | S. epidermidis | E. faecalis | ||
AQQ1 | EWG | 2-CF3 | - | - | - | - | 1250 | 1250 | - | |
AQQ2 | 3-CF3 | - | - | - | - | 625 | 78.12 | 312.50 | ||
AQQ3 | 4-CF3 | - | 312.50 | - | 625 | 625 | 312.50 | 625 | ||
AQQ4 | 4-CN | - | - | 625 | - | 625 | 312.50 | 625 | ||
AQQ5 | 3,5-diCF3 | - | - | - | - | 1250 | 39.06 | - | ||
AQQ6 | EDG | 3-CH3 | - | - | - | - | 1250 | 78.12 | 625 | |
AQQ7 | 4-CH3 | - | 312.50 | - | - | 625 | 78.12 | 625 | ||
AQQ8 | 2-CH(CH3)2 | - | - | - | - | 1.22 | - | 19.53 | ||
AQQ9 | 3-CH(CH3)2 | - | - | - | - | 1.22 | - | 9.76 | ||
AQQ10 | 4-CH(CH3)2 | - | - | - | - | 1.22 | - | 19.53 | ||
AQQ11 | 4-N(CH2CH3)2 | - | - | - | - | 19.53 | - | 312.50 | ||
AQQ12 | 2,3-diCH3 | - | - | - | - | 1.22 | - | 625 | ||
AQQ13 | 2,4-diCH3 | - | - | - | - | 1.22 | - | 625 | ||
AQQ14 | 2,5-diCH3 | - | - | - | - | 1.22 | - | 39.06 | ||
AQQ15 | 3,4-diCH3 | - | - | - | - | 625 | - | 156.25 | ||
AQQ16 | 3,5-diCH3 | - | - | - | - | 19.53 | - | 625 | ||
Ciprofloxacin | 0.125 | 0.007 | 0.125 | 0.007 | 0.25 | 0.25 | 0.25 |
AQQs | Subseries (X) | Substituent(s) | Fungi (MIC, μg/mL) | |||
---|---|---|---|---|---|---|
General Formula | ID | C. albicans | C. parapsilosis | C. tropicalis | ||
AQQ1 | EWG | 2-CF3 | 312.50 | 312.50 | - | |
AQQ2 | 3-CF3 | 312.50 | 312.50 | - | ||
AQQ3 | 4-CF3 | 312.50 | 156.25 | - | ||
AQQ4 | 4-CN | 1.22 | 2.44 | - | ||
AQQ5 | 3,5-diCF3 | 156.25 | 312.50 | - | ||
AQQ6 | EDG | 3-CH3 | 156.25 | 78.12 | - | |
AQQ7 | 4-CH3 | 156.25 | 156.25 | - | ||
AQQ8 | 2-CH(CH3)2 | 312.50 | 78.12 | 156.25 | ||
AQQ9 | 3-CH(CH3)2 | 312.50 | 9.76 | 312.50 | ||
AQQ10 | 4-CH(CH3)2 | - | 312.50 | - | ||
AQQ11 | 4-N(CH2CH3)2 | 312.50 | - | 312.50 | ||
AQQ12 | 2,3-diCH3 | 312.50 | 312.50 | - | ||
AQQ13 | 2,4-diCH3 | 312.50 | 312.50 | - | ||
AQQ14 | 2,5-diCH3 | 312.50 | 19.53 | 312.50 | ||
AQQ15 | 3,4-diCH3 | - | 312.50 | - | ||
AQQ16 | 3,5-diCH3 | - | 312.50 | - | ||
Clotrimazole | 4.88 | - | - | |||
Amphotericin B | - | 0.50 | 1.00 |
Protein | Compound | Binding Energy (Kcal/mol) | Inhibition Constant (Ki) (in µM) | No. of H-Bonds | Amino Acids Interactions |
---|---|---|---|---|---|
3CW0 | AQQ4 | −5.36 | 117.62 | 1 (LEU82) | 11 (ARG204, VAL97, PRO85, ALA81, VAL77, PHE76, LEU98, SER96, GLU95, TRP87, VAL90) |
AQQ9 | −5.66 | 70.88 | 1 (LEU82) | 10 (VAL90, PRO85, PRO83, ARG204, LEU98, ALA81, TRP87, VAL77, TRP80, LEU82) | |
3EAN | AQQ4 | −7.88 | 1.69 | 2 (GLU477, TRP407) | 13 (HIS472, ILE478, PHE406, GLN494, GLY496, SER495, ASN418, GLU410, PRO408, VAL474, PRO473, LEU409, CYS475) |
AQQ9 | −8.43 | 0.664 | 1 (TRP407) | 14 (HIS472, PRO408, LEU409, GLU477, PRO473, CYS475, GLU410, VAL474, PHE406, CYS497, SER495, GLY496, GLN494, THR412) | |
5XEX | AQQ4 | −8.06 | 1.24 | 2 (PRO101, PHE103) | 11 (ILE513, LYS105, ASP55, LYS108, GLY106, TYR107, PHE57, PRO104, ARG100, LYS514, ILE513) |
AQQ9 | −7.93 | 1.53 | 1 (PHE103) | 12 (PRO104, TYR107, GLY106, ARG100, PHE57, LEU102, PRO101, GLN146, ASP516, ILE515, LYS514, LYS105) |
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Yıldırım, H.; Bayrak, N.; Yıldız, M.; Yılmaz, F.N.; Mataracı-Kara, E.; Shilkar, D.; Jayaprakash, V.; TuYuN, A.F. Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans. Molecules 2022, 27, 2923. https://doi.org/10.3390/molecules27092923
Yıldırım H, Bayrak N, Yıldız M, Yılmaz FN, Mataracı-Kara E, Shilkar D, Jayaprakash V, TuYuN AF. Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans. Molecules. 2022; 27(9):2923. https://doi.org/10.3390/molecules27092923
Chicago/Turabian StyleYıldırım, Hatice, Nilüfer Bayrak, Mahmut Yıldız, Fatıma Nur Yılmaz, Emel Mataracı-Kara, Deepak Shilkar, Venkatesan Jayaprakash, and Amaç Fatih TuYuN. 2022. "Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans" Molecules 27, no. 9: 2923. https://doi.org/10.3390/molecules27092923
APA StyleYıldırım, H., Bayrak, N., Yıldız, M., Yılmaz, F. N., Mataracı-Kara, E., Shilkar, D., Jayaprakash, V., & TuYuN, A. F. (2022). Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans. Molecules, 27(9), 2923. https://doi.org/10.3390/molecules27092923