Inhibition of Aminoglycoside 6′-N-acetyltransferase Type Ib (AAC(6′)-Ib): Structure–Activity Relationship of Substituted Pyrrolidine Pentamine Derivatives as Inhibitors
Abstract
:1. Introduction
2. Materials and Methods
2.1. Bacterial Strain and Cultures
2.2. Synthesis of Small Molecule Compounds
2.3. High-Performance Liquid Chromatography (HPLC) Purification
2.4. Liquid Chromatography–Mass Spectrometry (LCMS) Analysis of Purified Material
2.5. Initial Growth Inhibition Assays
2.6. Modeling
2.7. Checkerboard Assays
3. Results
3.1. Synthesis and Preliminary Analysis of Analogs to Compound 2637.001
3.2. Molecular Docking
3.3. Potentiation
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound Name | Chemical Structure | Functionalities | %Inhibition (Average, n = 10) | Standard Error | Delta G Kcal/mL (Average, n = 3) |
---|---|---|---|---|---|
2637.001 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: 3-phenylbutyl | 62 | 4 | −9.5 ± 0.1 | |
R1 analogs | |||||
2637.002 | R1: S-methyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: 3-phenylbutyl | 18 * | 2 | −8.7 ± 0.1 | |
2637.003 | R1: S-benzyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: 3-phenylbutyl | 20 * | 3 | −8.0 ± 0.1 | |
2637.020 | R1: R-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: 3-phenylbutyl | 73 | 4 | −8.5 ± 0.3 | |
R2 analogs | |||||
2637.021 | R1: S-phenyl R2: R-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: 3-phenylbutyl | 28 * | 4 | −9.5 ± 0.3 | |
R3 analogs | |||||
2637.004 | R1: S-phenyl R2: S-pyrrolidine R3: S-methyl R4: S-phenyl R5: 3-phenylbutyl | 39 | 6 | −9.2 ± 0.1 | |
2637.005 | R1: S-phenyl R2: S-pyrrolidine R3: R-hydroxymethyl R4: S-phenyl R5: 3-phenylbutyl | 24 * | 2 | −8.2 ± 0.1 | |
2637.019 | R1: S-phenyl R2: S-pyrrolidine R3: R-methyl R4: S-phenyl R5: 3-phenylbutyl | 74 | 9 | −9.2 ± 0.1 | |
R4 analogs | |||||
2637.006 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-methyl R5: 3-phenylbutyl | 23 * | 2 | −7.9 ± 0.2 | |
2637.022 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: R-phenyl R5: 3-phenylbutyl | 28 * | 4 | −9.6 ± 0.1 | |
R5 analogs | |||||
2637.007 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: ethyl | 60 | 1 | −9.5 ± 0.1 | |
2637.008 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: butyl | 17 * | 2 | −9.4 ± 0.1 | |
2637.010 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: pentyl | 71 | 2 | −9.1 ± 0.2 | |
2637.012 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: 2-phenylbutyl | 40 | 6 | −8.5 ± 0.2 | |
2637.011 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: phenylbutyl | 66 | 6 | −8.1 ± 0.2 | |
2637.013 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: phenylpropyl | 62 | 3 | −9.1 ± 0.1 | |
2637.014 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: (pyridiin−3-yl)propyl | 46 | 3 | −9.1 ± 0.2 | |
Truncation Analogs | |||||
2637.015 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-phenyl R5: hydrogen | 26 * | 3 | −8.7 ± 0.1 | |
2637.016 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: S-methyl R5: hydrogen | 20 * | 3 | −8.2 ± 0.1 | |
2637.017 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: modified to ethyl R5: nothing | 21 * | 3 | −8.4 ± 0.1 | |
2637.018 | R1: S-phenyl R2: S-pyrrolidine R3: S-hydroxymethyl R4: nothing R5: nothing | 17 * | 2 | −8.2 ± 0.1 |
Compound Dose (μM) | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0 | 4 | 8 | 16 | 24 | ||||||||||||
Compound Name | R Group Modified | IC50 μM | 95% CI | IC50 μM | 95% CI | IC50 μM | 95% CI | IC50 μM | 95% CI | IC50 μM | 95% CI | |||||
2637.001 | NA | 24.9 | 18.2 | 31.5 | 12.9 | 11.1 | 14.7 | 8.5 | 5.5 | 11.5 | 0.8 | 0.2 | 1.3 | 0.2 | 0.2 | 1.3 |
2637.020 | R1 | 23.6 | 21.2 | 26.0 | 12.6 | 10.3 | 14.8 | 9.5 | 7.5 | 11.4 | 0.3 | 0.2 | 1.2 | 0.2 | 0.1 | 0.2 |
2637.004 | R3 | 33.9 | 28.5 | 39.3 | 25.0 * | 18.6 | 31.3 | 20.6 * | 14.9 | 26.2 | 10.1 * | 6.5 | 13.7 | 4.8 | 1.0 | 8.6 |
2637.019 | R3 | 31.9 | 24.6 | 39.2 | 33.1 * | 25.6 | 40.5 | 11.5 | 9.3 | 13.7 | 0.3 | 0.3 | 0.3 | NA | NA | NA |
2637.007 | R5 | 29.9 | 25.2 | 34.6 | 14.8 | 10.3 | 19.3 | 8.8 | 6.9 | 10.7 | 4.0 * | 2.4 | 5.6 | 3.0 | 0.8 | 5.2 |
2637.010 | R5 | 31.0 | 25.6 | 36.4 | 9.2 | 7.6 | 10.8 | 5.5 | 4.1 | 6.9 | 1.7 | 0.3 | 3.3 | 1.0 | 0.2 | 1.8 |
2637.012 | R5 | 33.3 | 27.4 | 39.1 | 25.9 * | 21.8 | 29.9 | 20.6 * | 17.9 | 23.3 | 10.4 * | 9.1 | 11.6 | 0.3 | 0.3 | 0.3 |
2637.011 | R5 | 22.7 | 18.3 | 27.0 | 16.0 | 14.0 | 18.0 | 11.0 | 9.9 | 12.2 | 0.6 | 0.2 | 1.9 | 0.3 | 0.3 | 0.3 |
2637.013 | R5 | 29.7 | 24.2 | 35.2 | 15.3 | 12.6 | 18.1 | 8.0 | 5.9 | 10.0 | 0.7 | 0.2 | 1.7 | 0.1 | 0.2 | 0.5 |
2637.014 | R5 | 33.6 | 29.1 | 38.1 | 24.9 * | 20.4 | 29.4 | 19.5 * | 14.8 | 24.2 | 9.1 * | 3.6 | 14.6 | 2.8 | 0.6 | 4.9 |
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Rocha, K.; Magallon, J.; Reeves, C.; Phan, K.; Vu, P.; Oakley-Havens, C.L.; Kwan, S.; Ramirez, M.S.; LaVoi, T.; Donow, H.; et al. Inhibition of Aminoglycoside 6′-N-acetyltransferase Type Ib (AAC(6′)-Ib): Structure–Activity Relationship of Substituted Pyrrolidine Pentamine Derivatives as Inhibitors. Biomedicines 2021, 9, 1218. https://doi.org/10.3390/biomedicines9091218
Rocha K, Magallon J, Reeves C, Phan K, Vu P, Oakley-Havens CL, Kwan S, Ramirez MS, LaVoi T, Donow H, et al. Inhibition of Aminoglycoside 6′-N-acetyltransferase Type Ib (AAC(6′)-Ib): Structure–Activity Relationship of Substituted Pyrrolidine Pentamine Derivatives as Inhibitors. Biomedicines. 2021; 9(9):1218. https://doi.org/10.3390/biomedicines9091218
Chicago/Turabian StyleRocha, Kenneth, Jesus Magallon, Craig Reeves, Kimberly Phan, Peter Vu, Crista L. Oakley-Havens, Stella Kwan, Maria Soledad Ramirez, Travis LaVoi, Haley Donow, and et al. 2021. "Inhibition of Aminoglycoside 6′-N-acetyltransferase Type Ib (AAC(6′)-Ib): Structure–Activity Relationship of Substituted Pyrrolidine Pentamine Derivatives as Inhibitors" Biomedicines 9, no. 9: 1218. https://doi.org/10.3390/biomedicines9091218