WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H526918
CAS#: 620175-39-5 (free base)
Description: AFN-1252, also known as AFN-12520000; API-1252; Debio-1452, is FASII Inhibitor which is potentially for the treatment of acute bacterial skin. AFN-1252 exhibits typical MIC(90) values of ≤0·015 μg/ml against diverse clinical isolates of S. aureus, oral absorption, long elimination half-live and efficacy in animal models. AFN-1252 efficiently blocked daptomycin-induced phospholipid decoy production, even in the case of isolates resistant to AFN-1252, which prevented the inactivation of daptomycin and resulted in sustained bacterial killing. In turn, daptomycin prevented the fatty acid-dependent emergence of AFN-1252-resistant isolates in vitro
Hodoodo Cat#: H526918
Name: AFN-1252
CAS#: 620175-39-5 (free base)
Chemical Formula: C22H21N3O3
Exact Mass: 375.16
Molecular Weight: 375.428
Elemental Analysis: C, 70.38; H, 5.64; N, 11.19; O, 12.78
Related CAS #: 1047981-31-6 (tosylate) 620175-39-5 (free base) 1047981-30-5 (tosylate hydrate)
Synonym: AFN-1252; AFN 1252; AFN1252; API-1252; API1252; API 1252; AFN12520000; AFN 12520000; AFN12520000; Debio1452; Debio 1452; Debio1452;
IUPAC/Chemical Name: (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide
InChi Key: QXTWSUQCXCWEHF-JXMROGBWSA-N
InChi Code: InChI=1S/C22H21N3O3/c1-14-17-5-3-4-6-18(17)28-19(14)13-25(2)21(27)10-7-15-11-16-8-9-20(26)24-22(16)23-12-15/h3-7,10-12H,8-9,13H2,1-2H3,(H,23,24,26)/b10-7+
SMILES Code: O=C(N(C)CC1=C(C)C2=CC=CC=C2O1)/C=C/C3=CC(CC4)=C(N=C3)NC4=O
Appearance: White to off-white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | AFN-1252 (Debio 1452) is a potent inhibitor of enoyl-acyl carrier protein reductase (FabI). |
| In vitro activity: | The effect of increasing concentrations of AFN-1252 on the growth rate of L. monocytogenes in planktonic culture was measured to determine the contribution of LmFabI versus LmFabK1 to fatty acid synthesis and growth. AFN-1252 caused the cessation of cell growth after 1 to 2 cellular doublings in bacterial genes encoding a single, essential FabI. In contrast, increasing concentrations of AFN-1252 slowed but did not stop the growth of L. monocytogenes (Fig. 3A). Pathway labeling experiments showed that AFN-1252 selectively inhibited lipid synthesis, with minimal perturbation to protein, DNA, and RNA synthesis (Fig. 3B). Therefore, the reduction of growth rate by AFN-1252 was attributed to on-target inhibition of LmFabI and fatty acid synthesis. Reference: Infect Immun. 2016 Dec; 84(12): 3597–3607. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116736/ |
| In vivo activity: | The first experiments involved administering a single oral dose of AFN-1252 (100 mg/kg) 2 h after infecting the granuloma pouches and examining the effect of AFN-1252 on pouch-associated CFU within 48 h of dosing (Fig. 3A). Little change in the bacterial load was detected within the first 12 h of AFN-1252 treatment, but between 24 and 48 h, there was a 3.0-log10 reduction in the mean CFU/ml of pouch fluid collected from AFN-1252-treated mice compared to untreated mice (Fig. 3A). Wood46 counts in untreated pouch fluid increased to 7.5 log10 CFU/ml at 24 h, while bacterial counts in AFN-1252-treated pouches dropped to 4.4 log10 CFU/ml in 24 h. When 100 mg/kg of AFN-1252 was orally administered once a day for 3 days (+2, +26, and +50 h), AFN-1252 reduced 72-hour S. aureus CFU counts in the pouches of treated animals by 5 orders of magnitude compared to untreated controls, which was near the detection limit for this model (Fig. 3B). These data illustrate that orally administered AFN-1252 can reach therapeutic levels in the mouse granuloma pouch and effectively resolve the S. aureus infection associated with the pouch fluid. Reference: Antimicrob Agents Chemother. 2013 May; 57(5): 2182–2190. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632907/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 5.8 | 15.45 |
The following data is based on the product molecular weight 375.43 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Yao J, Ericson ME, Frank MW, Rock CO. Enoyl-Acyl Carrier Protein Reductase I (FabI) Is Essential for the Intracellular Growth of Listeria monocytogenes. Infect Immun. 2016 Nov 18;84(12):3597-3607. doi: 10.1128/IAI.00647-16. PMID: 27736774; PMCID: PMC5116736. 2. Flamm RK, Rhomberg PR, Kaplan N, Jones RN, Farrell DJ. Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains. Antimicrob Agents Chemother. 2015 May;59(5):2583-7. doi: 10.1128/AAC.05119-14. Epub 2015 Feb 17. PMID: 25691627; PMCID: PMC4394798. 3. Parsons JB, Kukula M, Jackson P, Pulse M, Simecka JW, Valtierra D, Weiss WJ, Kaplan N, Rock CO. Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252. Antimicrob Agents Chemother. 2013 May;57(5):2182-90. doi: 10.1128/AAC.02307-12. Epub 2013 Mar 4. PMID: 23459481; PMCID: PMC3632907. 4. Banevicius MA, Kaplan N, Hafkin B, Nicolau DP. Pharmacokinetics, pharmacodynamics and efficacy of novel FabI inhibitor AFN-1252 against MSSA and MRSA in the murine thigh infection model. J Chemother. 2013 Feb;25(1):26-31. doi: 10.1179/1973947812Y.0000000061. PMID: 23433441; PMCID: PMC3558988. |
| In vitro protocol: | 1. Yao J, Ericson ME, Frank MW, Rock CO. Enoyl-Acyl Carrier Protein Reductase I (FabI) Is Essential for the Intracellular Growth of Listeria monocytogenes. Infect Immun. 2016 Nov 18;84(12):3597-3607. doi: 10.1128/IAI.00647-16. PMID: 27736774; PMCID: PMC5116736. 2. Flamm RK, Rhomberg PR, Kaplan N, Jones RN, Farrell DJ. Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains. Antimicrob Agents Chemother. 2015 May;59(5):2583-7. doi: 10.1128/AAC.05119-14. Epub 2015 Feb 17. PMID: 25691627; PMCID: PMC4394798. |
| In vivo protocol: | 1. Parsons JB, Kukula M, Jackson P, Pulse M, Simecka JW, Valtierra D, Weiss WJ, Kaplan N, Rock CO. Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252. Antimicrob Agents Chemother. 2013 May;57(5):2182-90. doi: 10.1128/AAC.02307-12. Epub 2013 Mar 4. PMID: 23459481; PMCID: PMC3632907. 2. Banevicius MA, Kaplan N, Hafkin B, Nicolau DP. Pharmacokinetics, pharmacodynamics and efficacy of novel FabI inhibitor AFN-1252 against MSSA and MRSA in the murine thigh infection model. J Chemother. 2013 Feb;25(1):26-31. doi: 10.1179/1973947812Y.0000000061. PMID: 23433441; PMCID: PMC3558988. |
1: Rao NK, Nataraj V, Ravi M, Panchariya L, Palai K, Talapati SR, Lakshminarasimhan A, Ramachandra M, Antony T. Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies. Chem Biol Drug Des. 2020 Aug;96(2):704-713. doi: 10.1111/cbdd.13686. Epub 2020 Apr 22. PMID: 32227402.
2: Kénanian G, Morvan C, Weckel A, Pathania A, Anba-Mondoloni J, Halpern D, Gaillard M, Solgadi A, Dupont L, Henry C, Poyart C, Fouet A, Lamberet G, Gloux K, Gruss A. Permissive Fatty Acid Incorporation Promotes Staphylococcal Adaptation to FASII Antibiotics in Host Environments. Cell Rep. 2019 Dec 17;29(12):3974-3982.e4. doi: 10.1016/j.celrep.2019.11.071. PMID: 31851927.
3: Parker EN, Drown BS, Geddes EJ, Lee HY, Ismail N, Lau GW, Hergenrother PJ. Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens. Nat Microbiol. 2020 Jan;5(1):67-75. doi: 10.1038/s41564-019-0604-5. Epub 2019 Nov 18. PMID: 31740764; PMCID: PMC6953607.
4: Pee CJE, Pader V, Ledger EVK, Edwards AM. A FASII Inhibitor Prevents Staphylococcal Evasion of Daptomycin by Inhibiting Phospholipid Decoy Production. Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02105-18. doi: 10.1128/AAC.02105-18. PMID: 30718253; PMCID: PMC6496159.
5: Menetrey A, Janin A, Pullman J, Overcash JS, Haouala A, Leylavergne F, Turbe L, Wittke F, Nicolas-Métral V. Bone and Joint Tissue Penetration of the Staphylococcus-Selective Antibiotic Afabicin in Patients Undergoing Elective Hip Replacement Surgery. Antimicrob Agents Chemother. 2019 Feb 26;63(3):e01669-18. doi: 10.1128/AAC.01669-18. PMID: 30559136; PMCID: PMC6395911.
6: Yao J, Rock CO. Therapeutic Targets in Chlamydial Fatty Acid and Phospholipid Synthesis. Front Microbiol. 2018 Sep 25;9:2291. doi: 10.3389/fmicb.2018.02291. PMID: 30319589; PMCID: PMC6167442.
7: Morvan C, Halpern D, Kénanian G, Pathania A, Anba-Mondoloni J, Lamberet G, Gruss A, Gloux K. The Staphylococcus aureus FASII bypass escape route from FASII inhibitors. Biochimie. 2017 Oct;141:40-46. doi: 10.1016/j.biochi.2017.07.004. Epub 2017 Jul 17. PMID: 28728970.
8: Yao J, Ericson ME, Frank MW, Rock CO. Enoyl-Acyl Carrier Protein Reductase I (FabI) Is Essential for the Intracellular Growth of Listeria monocytogenes. Infect Immun. 2016 Nov 18;84(12):3597-3607. doi: 10.1128/IAI.00647-16. PMID: 27736774; PMCID: PMC5116736.
9: Hafkin B, Kaplan N, Murphy B. Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities. Antimicrob Agents Chemother. 2015 Dec 28;60(3):1695-701. doi: 10.1128/AAC.01741-15. PMID: 26711777; PMCID: PMC4775962.
10: Yao J, Bruhn DF, Frank MW, Lee RE, Rock CO. Activation of Exogenous Fatty Acids to Acyl-Acyl Carrier Protein Cannot Bypass FabI Inhibition in Neisseria. J Biol Chem. 2016 Jan 1;291(1):171-81. doi: 10.1074/jbc.M115.699462. Epub 2015 Nov 13. PMID: 26567338; PMCID: PMC4697154.
11: Hunt T, Kaplan N, Hafkin B. Safety, tolerability and pharmacokinetics of multiple oral doses of AFN-1252 administered as immediate release (IR) tablets in healthy subjects. J Chemother. 2016 Jun;28(3):164-71. doi: 10.1179/1973947815Y.0000000075. Epub 2016 May 13. PMID: 26431470.
12: Hafkin B, Kaplan N, Hunt TL. Safety, tolerability and pharmacokinetics of AFN-1252 administered as immediate release tablets in healthy subjects. Future Microbiol. 2015;10(11):1805-13. doi: 10.2217/fmb.15.101. Epub 2015 Sep 11. PMID: 26357940.
13: Flamm RK, Rhomberg PR, Kaplan N, Jones RN, Farrell DJ. Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains. Antimicrob Agents Chemother. 2015 May;59(5):2583-7. doi: 10.1128/AAC.05119-14. Epub 2015 Feb 17. PMID: 25691627; PMCID: PMC4394798.
14: Rao KN, Lakshminarasimhan A, Joseph S, Lekshmi SU, Lau MS, Takhi M, Sreenivas K, Nathan S, Yusof R, Abd Rahman N, Ramachandra M, Antony T, Subramanya H. AFN-1252 is a potent inhibitor of enoyl-ACP reductase from Burkholderia pseudomallei--Crystal structure, mode of action, and biological activity. Protein Sci. 2015 May;24(5):832-40. doi: 10.1002/pro.2655. Epub 2015 Apr 2. PMID: 25644789; PMCID: PMC4420531.
15: Yao J, Abdelrahman YM, Robertson RM, Cox JV, Belland RJ, White SW, Rock CO. Type II fatty acid synthesis is essential for the replication of Chlamydia trachomatis. J Biol Chem. 2014 Aug 8;289(32):22365-76. doi: 10.1074/jbc.M114.584185. Epub 2014 Jun 23. PMID: 24958721; PMCID: PMC4139244.
16: Yao J, Maxwell JB, Rock CO. Resistance to AFN-1252 arises from missense mutations in Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI). J Biol Chem. 2013 Dec 20;288(51):36261-71. doi: 10.1074/jbc.M113.512905. Epub 2013 Nov 4. PMID: 24189061; PMCID: PMC3868742.
17: Kaplan N, Garner C, Hafkin B. AFN-1252 in vitro absorption studies and pharmacokinetics following microdosing in healthy subjects. Eur J Pharm Sci. 2013 Nov 20;50(3-4):440-6. doi: 10.1016/j.ejps.2013.08.019. Epub 2013 Aug 27. Erratum in: Eur J Pharm Sci. 2014 Feb 14;52:223. PMID: 23988847.
18: Parsons JB, Kukula M, Jackson P, Pulse M, Simecka JW, Valtierra D, Weiss WJ, Kaplan N, Rock CO. Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252. Antimicrob Agents Chemother. 2013 May;57(5):2182-90. doi: 10.1128/AAC.02307-12. Epub 2013 Mar 4. PMID: 23459481; PMCID: PMC3632907.
19: Tsuji BT, Harigaya Y, Lesse AJ, Forrest A, Ngo D. Activity of AFN-1252, a novel FabI inhibitor, against Staphylococcus aureus in an in vitro pharmacodynamic model simulating human pharmacokinetics. J Chemother. 2013 Feb;25(1):32-5. doi: 10.1179/1973947812Y.0000000060. PMID: 23433442; PMCID: PMC3558987.
20: Banevicius MA, Kaplan N, Hafkin B, Nicolau DP. Pharmacokinetics, pharmacodynamics and efficacy of novel FabI inhibitor AFN-1252 against MSSA and MRSA in the murine thigh infection model. J Chemother. 2013 Feb;25(1):26-31. doi: 10.1179/1973947812Y.0000000061. PMID: 23433441; PMCID: PMC3558988.
