Structure of 284462-37-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Synthesis and Exploration of Quinolino-Benzoxaboroles as Potential Therapeutic Agents
Kumpati, Greeshma P ;
Abstract: Benzoxaborole structure contains a phenyl ring fused with a heterocyclic oxaborole ring moiety. Benzoxaboroles are considerably more stable and exhibit high hydrolytic resistance compared with corresponding phenylboronic acids. The enhanced acidity of benzoxaboroles allows them to be predominantly in anionic forms in aqueous solution at physiological pH, which causes them to exhibit higher water solubility and better pharmacokinetic properties than phenylboronic acids. Increasing interest in benzoxaborole compounds is mainly due to their broad-spectrum biological activity including antimicrobial, anti-inflammatory and other medicinal properties. Quinoline is a highly privileged nitrogen containing a bicyclic ring system where a benzene ring is fused to a pyridine ring. The quinoline moiety is found in many natural products and has been traditionally used as a medicine for treating a wide variety of diseases. Quinoline-based molecules have been found to exhibit a diverse range of pharmacological properties with uses as antimalarial, antibacterial, anticonvulsant, cardiotonic, anticancer, anthelmintic, antifungal, anti-inflammatory and analgesic agents. In this regard, we envisioned that introduction of aminobenzoxaborole unit on quinolines would result in novel molecular entities with favorable pharmacological and pharmaceutical properties for developing therapeutic agents for a wide variety of diseases. The aims of the current work include: 1) Develop a new synthetic methodology for the rapid creation of aminobenzoxaborole containing quinolines; and 2) Explore the efficacy of synthesized candidate compounds as antibacterial, antifungal, antiviral, antiinflammatory, and antimalarial agents. As a part of this thesis, we developed a novel synthetic methodology for preparing quinolino aminobenzoxaboroles. The synthesized compounds were initially evaluated for their cytotoxic properties against various human and murine proliferating cancer cells. All the compounds were found to be well tolerated did not display toxicity even at high concentrations. Encouraged by their lack of toxicity, the test compounds were evaluated for their antibacterial activity against E. coli, B. subtilis, and M. smegmatis and for their antifungal activity against C. neoformans and C. albicans. Some of the synthesized derivatives exhibited good and selective activity against M. smegmatis. Future studies will involve evaluation of synthesized candidate compounds as antitubercular, antiviral, antimalarial, and anti-inflammatory agents.
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Purchased from AmBeed: 391-82-2 ; 611-35-8 ; 61964-08-7 ; 86-98-6 ; 284462-37-9 ; 89415-43-0
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CAS No. : | 284462-37-9 |
Formula : | C13H13N3O2 |
M.W : | 243.26 |
SMILES Code : | NC2=CC=C(OC1=CC=NC(=C1)C(=O)NC)C=C2 |
MDL No. : | MFCD08692047 |
InChI Key : | RXZZBPYPZLAEFC-UHFFFAOYSA-N |
Pubchem ID : | 16655129 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.08 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 68.15 |
TPSA ? Topological Polar Surface Area: Calculated from |
77.24 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.17 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.31 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.82 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.6 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.34 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.45 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.4 |
Solubility | 0.962 mg/ml ; 0.00396 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.53 |
Solubility | 0.714 mg/ml ; 0.00293 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.32 |
Solubility | 0.0117 mg/ml ; 0.0000481 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.85 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
1.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.99 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70%; 69% | [0137] A solution of 4-aminophenol (256 mg, 2.35 mmol) in dry N,Ndimethylformamide (40 mL) was treated with potassium tert-butoxide (274 mg, 2.44 mmol), and the reddish-brown mixture was stirred at room temperature for 1 hour. The contents were treated with 3a and 3b (400 mg, 2.35 mmol) and potassium carbonate (974 mg, 7.05 mmol) and then heated to 80 C under argon for 4 h. The mixture was cooled to room temperature and poured into ethyl acetate (100 mL) and brine (400 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to afford the desired 4-(4-aminophenoxy)-N- methylpyridine-2-carboxamide 4a (400 mg, 1 .65 mmol, 70%) and 4-(4- aminophenoxy)-N,N-dimethylpyridine-2-carboxamide (69%) 4b after column as a light-brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.1% | With toluene-4-sulfonic acid; In 1,4-dioxane; at 80℃; for 12h; | General procedure: To a solution of key intermediates 14a-b, 14c-d and 14e in 1,4-dioxane was added 4-substituted-2-chloro-pyrimidine and p-toluene sulfonic acid, and heated to 80 C for 12 h. The reaction was monitored by TLC until completed. The solution was evaporated to afford a crude product, which was purified by column chromatography (CH2Cl2/CH3OH, 100:1) on silica gel to afford the target compounds 17-19, 20-27, 28-36 and 37-40. |
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