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Structure of 100-81-2
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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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Batch number can be found on the product's label following the word 'Batch'.
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Dube, Phelelisiwe S. ; Legoabe, Lesetja J. ; Jordaan, Audrey ; Sigauke, Lester ; Warner, Digby F. ; Beteck, Richard M.
Abstract: Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clin. development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a quinolone nucleus. Twenty-two compounds were synthesized and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC90 <0.244 μM. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.
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Keywords: DprE1 ; Quinolone ; Nitro compounds ; Mycobacterium tuberculosis ; Benzothiazinone
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Purchased from AmBeed: 104-86-9 ; 100-82-3 ; 4152-90-3 ; 1377239-83-2 ; 100-81-2 ; 400-98-6 ; 72235-53-1 ; 89-97-4 ; 190140-20-6
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CAS No. : | 100-81-2 |
Formula : | C8H11N |
M.W : | 121.18 |
SMILES Code : | NCC1=CC=CC(C)=C1 |
MDL No. : | MFCD00008118 |
InChI Key : | RGXUCUWVGKLACF-UHFFFAOYSA-N |
Pubchem ID : | 66015 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314-H227 |
Precautionary Statements: | P501-P210-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 |
Class: | 8 |
UN#: | 2735 |
Packing Group: | Ⅲ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 39.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.68 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.34 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.3 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.87 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.92 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.62 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.86 |
Solubility | 1.66 mg/ml ; 0.0137 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.49 |
Solubility | 3.94 mg/ml ; 0.0325 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.78 |
Solubility | 0.2 mg/ml ; 0.00165 mol/l |
Class? Solubility class: Log S scale |
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 |
Yes |
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 |
-6.09 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 |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 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) |
1.0 |
* 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 |
---|---|---|
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 8h;Inert atmosphere; | General procedure: To a solution of o-10 (915 mg, 4.71 mmol) in DMF (15.7 mL), 3-methylbenzylamine (701 muL, 5.65 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC: 1.20 g, 6.26 mmol) and N,N-dimethyl-4-aminopyridine (DMAP: 153 mg, 1.25 mmol) were added at 0 C. The mixture was stirred for 7.5 h at room temperature, then water and ethyl acetate were added at 0 C. The organic layer was separated and washed with water and brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Further purification was carried out by silica gel column chromatography (eluent: hexane/ethylacetate = 1:1) to give o-13 (1.38 g, 99 %) as a pale yellow oil. IR (neat) 3296, 2943, 1643, 1608, 1593, 1535, 1456, 1240 cm-1; 1HNMR (400 MHz, CDCl3) d 1.65-1.78 (m, 4H), 2.30 (t, J = 6.8 Hz,2H), 2.33 (s, 3H), 2.65 (br t, J = 7.2 Hz, 2H), 4.40 (d, J = 5.2 Hz, 2H),5.74 (br, 1H), 5.98 (s, 1H), 6.78 (dd, J = 0.8 Hz, 7.6 Hz, 1H), 6.82(td, J = 7.6 Hz, 0.8 Hz, 1H), 7.05-7.10 (m, 5H), 7.22 (br t,J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.3, 25.4, 29.3, 29.5, 36.2, 43.6, 115.6, 120.0, 124.8, 127.0, 128.2, 128.4, 128.6 (2C), 130.0, 137.9, 138.4, 154.3, 173.7; HRMS-ESI (m/z): [M+Na+] calcd for C19H23NO2Na, 297.1729; found, 297.1728. m-13 (65.3 mg, 85 %): IR (neat) 3282, 2931, 1645, 1587, 1533, 1455, 1275, 1240,1157 cm-1; 1H NMR (400 MHz, CDCl3) d 1.58-1.76 (m, 4H), 2.22 (t, J = 6.8 Hz, 2H), 2.33 (s, 3H), 2.58 (t, J = 7.2 Hz, 2H), 4.39 (d,J = 5.6 Hz, 2H), 5.61 (br, 1H), 5.69 (br, 1H), 6.64-6.68 (m, 2H), 6.71 (br d, J = 7.6 Hz, 1H), 7.04-7.14 (m, 4H), 7.22 (t, J = 7.6 Hz,1H); 13C NMR (100 MHz, CDCl3) d 21.3, 25.2, 30.6, 35.3, 36.5,43.7, 112.9, 115.4, 120.2, 124.8, 128.3, 128.6 (2C), 129.4, 137.8, 138.4, 143.7, 156.3, 173.4; HRMS-ESI (m/z): [M+Na+] calcd for C19H23NO2Na, 297.1729; found, 297.1729. p-13 (905 mg, quant.): IR(neat) 3290, 2925, 1641, 1612, 1541, 1514, 1446, 1230 cm-1; 1HNMR (400 MHz, CDCl3) d 1.57-1.73 (m, 4H), 2.30 (t, J = 7.2 Hz,2H), 2.33 (s, 3H), 2.54 (t, J = 7.6 Hz, 2H), 4.39 (d, J = 5.6 Hz, 2H), 5.69 (br, 1H), 5.74 (br, 1H), 6.74 (d, J = 8.4 Hz, 2H), 6.99 (d,J = 8.4 Hz, 2H), 7.04-7.10 (m, 3H), 7.22 (t, J = 7.2 Hz, 1H); 13CNMR (100 MHz, CDCl3) d 21.2, 25.2, 31.1, 34.6, 36.4, 43.5, 115.2(2C), 124.7, 128.1, 128.4, 128.5, 129.1 (2C), 133.2, 137.7, 138.2,154.5, 173.7; HRMS-ESI (m/z): [M+ Na+] calcd for C19H23NO2Na, 297.1729; found, 297.1728. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The compounds 1-9 were synthesized using themixed anhydrides method of peptide synthesis (18).The suitable acid (10 mM) was dissolved in DMF(15 mL) and THF (15 mL) was added. Next N-methylmorpholine (10 mM, 1.1 mL) was added andthe mixture was stirred under nitrogen and chilled to-15 O C. Isobutyl chloroformate (10 mM, 1.3 mL) wasadded dropwise to keep the temperature below -15 O C. Then, the suitable amine: 2- or 4-fluorobenzy-lamine (2-F-BZA, 4-F-BZA); 2- or 4-methoxyben-zylamine (2-OMe-BZA, 4-OMe-BZA); 3- or 4-methylbenzylamine (3-Me-BZA, 4-Me-BZA) or 1-naphthylmethylamine (10 mM) in THF was added insmall portions and the reaction mixture was stirred at -15 O C for 30 min and at room temperature for 1 h.The solution was concentrated in vacuo and theresidue was dissolved in CHCl 3 (40 mL). This solu-tion was washed with 20 mL portions of 1M HCl,saturated NaHCO 3 solution and saturated NaCl solu-tion, then dried with anhydrous MgSO 4 , filtered andconcentrated in vacuo. The obtained compoundswere purified by crystallization with EtOAc/hexaneor MeOH/Et 2 O. All stages of the synthesis were con-trolled by TLC. The purity and identity of the finalcompounds were determined by HPLC, elementalanalyses, 1 H NMR, MS. The elemental analyses werewithin ± 0.4percent of the theoretical value. The analyticaldata confirmed that the purity of the products was ?95percent. The general procedure for the synthesis of theobtained compounds is shown in Schemes 1 and 2. |
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