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Structure of 89-97-4
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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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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. : | 89-97-4 |
Formula : | C7H8ClN |
M.W : | 141.60 |
SMILES Code : | NCC1=CC=CC=C1Cl |
MDL No. : | MFCD00008108 |
InChI Key : | KDDNKZCVYQDGKE-UHFFFAOYSA-N |
Pubchem ID : | 66648 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H227-H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 2735 |
Packing Group: | Ⅲ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 39.13 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.8 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.51 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.65 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.14 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.84 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.1 |
Solubility | 1.13 mg/ml ; 0.00801 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.66 |
Solubility | 3.07 mg/ml ; 0.0216 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.03 |
Solubility | 0.131 mg/ml ; 0.000927 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 |
---|---|---|
With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; N,N-dimethyl-formamide; at -15 - 20℃; for 1.5h;Inert atmosphere; | General procedure: Compounds 1-13 were synthesized using the mixed anhydrides method of peptide synthesis (10). Suitable acid (10 mmol) was dissolved in DMF (15 mL) and THF (15 mL) was added. Next, N-methylmorpholine (10 mmol, 1.1 mL) was added and the mixture was stirred under nitrogen and chilled to -15°C. Isobutyl chloroformate (10 mmol, 1.3 mL) was added dropwise to keep the temperature below -15°C. Then, benzylamine or halogenated benzylamine (10 mmol) in THF was added in small portions and the reaction mixture was stirred at -15°C for 30 min, at room temperature for 1 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc (20 mL). This solution was washed with 20 mL portions of 1 M HCl, saturated NaHCO3 solution and saturated NaCl solution, then dried with anhydrous MgSO4, filtered and concentrated in vacuo. The obtained compounds were purified by crystallization with EtOAc/hexane o MeOH/Et2O. All stages of the synthesis were controlled by TLC. The purity of the final compound was determined by HPLC and identity by 1H NMR. The pathway for the synthesis of the obtained compounds is shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | To a stirring solution of 2,6-difluoro nitrobenzene (3.83 g, 24 mmol) in acetonitrile (50 mL), 2-chlorobenzylamine (2.9 mL, 24 mmol) and DIPEA (5.1 mL, 28.9 mmol) were added. The solution was stirred at room temperature overnight. Water (100 mL) was added and the solution was extracted with ethyl acetate (3 X 50 mL). The combined organic solution was extracted with water (50 mL), brine (50 mL) and dried over sodium sulfate. The solution was filtered and concentrated. The residue was purified by ISCO, eluting with ethyl acetate/hexane (0-20%) to give the title compound as a purple solid (2.87 g, 43% yield). MS (ES+) m/z 281.0 [M+H]+.1H MR (400 MHz, chloroform-i ) δ ppm 4.56 - 4.65 (m, 2 H) 6.44 - 6.55 (m, 2 H) 7.22 - 7.37 (m, 3 H) 7.40 - 7.52 (m, 1 H) 7.62 (br. s., 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; In methanol; at 140℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: Compounds 1-6 were prepared according to conventional organic synthesis methods. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was dissolved in THF (20 mL) in a round bottom flask and after that treated with two equivalents of the corresponding benzylamine and an equimolar amount of triethylamine. The reaction was conducted with continuous stirring and heating (70 C) under reflux in an oil bath for 15 h. Compounds 7-15 were synthesised using a microwave reactor with a focused field. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was put into a thick-walled tube together with the corresponding benzylamine (2.54 mmol), pyridine (1.27 mmol), methanol (approx. 5 mL) and a magnetic stir bar and then sealed with a special cap. The reaction parameters were set according to the previously published paper as follows-140 C, 30 min, 200 W [29]. Reaction progress was checked by TLC (hexane:ethyl acetate-1:1). Regardless of the synthesis method used,all reaction mixtures were adsorbed on silica and subjected to preparative flash chromatography (hexane and ethyl acetate, gradient elution, detection wavelengths 260 nm and 280 nm). Products were recrystallized from ethanol or ethanol and water if necessary. All final substances were chemically characterized (1H-NMR, 13C-NMR, IR, melting point and elemental analysis). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With tetrabutylammomium bromide; sodium carbonate; N-ethyl-N,N-diisopropylamine; In water; for 3h;Reflux; | In a round bottom flask, 5 cm3 water, 0.453 gof <strong>[94088-46-7]2-fluoro-6-methoxybenzonitrile</strong> (0.003 mol), 0.423 g of 2-chlorobenzylamine (0.003 mol), 0.387 g of DIPEA (0.003 mol), 0.096 of TBAB (0.0003 mol), and 0.318 g of Na2CO3 (0.003 mol) was taken. Reaction was carried outat reflux for 3 h. Then reaction mixture was cooled and extracted with ethyl acetate. The product was purified by flash chromatography on silica using hexane-ethyl acetate mobile phase to afford 0.26 g 14 (33%). M.p.: 116-118 C; 1H NMR (400 MHz, CDCl3):delta = 3.894 (s, 2H), 3.972 (s,3H), 4.541-4.553 (m, 1H), 6.175-6.264 (dd, J = 24.0 Hz,8.0 Hz, 1H), 6.800-6.806 (m, 2H), 7.239-7.284 (m, 2H),7.336-7.424 (m, 1H), 7.499-7.558 (m, 1H) ppm; 13C NMR(100 MHz, CDCl3):delta = 45.1 (OCH3), 56.6 (CH2), 99.2(CCN), 103.5 (CH), 106.8 (CH), 107.9 (CH), 108.1 (CN),127.0 (CH), 128.4 (CH), 128.7 (CH), 129.6 (CH), 134.8(CCl), 151.1 (CCH2), 162.3 (CNH), 165.3 (CO) ppm; IR(KBr): nu= 3352, 3037, 2849, 2222, 1611, 1508, 1479, 1298,1083 cm-1; ESI-MS: m/z = 273.0783 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.0% | In ethanol; for 24h;Reflux; Sealed tube; | General procedure: To a Radley reaction carousel tube, add 1 equivalent 1, 1.1 equivalents of the amine, a stir bar, and 5 mL 95% ethanol. Reflux while stirring for 24 hours. After cooling to room temperature the resulting precipitate was collected by vacuum filtration, washing with 10 mL deionized water and 5 mL chloroform. |
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