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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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Design and Development of Antibiotics and Synthesis of Modified Nucleosides
Hegde, Pooja Venkatesh ;
Abstract: Tuberculosis (TB) remains a leading cause of infectious disease mortality and morbidity resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. Chapter 1 discusses the epidemiology, control, and management of TB. Isoniazid (INH) is a cornerstone for the treatment of drug-susceptible TB, yet the quantitative structure-activity relationships for INH are not well documented in the literature. Chapter 2 evaluates a systematic series of INH analogs against contemporary Mycobacterium tuberculosis (Mtb) strains from different lineages and several key species of non-tuberculous mycobacteria (NTM). To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of Gram-positive and Gram-negative bacteria, as well as a number of fungi. Our findings provide an updated analysis of the structure-activity relationship of INH that will serve as a valuable resource for the development of a next generation antitubercular compounds. para-Aminosalicylic acid (PAS), is an important second-line agent for treating drug-resistant Mtb. PAS has a moderate bioavailability and rapid clearance that necessitate high doses in order to facilitate an effective treatment. Consequently, such high doses commonly results in gastrointestinal disturbances (presumably by disruption of gut microbiota and host epithelial cells). Chapter 3 discusses the design, synthesis and evaluation of PAS prodrugs and analogs with improved oral bioavailability, thereby preventing intestinal accumulation as well as undesirable bioactivation by the gut microbiome to cytotoxic folate species. The pivoxyl prodrug and fluorination at the 5- position address the primary limitations of PAS and have the potential to revitalize this second-line TB drug. vi Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mtb, but its mechanism of action has remained enigmatic. PZA is a prodrug converted to the active moiety- pyrazinoic acid (POA), by pyrazinamidase, an amidase within the nicotinamide adenine dinucleotide (NAD) salvage pathway encoded by pncA in Mtb. PZA resistance is most commonly induced via loss-of-function mutations within PncA. It has recently been demonstrated that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway, essential in Mtb. Chapter 4 describes the structure activity relationship (SAR) evaluation of various POA analogs. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB. The salicylic acid derived small molecule siderophores known as mycobactins are essential for mycobacterial iron acquisition and mycobactin biosynthesis has been biochemically and genetically validated as essential for survival in vivo. Sal-AMS, a modified nucleoside derivative that mimics an intermediate in the mycobactin biosynthetic pathway, is a potent Mtb inhibitor. Chapter 5 explores polyfluorinated salicylic acid derivatives as antimetabolites, designed to antagonize mycobactin synthesis. Enzymatic studies demonstrated that the tri- and tetra- fluorinated salicylic acid analogs were neither substrates nor inhibitors of MbtA, but the di-fluorinated compounds were readily activated by the bifunctional adenylating enzyme MbtA, responsible for processing salicylic acid moieties for synthesis of mycobactins. However further microbiological analysis revealed that the polyfluorinated derivatives have low potential as anti-TB agents and do not appear to operate by inhibiting mycobactin synthesis. vii Lastly, the chemical synthesis of nucleoside analogs, an important class of compounds with applications as anti-infective, anti-cancer, and diagnostic agents, is extremely challenging, typically requiring linear synthesis, multiple protectiondeprotection sequences, and stereoselective formation of the critical glycosidic linkage. Nucleoside phosphorylases (NPs) have tremendous biocatalytic potential and aid in the selective modification of nucleosides under green conditions. Chapter 6 focuses on the functional characterization of 15 thermostable purine NPs. Four of these were further selected for a comprehensive analysis of their substrate scope. Next, chemoenzymatic methods for the synthesis of modified nucleosides were extensively studied using various coupled systems, and 12 modified nucleosides were synthesized, isolated, and characterized. viii Table of Contents Acknowledgments......................
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Reinvestigation of the structure-activity relationships of isoniazid
Hegde, Pooja ; Boshoff, Helena I. M. ; Rusman, Yudi ; Aragaw, Wassihun Wedajo ; Salomon, Christine E. ; Dick, Thomas , et al.
Abstract: Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quant. structure-activity relationships for INH are not well documented in the literature. In this paper, we have evaluated a systematic series of INH analogs against contemporary Mycobacterium tuberculosis strains from different lineages and a few non-tuberculous mycobacteria (NTM). Deletion of the pyridyl nitrogen atom, isomerization of the pyridine nitrogen to other positions, replacement of the pyridine ring with isosteric heterocycles, and modification of the hydrazide moiety of INH abolishes antitubercular activity. Similarly, substitution of the pyridine ring at the 3-position is not tolerated while substitution at the 2-position is permitted with 2-methyl-INH 9 displaying antimycobacterial activity comparable to INH. To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-pos. and gram-neg. bacteria, as well as a few fungi. As expected INH and its analogs display a narrow spectrum of activity and are inactive against all non-mycobacterial strains evaluated, except for 4, which has modest inhibitory activity against Cryptococcus neoformans. Our findings provide an updated anal. of the structure-activity relationship of INH that we hope will serve as useful resource for the community.
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Keywords: Isoniazid ; SAR
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CAS No. : | 3326-71-4 |
Formula : | C5H6N2O2 |
M.W : | 126.11 |
SMILES Code : | O=C(C1=CC=CO1)NN |
MDL No. : | MFCD00003235 |
InChI Key : | SKTSVWWOAIAIKI-UHFFFAOYSA-N |
Pubchem ID : | 18731 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 29.6 |
TPSA ? Topological Polar Surface Area: Calculated from |
68.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.15 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.52 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.12 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.8 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.33 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.12 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.57 |
Solubility | 33.7 mg/ml ; 0.267 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.45 |
Solubility | 45.3 mg/ml ; 0.359 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.21 |
Solubility | 7.76 mg/ml ; 0.0615 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 |
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) |
No |
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 |
-7.44 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 |
1.0 |
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 |
2.0 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) |
1.93 |
* 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 |
---|---|---|
In ethanol; at 80℃; for 3h; | General procedure: 8-Methoxyquinoline-2-carbaldehyde (25, 0.534 mmol) was refluxedwith various substituted acylhydrazines (0.587 mmol, 1.1 eq) in ethanol(5-10 mL) to get acyl hydrazides of 8-hydroxyquinoline. After completionof reaction, quinoline acyl hydrazides were found as precipitateson cooling to -15 C. Precipitates were washed with coldethanol and dried under vacuum. These acyl hydrazides were used directlyfor one pot synthesis of 2,5-disubstituted-1,3,4-oxadiazole usingiodine/K2CO3 catalysed oxidative cyclization. To the acyl hydrazides(1.0 eq) in DMSO (5-10 mL), K2CO3 (3.0 eq) and iodine (1.2 eq) wereadded in sequence and refluxed at 110 C. After the completion, thereaction mixture was cooled and saturated solution of sodium thiosulfatewas added. The precipitates were collected and dried under highvacuum to get the respective compounds (33-50). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With toluene-4-sulfonic acid; In ethanol; water; at 20℃; for 0.916667h;Sonication; | General procedure: An equimolar amount of Isatoic anhydride (1mmol) and 2-Furoic hydrazide (1mmol) was taken in 50mL round bottom flask containing 10mL of ethanol: water (5:5 v/v) mixed solvent and P-TSA (20mol%). The resultant reaction mixture was sonicated till the completion of reaction. Then the respective substituted salicylaldehydes (1mmol) were added in it. The reaction mixture was further sonicated, and the progress of reaction was monitored on thin layer chromatography (TLC). After completion of reaction the product was isolated by simple filtration method and washed with ethanol. The formation of product was confirmed by spectral techniques such as IR, NMR and LCMS Analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide; for 1h;Reflux; | 3,5-Diiodosalicyaldehyde (0.374 g, 1 mmol) in N,N-dimethylformamidesolution and 2-furoic hydrazide (0.126 g, 1 mmol) inthe same solvent were mixed and refluxed for an hour. Yellowmicrocrystalline product formed was separated and recrystallizedfrom CH3CN-DMF mixture. The product obtained was filtered anddried.Analytical data for C12H8I2N2O3 (H2ISF) Yield: 0.4104 g (85%);color: Yellow; M.W, 482.01 g mol1; Anal. Calc. (Found) (%): C 29.9(29.52), H 1.67(1.88), N 5.81(5.96); 1H NMR (400 MHz, DMSO-d6):d 7.1 (2H, d, aromatic), 7.5 (1H, q, aromatic), 7.86 (1H, d, aromatic),8.006 (1H, d, aromatic), 8.06 (1H, d, aromatic), 8.44 (1H, s, CH),12.58 (1H, br, OH), 12.78 (1H, br, NH); FTeIR: n (cm1) 3437 n(OeH),3166 n(NeH), 1650 n(C]O), 1600, n(C]N); MS (ESI) m/z (M1)482.9, calculated m/z 481.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In tetrahydrofuran; ethanol; for 3h;Reflux; | The ethanolic solution of furan-2-carbohydrazide (1 mM, 0.6305 g)was added dropwise to the solution of <strong>[42059-80-3]3-formyl-6-nitrochromone</strong>(1 mM, 0.2191 g) in THF with continuous stirring. The immediate precipitatewas observed in the reaction mixture, therefore reflux the reaction mixture for 3 h and then check the TLC for reaction completionand found that reaction has been completed. The precipitate waswashed with Methanol and dry it in the air Scheme 1.Yield. 70%, Anal. Calculation for C15H9N3O6: C, 55.05; H, 2.77; N,12.84; Found: C, 55.37; H, 2.292; N, 13.21; FT-IR data (KBr, νmax/cm-1): -N-H: 3430, C-H: 3145, C=O: 1695, C=O: 1632, -C=N: 1592and NO (nitro): 1539, 1468 (Supplementary information, Fig-S1).1H NMR (400 MHz,) δ 11.85 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.31(dd, J = 9.0, 2.9 Hz, 1H), 8.28 (d, J = 2.8 Hz, 2H), 8.06 (d, J = 3.6 Hz,1H), 7.16 (d, J=9.0 Hz, 1H), 6.88 (dd, J=3.7, 1.5 Hz, 1H) (Supplementaryinformation, Fig-S3). 13C NMR (100 MHz) δ 187.040, 162.91,154.36, 151.11, 145.04, 143.97, 139.95, 135.207, 128.87, 126.81, 126.51,126.48, 125.35, 118.11, 113.97 (Supplementary information, Fig-S4).ESI-mass of La: 350.0440 (M + Na)+ (Supplementary information,Fig-S7). |
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