NITD-349
目录号 : GC32166
NITD-349是MmpL3的抑制剂，具有高效的抗分枝杆菌活性，对结合分歧杆菌H37Rv的MIC50值为23nM。
Cas No.:1473450-62-2
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | For determining growth inhibition against nine diverse MDR Mtb clinical isolates, pellet formation method is used. MIC is defined as the minimum concentration of the drug required to inhibit 50% of H37Rv growth or 99% of growth in MDR clinical isolates after 5 or 10 days of incubation, respectively. Five milliliters of H37Rv culture (1 × 107 CFU/mL) is incubated with varying concentrations of NITD-349 for 6 days at 37°C, and an aliquot of culture is plated onto Middlebrook 7H11 agar plates; the CFU are enumerated after incubating plates for 3 weeks in a 37°C incubator[1]. |
Animal experiment: | Mouse: In the acute murine efficacy model, mice are orally treated with a daily dose of NITD-349 (12.5, 25, 37.5, 50 mg/kg) for 4 weeks, 1 week after intranasal infection with low-dose Mtb (1000 CFU). Bacterial load in lungs (mean ± SD from six mice per group and per time point) is analyzed after treatment by enumerating CFU[1]. |
References: [1]. Rao SP, et al. Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Sci Transl Med. 2013 Dec 4;5(214):214ra168. | |
NITD-349 is an MmpL3 inhibitor that shows highly potent anti-mycobacterial activity with MIC50 of 23 nM against virulent Mycobacterium tuberculosis H37Rv.
NITD-349 shows bactericidal activity against in vitro replicating Mycobacterium tuberculosis (Mtb) and also are active against intramacrophage Mtb. Kill kinetic analysis of these compounds showed both concentration- and time-dependent killing of Mtb cells with 3- to 4-log colony-forming unit (CFU) reductionwithin 3 days of treatment. The cidal activity profile of NITD-304 is similar to that of isoniazid for which rapid killing is noticed at concentrations greater than 0.2 μM. The MIC activity of NITD349 against various MDR Mtb strains ranges from 0.04 to 0.08 μM. NITD-349 shows high permeability and moderate in vitro metabolic clearance in mouse and human hepatic microsomes[1].
In the acute murine efficacy modelNITD-349 shows favorable oral pharmacokinetic (PK) properties in rodents and dogs and are efficacious in mouse models of both acute and chronic Mycobacterium tuberculosis infection. In the acute murine efficacy model, treatment of mice with NITD-349 at doses of 12.5 and 50 mg/kg resulted in 0.9- and 3.4-log CFU reduction in lung tissue. In an established infection mouse model, after 2 weeks of treatment, the efficacy of NITD-349 is comparable to the first-line TB drug rifampicin and is better than ethambutol. Four weeks of treatment at 100 mg/kg with NITD-349 results in 2.38-log CFU reductions[1].
[1]. Rao SP, et al. Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Sci Transl Med. 2013 Dec 4;5(214):214ra168.
| Cas No. | 1473450-62-2 | SDF | |
| Canonical SMILES | O=C(C(N1)=CC2=C1C=C(F)C=C2F)NC3CCC(C)(C)CC3 | ||
| 分子式 | C17H20F2N2O | 分子量 | 306.35 |
| 溶解度 | DMSO : ≥ 310 mg/mL (1011.91 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 3.2642 mL | 16.3212 mL | 32.6424 mL |
| 5 mM | 0.6528 mL | 3.2642 mL | 6.5285 mL |
| 10 mM | 0.3264 mL | 1.6321 mL | 3.2642 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO
J Mol Biol 2020 Jul 24;432(16):4426-4434.PMID:32512002DOI:10.1016/j.jmb.2020.05.019.
Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3.
Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis
Sci Transl Med 2013 Dec 4;5(214):214ra168.PMID:24307692DOI:10.1126/scitranslmed.3007355.
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.
Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
bioRxiv 2023 Feb 23;2023.02.22.529622.PMID:36865226DOI:10.1101/2023.02.22.529622.
Indolcarboxamides are a promising series of anti-tubercular agents which target Mycobacterium tuberculosis MmpL3, the exporter of trehalose monomycolate, a key cell wall component. We determined the kill kinetics of the lead indolcarboxamide NITD-349 and determined that while kill was rapid against low density cultures, bactericidal activity was inoculum-dependent. A combination of NITD-349 with isoniazid (which inhibits mycolate synthesis) had an increased kill rate; this combination prevented the appearance of resistant mutants, even at higher inocula.