NBD-14270
目录号 : GC65903
NBD-14270,一种吡啶类似物,是一种有效的 HIV-1 进入拮抗剂,对 50 株 HIV-1 假型病毒的 IC50 为 89 nM。NBD-14270 与 HIV-1 gp120 结合并显示出强大的抗病毒活性 (EC50<200 nM)。NBD-14270 显示低细胞毒性 (CC50>100 μM)。
Cas No.:2411819-82-2
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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NBD-14270, a pyridine analogue, is a potent HIV-1 entry antagonist with an IC50 of 180 nM against 50 HIV-1 Env-pseudotyped viruses. NBD-14270 binds to HIV-1 gp120 and shows potent antiviral activity. NBD-14270 shows low cytotoxicity (CC50>100 μM)[1][2].
NBD-14270 has anti-HIV-1 activity (IC50=0.16 μM ) and Cytotoxicity (CC50=109.3 μM) in single-cycle (TZM-bl Cells) assay[1].
NBD-14270 does not induce toxicity in the U87-CD4-CXCR4 cell line at the doses used for this assay[1].
Cas No. | 2411819-82-2 | SDF | Download SDF |
分子式 | C18H18F3N5O2S | 分子量 | 425.43 |
溶解度 | DMSO : 100 mg/mL (235.06 mM; Need ultrasonic) | 储存条件 | 4°C, away from moisture and light |
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1 mg | 5 mg | 10 mg |
1 mM | 2.3506 mL | 11.7528 mL | 23.5056 mL |
5 mM | 0.4701 mL | 2.3506 mL | 4.7011 mL |
10 mM | 0.2351 mL | 1.1753 mL | 2.3506 mL |
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Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV-1 Entry Inhibitor NBD-14270
ChemMedChem 2022 Nov 18;17(22):e202200344.PMID:36097139DOI:10.1002/cmdc.202200344.
The envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV-1) plays a critical role in virus entry to the cells by binding to the host cellular protein CD4. Earlier, we reported the design and discovery of a series of highly potent small-molecule entry antagonists containing a thiazole ring (Scaffold A). Since this thiazole ring connected with an ethyl amide linkage represents the molecule's flexible part, we decided to explore substituting Scaffold A with two other positional isomers of the thiazole ring (Scaffold B and C) to evaluate their effect on the antiviral potency and cellular toxicity. Here we report the novel synthesis of two sets of positional thiazole isomers of the NBD-14270 by retrosynthetic analysis approach, their anti-HIV-1 activity, cellular toxicity, and structure-activity relationships. The study revealed that Scaffold A provided the best HIV-1 inhibitors with higher potency and better selectivity index (SI).
HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites
J Med Chem 2021 Nov 25;64(22):16530-16540.PMID:34735153DOI:10.1021/acs.jmedchem.1c01104.
HIV-1 infection is typically treated using ≥2 drugs, including at least one HIV-1 reverse transcriptase (RT) inhibitor. Drugs targeting RT comprise nucleos(t)ide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). NRTI-triphosphates bind at the polymerase active site and, following incorporation, inhibit DNA elongation. NNRTIs bind at an allosteric pocket ∼10 Å away from the polymerase active site. This study focuses on compounds ("NBD derivatives") originally developed to bind to HIV-1 gp120, some of which inhibit RT. We have determined crystal structures of three NBD compounds in complex with HIV-1 RT, correlating with RT enzyme inhibition and antiviral activity, to develop structure-activity relationships. Intriguingly, these compounds bridge the dNTP and NNRTI-binding sites and inhibit the polymerase activity of RT in the enzymatic assays (IC50 < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC50 < 200 nM), and NBD-14270 shows low cytotoxicity (CC50 > 100 μM).
Preclinical Optimization of gp120 Entry Antagonists as anti-HIV-1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation
J Med Chem 2020 Feb 27;63(4):1724-1749.PMID:32031803DOI:10.1021/acs.jmedchem.9b02149.
We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.