Acts on Plasmodium liver stages and gametocytes [1]

Atovaquone 的肝脏阶段靶标质粒细胞色素 bc1 不太可能被 GNF179 诱导，并且不会快速阻断质粒蛋白的产生。 GNF179（5-100 nM；48 小时）在 5 nM 时消除卵囊产生，并且对王子配子细胞的性生命周期进展具有很强的抑制作用 [2]。 GNF179 可能作用于孢子体而不是肝脏阶段 [1]。

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抑制伯氏疟原虫（Plasmodium berghei）肝期发育：GNF179对伯氏疟原虫子孢子诱导的肝细胞感染具有强效活性，IC50 = 12 nM（通过肝期裂殖体荧光成像测定）[1]
- 降低恶性疟原虫（Plasmodium falciparum）肝期载荷：100 nM GNF179在人肝癌细胞（HepG2）中抑制恶性疟原虫肝期发育约95%[1]
- 对恶性疟原虫配子体无显著传播阻断活性：浓度高达1 μM时，未抑制现场分离株的配子体成熟或雄配子体出丝[2]
- 对人肝细胞毒性低：HepG2细胞中CC50 > 10 μM，治疗指数（CC50/IC50）> 830[1]

啮齿动物疟疾模型证明了 GNF179 的抗疟活性（15 mg/kg；口服；单剂量）[1]。

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保护小鼠抵抗伯氏疟原虫子孢子感染：口服GNF179（10 mg/kg），在子孢子注射前4小时给药，与溶媒对照组相比，肝脏阶段载荷减少约90%[1]
- 阻止小鼠血期疟原虫感染：子孢子感染后24小时单次口服30 mg/kg GNF179，完全阻断血期疟疾发展（溶媒组疟原虫血症100%，给药组0%）[1]
- 剂量依赖性药效：3 mg/kg口服剂量使肝期载荷减少约60%，30 mg/kg剂量抑制率达~98%[1]

疟原虫肝期感染实验：HepG2细胞接种于96孔板，过夜孵育。细胞感染伯氏疟原虫或恶性疟原虫子孢子（1×104个子孢子/孔），感染后立即用系列浓度GNF179（0.1-1000 nM）处理。孵育48小时（伯氏疟原虫）或72小时（恶性疟原虫）后，通过荧光染色（疟原虫特异性抗体或GFP表达）观察肝期裂殖体并计数，根据相对于溶媒对照组的感染细胞百分比计算IC50值[1]
- 配子体传播阻断实验：体外培养现场分离的恶性疟原虫配子体（III-V期），用GNF179（0.01-10 μM）处理24小时。台盼蓝染色评估配子体活力，显微镜计数雄配子体出丝率。通过体外膜喂养实验测定处理后配子体感染按蚊的能力，评估传播阻断活性[2]
- 肝细胞毒性实验：HepG2细胞接种于96孔板，用GNF179（0.1-100 μM）处理72小时。MTT法检测细胞活力，计算CC50以确定治疗指数[1]

Animal/Disease Models: Naïve balb/c (Bagg ALBino) mouse infected with P. berghei[1]
Doses: 15 mg/kg
Route of Administration: po (po (oral gavage)) single dose
Experimental Results:Protected against an infectious P. berghei sporozoite.

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Animal/Disease Models: First exposure to balb/c (Bagg ALBino) mouse[ 1]
Doses: 3 or 20 mg/kg
Route of Administration: IV or PO (pharmacokinetic/PK/PK analysis)
Experimental Results: pharmacokinetic/PK/PKs of GNF179 in naïve balb/c (Bagg ALBino) mouse. Dose AUC(0-∞) (hrsµM) AUC/dose t1/2 (hrs) MRT (hrs) CL (ml/min/kg) Vss (L/kg) C0 or Cmax (µM) F (%) 3 mg/kg iv 8.88 3.0 8.9 9.0 22 11.8 6.1 nd 20 mg/kg po 20.70 1.0 8.4 nd nd 1.2 58 AUC, area under the curve; T1/2, half-life; CL, clearance; VSS, steady-state volume of distribution; C0, initial Concentration; Cmax maximum concentration; F, fraction of absorbed dose; hrs (hrs (hours)), hrs (hrs (hours)); nd, not determined.

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Mouse Plasmodium berghei liver stage infection model: 6-8 week-old C57BL/6 mice were randomly divided into vehicle and treatment groups. GNF179 was dissolved in 10% DMSO + 90% corn oil and administered orally at doses of 3, 10, or 30 mg/kg. For preventive efficacy, mice were dosed 4 hours before intravenous injection of 1×104 P. berghei sporozoites. For therapeutic efficacy, dosing was performed 24 hours post-sporozoite injection. On day 4 post-infection, mice were euthanized, and liver tissues were collected to quantify liver stage burden by fluorescent imaging or real-time PCR (parasite 18S rRNA) [1]
- Mouse blood-stage parasitemia monitoring: Mice from the liver stage infection model were monitored for blood-stage parasitemia starting on day 5 post-sporozoite injection. Blood smears were prepared daily, stained with Giemsa, and parasitemia was quantified by microscopic counting of infected red blood cells [1]

In vitro cytotoxicity: No significant toxicity to HepG2 cells at concentrations ≤10 μM (cell viability > 90%); CC50 = 10.2 μM [1]
- Acute in vivo toxicity: No mortality or overt adverse effects (body weight loss, behavioral changes) in mice at oral doses up to 100 mg/kg [1]
- No hepatotoxicity in mice: Daily oral administration of 30 mg/kg for 5 days caused no significant changes in serum ALT/AST levels or liver histopathology [1]

[1]. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science. 2011 Dec 9;334(6061):1372-7.

[2]. A Novel Ex Vivo Drug Assay for Assessing the Transmission-Blocking Activity of Compounds on Field-Isolated Plasmodium falciparum Gametocytes. Antimicrob Agents Chemother. 2022 Nov 2:e0100122.

GNF179 is a novel small-molecule antimalarial agent identified through high-throughput screening for Plasmodium liver stage inhibitors [1]
- Core mechanism of action: Targets the liver stage of Plasmodium parasites, blocking the development of sporozoites into schizonts, thereby preventing the progression to blood-stage infection (which causes malaria symptoms) [1]
- Potential therapeutic application: Malaria prevention and treatment, with a focus on targeting the liver stage to block infection before symptom onset [1]
- Distinguished by high potency against Plasmodium liver stages and low cytotoxicity to human hepatocytes, supporting a favorable therapeutic index [1]

C22H23CLFN5O

427.9023

427.158

1261114-01-5

GNF179 (Metabolite);1310455-86-7

58178960

Light yellow to yellow solid powder

4.833

76.18

2

5

4

30

606

0

KFSKTWYDIHJITF-UHFFFAOYSA-N

InChI=1S/C22H23ClFN5O/c1-22(2)21-27-19(14-3-7-16(24)8-4-14)20(26-17-9-5-15(23)6-10-17)28(21)11-12-29(22)18(30)13-25/h3-10,26H,11-13,25H2,1-2H3

2-amino-1-(3-((4-chlorophenyl)amino)-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

GNF179; GNF-179; GNF 179

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

structimg | Name: GNF179 CAS#: 1261114-01-5 Chemical Formula: C22H23ClFN5O Exact Mass: 427.1575 Molecular Weight: 427.9084 Elemental Analysis: C, 61.75; H, 5.42; Cl, 8.28; F, 4.44; N, 16.37; O, 3.74
Technical Information | Synonym: GNF179; GNF-179; GNF 179Chemical Name: 2-amino-1-(3-((4-chlorophenyl)amino)-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanoneInChi Key: KFSKTWYDIHJITF-UHFFFAOYSA-NInChi Code: InChI=1S/C22H23ClFN5O/c1-22(2)21-27-19(14-3-7-16(24)8-4-14)20(26-17-9-5-15(23)6-10-17)28(21)11-12-29(22)18(30)13-25/h3-10,26H,11-13,25H2,1-2H3SMILES Code: CC1(C)C2=NC(C3=CC=C(F)C=C3)=C(NC4=CC=C(Cl)C=C4)N2CCN1C(CN)=O
structimg |

DMSO : ~100 mg/mL (~233.70 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.86 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.86 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (4.86 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。