Referencia número: HY-187550

BRD7929

BRD7929 is an orally active phenylalanyl-tRNA synthetase (PheRS) inhibitor and parasiticide, with an IC₅₀ value of 0.023 μM against Plasmodium falciparum PheRS. BRD7929 inhibits the aminoacylation activity of the target enzyme, blocking protein synthesis, DNA replication and parasite nuclear division. BRD7929 clears the asexual blood stage, liver stage and mature gametocyte stage of malaria parasite species, and prevents parasite transmission to mosquitoes. BRD7929 shows moderate cytotoxicity against mammalian cells and inhibits hERG ion channels. BRD7929 achieves cure of malaria in animal models. BRD7929 can be used in research related to cryptosporidiosis and malaria.

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No. CAS: 1771650-41-9
Fòrmula: C₃₃H₃₈N₄O₂
Peso molecular:522.68

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BRD7929 Chemical Structure

No. CAS: 1771650-41-9

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Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Actividad biológica
- Descripciòn
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
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Referencias
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Actividad biológica

Descripciòn

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Cellular Effect

Cell Line	Type	Value	Description	References
HCT-8	EC50	0.033 μM	Inhibition of Cryptosporidium parvum growth in human ileocecal adenocarcinoma HCT-8 cells assessed via imaging after 24 h incubation. Inhibition of Cryptosporidium parvum growth in human ileocecal adenocarcinoma HCT-8 cells assessed via imaging after 24 h incubation.	32127445
HCT-8	EC90	0.225 μM	Inhibition of Cryptosporidium parvum growth in human ileocecal adenocarcinoma HCT-8 cells assessed via imaging after 24 h incubation. Inhibition of Cryptosporidium parvum growth in human ileocecal adenocarcinoma HCT-8 cells assessed via imaging after 24 h incubation.	32127445
HepG2	CC₅₀	9 μM	Cytotoxicity against human HepG2 liver cancer cells assessed as reduction in cell viability. Cytotoxicity against human HepG2 liver cancer cells assessed as reduction in cell viability.	nature19804
A549	CC₅₀	6 μM	Cytotoxicity against human A549 lung cancer cells assessed as reduction in cell viability. Cytotoxicity against human A549 lung cancer cells assessed as reduction in cell viability.	nature19804
HEK293	CC₅₀	10 μM	Cytotoxicity against human HEK293 embryonic kidney cells assessed as reduction in cell viability. Cytotoxicity against human HEK293 embryonic kidney cells assessed as reduction in cell viability.	nature19804
HepG2	EC50	0.162 μM	Inhibition of liver-stage development of Plasmodium berghei strain ANKA in human HepG2 cells. Inhibition of liver-stage development of Plasmodium berghei strain ANKA in human HepG2 cells.	nature19804
HCT-8	EC50	9 nM	Inhibition of Cryptosporidium parvum (Iowa isolate, Bunch Grass Farm) growth in human ileocecal adenocarcinoma HCT-8 cells with 1% fetal bovine serum via cell-based growth inhibition assay. Inhibition of Cryptosporidium parvum (Iowa isolate, Bunch Grass Farm) growth in human ileocecal adenocarcinoma HCT-8 cells with 1% fetal bovine serum via cell-based growth inhibition assay.	32998973
HCT-8	EC50	73 nM	Inhibition of Cryptosporidium parvum (Iowa isolate, Bunch Grass Farm) growth in human ileocecal adenocarcinoma HCT-8 cells with 10% fetal bovine serum via cell-based growth inhibition assay. Inhibition of Cryptosporidium parvum (Iowa isolate, Bunch Grass Farm) growth in human ileocecal adenocarcinoma HCT-8 cells with 10% fetal bovine serum via cell-based growth inhibition assay.	32998973
HCT-8	EC50	8 nM	Inhibition of Cryptosporidium parvum (Iowa isolate, Sterling) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay. Inhibition of Cryptosporidium parvum (Iowa isolate, Sterling) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay.	32998973
HCT-8	EC50	23 nM	Inhibition of Cryptosporidium parvum (field isolate, WSU) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay. Inhibition of Cryptosporidium parvum (field isolate, WSU) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay.	32998973
HCT-8	EC50	10 nM	Inhibition of Cryptosporidium hominis (TU 502) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay. Inhibition of Cryptosporidium hominis (TU 502) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay.	32998973
HepG2	CC₅₀	5000 nM	Cytotoxicity against human HepG2 cells via cytotoxicity assay. Cytotoxicity against human HepG2 cells via cytotoxicity assay.	32998973
HEK-293T	CC₅₀	5000 nM	Cytotoxicity against human HEK293T cells via cytotoxicity assay. Cytotoxicity against human HEK293T cells via cytotoxicity assay.	32998973
HCT-8	CC₅₀	9000 nM	Cytotoxicity against human ileocecal adenocarcinoma HCT-8 cells via cytotoxicity assay. Cytotoxicity against human ileocecal adenocarcinoma HCT-8 cells via cytotoxicity assay.	32998973
HCT-8	EC90	0.15 μM	Inhibition of Cryptosporidium parvum asexual growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based asexual growth inhibition assay incubated for 48 h. Inhibition of Cryptosporidium parvum asexual growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based asexual growth inhibition assay incubated for 48 h.	32998973
HCT-8	EC90	0.23 μM	Inhibition of Cryptosporidium parvum asexual-to-sexual conversion in human ileocecal adenocarcinoma HCT-8 cells via cell-based asexual-to-sexual conversion inhibition assay incubated for 24 h (from 48 to 72 h post-infection). Inhibition of Cryptosporidium parvum asexual-to-sexual conversion in human ileocecal adenocarcinoma HCT-8 cells via cell-based asexual-to-sexual conversion inhibition assay incubated for 24 h (from 48 to 72 h post-infection).	32998973
HCT-8	EC50	29 nM	Inhibition of Cryptosporidium parvum (parent Bunchgrass strain) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay incubated for 48 h, measured via whole-well luciferase activity. Inhibition of Cryptosporidium parvum (parent Bunchgrass strain) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay incubated for 48 h, measured via whole-well luciferase activity.	32998973
HCT-8	EC50	47 nM	Inhibition of Cryptosporidium parvum (wild-type transgenic L482 strain) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay incubated for 48 h, measured via whole-well luciferase activity. Inhibition of Cryptosporidium parvum (wild-type transgenic L482 strain) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay incubated for 48 h, measured via whole-well luciferase activity.	32998973
HCT-8	EC50	1059 nM	Inhibition of Cryptosporidium parvum (PheRS L482V mutant transgenic strain) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay incubated for 48 h, measured via whole-well luciferase activity. Inhibition of Cryptosporidium parvum (PheRS L482V mutant transgenic strain) growth in human ileocecal adenocarcinoma HCT-8 cells via cell-based growth inhibition assay incubated for 48 h, measured via whole-well luciferase activity.	32998973

In Vitro

BRD7929 (24 h) potently inhibits the proliferation of Cryptosporidium parvum in HCT-8 cells, with an EC₅₀ of 0.033 μM and an EC₉₀ of 0.225 μM^[1].
BRD7929 (48 h) inhibits the growth of Cryptosporidium parvum in mouse intestinal ALI cultures, with an EC₅₀ of 0.113 μM and an EC₉₀ of 0.847 μM^[1].
BRD7929 (0.225 μM) targets multiple stages of the Cryptosporidium parvum life cycle in HCT-8 cells, with the strongest inhibitory activity observed during the early stage of asexual development (0-20 hpi)^[1].
BRD7929 (0.225 μM) blocks DNA replication and arrests Cryptosporidium parvum at the trophozoite stage of asexual development within HCT-8 cells^[1].
BRD7929 potently inhibits the asexual blood-stage growth of Plasmodium falciparum strains Dd2 and 3D7HLH/BRD, with EC₅₀ values of 0.005 μM and 0.009 μM, respectively^[2].
BRD7929 inhibits the viability of late-stage (Stage IV-V) gametocytes of Plasmodium falciparum strain 3D7, with an EC₅₀ of 0.16 μM^[2].
BRD7929 inhibits liver-stage development of the NF54 strain of Plasmodium falciparum in primary human hepatocytes, with an EC₅₀ of 0.340 μM^[2].
BRD7929 inhibits the liver-stage development of Plasmodium berghei ANKA strain in HepG2 cells, with an EC₅₀ of 0.162 μM^[2].
BRD7929 inhibits the small and large hepatic forms of Plasmodium cynomolgi strain M in primary rhesus monkey hepatocytes, with EC₅₀ values of 0.933 μM and 1.04 μM, respectively^[2].
BRD7929 potently inhibits the aminoacylation activity of purified recombinant Plasmodium falciparum cytoplasmic phenylalanyl-tRNA synthetase, with an IC₅₀ of 0.023 μM^[2].
BRD7929 potently inhibits the growth of Cryptosporidium parvum (Iowa isolate, Bunch Grass Farm) in HCT-8 cells containing 1% and 10% FBS, with EC₅₀ values of 9 nM and 73 nM, respectively^[3].
BRD7929 potently inhibits the growth of Cryptosporidium parvum (Iowa isolate, Sterling, field isolate, WSU) in HCT-8 cells, with EC₅₀ values of 8 nM and 23 nM, respectively^[3].
BRD7929 potently inhibits the growth of Cryptosporidium hominis (TU 502) in HCT-8 cells, with an EC₅₀ of 10 nM^[3].
BRD7929 (incubated for 24 h) inhibits the transition of Cryptosporidium parvum from asexual reproduction to sexual reproduction in HCT-8 cells, with an EC₉₀ of 0.23 μM^[3].
BRD7929 reduces the viability of human HepG2, A549 and HEK293 cells, with CC₅₀ values of 9, 6 and 10 μM^[2].
BRD7929 inhibits hERG channel activity with an IC₅₀ of 2.1 μM^[2].
BRD7929 exhibits cytotoxicity against human HepG2, HEK293T and HCT-8 cells, with CC₅₀ values of 5000 nM, 5000 nM and 9000 nM, respectively^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Parmacokinetics

Species	Dose	Route	C_max	T_max	AUC_0-24	Bioavailability	T_1/2	AUC_0-t	AUC_0-inf	MRT_0-inf	V_ss	CL
Mice^[2]	2.5 mg/kg	i.v.	/	/	/	/	32 h	9 μM·h	11.2 μM·h	45 h	19 L/kg	7.1 mL/min/kg
Mice^[2]	2.5 mg/kg	i.v.	/	/	3.5 μM·h	/	/	/	/	40.5 h	24 L/kg	9.9 mL/min/kg
Mice^[2]	10 mg/kg	p.o.	0.54 μM	8 h	11 μM·h	79.5 %	/	/	/	/	/	/

In Vivo

BRD7929 (25-50 mg/kg; p.o.; single administration) achieves sterile cure of Plasmodium berghei malaria in CD-1 mice^[2].
BRD7929 (12.5-50 mg/kg; p.o.; single administration) achieves sterile cure of P. falciparum malaria in huRBC NSG mice at a single oral dose as low as 12.5 mg/kg^[2].
BRD7929 (10 mg/kg; p.o.; single dose), administered 1 day after sporozoite inoculation, clears Plasmodium falciparum liver-stage parasites in huHep FRG mice^[2].
BRD7929 (5-20 mg/kg; p.o.; single administration) completely blocks the transmission of P. berghei to mosquitoes when administered to mice 2 days prior to mosquito bites^[2].
BRD7929 (5-50 mg/kg; p.o.; daily; 4-7 days) potently reduces the oocyst excretion of C. parvum in immunodeficient NSG mice: when administered at 14 days post-infection, 40 mg/kg once daily for 4 consecutive days reduces oocyst excretion by 99.8%, while 10 mg/kg once daily for 4 consecutive days prevents infection recurrence^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

CD-1 (female, 6-7-week-old, 20-24 g, malaria model with intravenous inoculation of ~1×10⁵ Plasmodium berghei ANKA GFP-luc blood-stage parasites)^[2]
Dosage:

25 mg/kg; 50 mg/kg
Administration:

p.o.; single dose
Result:

Rendered all treated mice parasite-free and maintained this state for the 30-day end-point.
Confirmed a sterile cure, with no parasites detected in naive mice inoculated with blood from treated mice over an additional 30 days.

Animal Model:

NOD/SCID Il2rγ^-/^- (huRBC NSG) (female, 4-5-week-old, 19-21 g, malaria model with intravenous inoculation of ~1×10⁷ Plasmodium falciparum 3D7HLH/BRD blood-stage parasites)^[2]
Dosage:

12.5 mg/kg; 25 mg/kg; 50 mg/kg
Administration:

p.o.; single dose
Result:

Rendered all treated mice parasite-free and maintained this state for the 30-day end-point.
Confirmed a sterile cure, with no parasites detected in in vitro cultures of blood from treated mice over an additional 30 days.

Animal Model:

C57BL/6 FRG knockout (huHep FRG) (female, 5.5-6-month-old, 19-21 g, human hepatocyte repopulated >70%, malaria model with intravenous inoculation of ~1×10⁵ Plasmodium falciparum NF54HT-GFP-luc sporozoites)^[2]
Dosage:

10 mg/kg
Administration:

p.o.; single dose
Result:

Prevented increases in liver-stage bioluminescent signals in treated mice.
Detected no blood-stage parasite transcripts via qRT-PCR.
Confirmed no viable parasites in in vitro cultures of blood from treated mice over an additional 30 days.

Animal Model:

CD-1 (female, 6-7-week-old, 21-24 g, malaria model with infection of Plasmodium berghei ANKA GFP-luc for 96 hours before treatment)^[2]
Dosage:

5 mg/kg; 20 mg/kg
Administration:

p.o.; single dose
Result:

Detected no oocysts in mosquito midguts fed on mice treated with 5 mg/kg or 20 mg/kg.

Animal Model:

Nonobese Diabetic Severe Combined Immunodeficient Gamma (NSG) (3- to 4-week-old, freshly weaned, established intestinal infection induced by oral gavage of Cryptosporidium parvum Iowa isolate oocysts)^[3]
Dosage:

50 mg/kg; 40 mg/kg; 20 mg/kg; 10 mg/kg; 5 mg/kg; 10 mg/kg (7-day regimen)
Administration:

p.o.; daily; 4 days; p.o.; daily; 7 days
Result:

Caused an almost 3-log reduction in oocysts per milligram of stool.
Reduced oocysts per milligram of feces by 99.8%.
Prevented infection relapse over 14 days of monitoring when initiated 14 days post-infection.

Chemical Information

No. CAS 1771650-41-9
Peso molecular 522.68
Fòrmula C₃₃H₃₈N₄O₂
SMILES

CN(C)C[C@@H]1[C@H](C2=CC=C(C=C2)C#CC3=CC=CC=C3)[C@@]4([H])N1CCCCN(C4)C(NC5=CC=C(C=C5)OC)=O
Envío

Room temperature in continental US; may vary elsewhere.
Almacenamiento

Please store the product under the recommended conditions in the Certificate of Analysis.

Pureza y Documentación

Instrucciones de manejo (2659 KB)

Referencias

[1]. Funkhouser-Jones LJ, et al. Defining Stage-Specific Activity of Potent New Inhibitors of Cryptosporidium parvum Growth . mBio. 2020 Mar 03;11(2):e00052-20.

[2]. Kato, N., et al. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 538, 344–349 (2016).

[3]. Vinayak S, et al. Bicyclic azetidines kill the diarrheal pathogen Cryptosporidium in mice by inhibiting parasite phenylalanyl-tRNA synthetase. Sci Transl Med. 2020 Sep 30;12(563):eaba8412. [Content Brief]

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1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

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BRD7929

Ver todos los productos específicos de isoformas Parasite