[CAS NO. 500-92-5] Proguanil
PRODUCTS SPECIFICATIONS [500-92-5]
DESCRIPTION [500-92-5]
Overview
| MDL | MFCD00866201 |
|---|---|
| Molecular Weight | 253.73 |
| Molecular Formula | C11H16ClN5 |
| SMILES | N=C(NC1=CC=C(Cl)C=C1)NC(NC(C)C)=N |
Summary
Proguanil, an antimalarial prodrug, is metabolized to the active metabolite Cycloguanil (HY-12784). Proguanil is a dihydrofolate reductase ( DHFR ) inhibitor [1] [2] .
In Vitro
Proguanil per se has only weak antimalarial activity
in vitro
(IC
50
=2.4-19 μM), and its effectiveness depends on the active metabolite Cycloguanil (IC
50
=0.5-2.5 nM). The Cycloguanil is a dihydrofolate reductase (DHFR) inhibitor. The combination of Atovaquone and Proguanil is synergistic
in vitro
. Both drugs also have activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites
[1]
.
Proguanil acts as a biguanide rather than as its metabolite Cycloguanil (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the Atovaquone effect. Proguanil-mediated enhancement is specific for Atovaquone, since the effects of other mitochondrial electron transport inhibitors, such as Myxothiazole and Antimycin, are not altered by inclusion of Proguanil
[2]
.
5-HT
3
receptor responses are reversibly inhibited by Proguanil, the metabolite 4-chlorophenyl-1-biguanide (CPB) and the active metabolite Cycloguanil (CG), with an IC
50
of 1.81, 1.48 and 4.36 μM, respectively
[3]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
Proguanil (p.o.; 2.9 mg/kg body weight; daily for 5 days and 6 weeks respectively) shows mild degenerative changes for five days, while shows severe degenerative changes for six weeks in wistar strain albino rats
[4]
.
Serum testosterone level is significantly decreased for proguanil treatment rats
[4]
.
Administration of Malarone (atovaquone and proguanil) to experimentally
B. gibsoni
infected two dogs in chronic stage and three dogs in acute stage results in decrease in parasitemia, and clinical improvements are observed
[5]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT00421473 | Radboud University Medical Center |
HIV Infections|Malaria
|
March 2007 | Phase 4 |
| NCT01319448 | London School of Hygiene and Tropical Medicine|Medical Research Council Unit, The Gambia|Wellcome Trust|University of Ilorin Teaching Hospital |
Malaria|Sickle Cell Crisis
|
September 2011 | Phase 1|Phase 2 |
| NCT03454048 | Radboud University Medical Center|The PATH Malaria Vaccine Initiative (MVI)|QIMR Berghofer Medical Research Institute |
Malaria,Falciparum|Gametocytes|Controlled Human Malaria Infection|Transmission
|
May 7, 2018 | Not Applicable |
| NCT04568772 | Seoul National University Hospital |
Gastroesophageal Reflux Disease
|
November 25, 2020 | Phase 1 |
| NCT03726593 | Armed Forces Research Institute of Medical Sciences, Thailand|National Center for Parasitology, Entomology, and Malaria Control (CNM)|Naval Medical Research Unit-2 (NAMRU-2) |
Plasmodium Falciparum Malaria (Drug Resistant)
|
October 4, 2018 | Phase 4 |
| NCT02054299 | University Medical Center Goettingen |
Drug Metabolism|Membrane Transport
|
April 2013 | Phase 1 |
| NCT03813108 | Radboud University Medical Center|The PATH Malaria Vaccine Initiative (MVI) |
Malaria,Falciparum|Controlled Human Malaria Infection|Immunization; Infection
|
April 1, 2019 | Not Applicable |
| NCT02564471 | State University of New York - Upstate Medical University|Walter Reed Army Institute of Research (WRAIR)|Kansas State University |
Rabies
|
November 11, 2016 | Phase 4 |
| NCT00984256 | U.S. Army Medical Research and Development Command |
Malaria
|
September 2009 | Phase 2 |
| NCT01456546 | University of Southern Denmark |
CYP2C19 Genotypes
|
October 2011 | Phase 1 |
| NCT03178643 | Duke University|National Heart, Lung, and Blood Institute (NHLBI) |
Malaria,Falciparum
|
January 23, 2018 | Phase 4 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
| Powder | -20°C | 3 years |
|---|---|---|
| 4°C | 2 years | |
| In solvent | -80°C | 6 months |
| -20°C | 1 month |
Solvent & Solubility
DMSO : ≥ 130 mg/mL ( 512.36 mM )
* "≥" means soluble, but saturation unknown.
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 3.9412 mL | 19.7060 mL | 39.4120 mL |
| 5 mM | 0.7882 mL | 3.9412 mL | 7.8824 mL |
| 10 mM | 0.3941 mL | 1.9706 mL | 3.9412 mL |
References
- [1] Pudney M, et al. Atovaquone and proguanil hydrochloride: a review of nonclinical studies. J Travel Med. 1999 May;6 Suppl 1:S8-12.
- [2] Srivastava IK, et al. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999 Jun;43(6):1334-9.
- [3] Lochner M, et al. The antimalarial drug proguanil is an antagonist at 5-HT3 receptors. J Pharmacol Exp Ther. 2014 Dec;351(3):674-84.
- [4] Stephen AO, et al. Prolonged administration of proguanil induces reproductive toxicity in male rats. J Toxicol Sci. 2011 Oct;36(5):587-99.
- [5] Iguchi A, et al. The in vitro interactions and in vivo efficacy of atovaquone and proguanil against Babesia gibsoni infection in dogs. Vet Parasitol. 2013 Nov 8;197(3-4):527-33.
Synonyms