Structure of Pyrimethamine
CAS No.: 58-14-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Pyrimethamine inhibits multidrug and toxin extrusion (MATE) transporter potently, it also inhibits dihydrofolate reductase (DHFR), used for protozoal infections and interferes with tetrahydrofolic acid synthesis from folic acid. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways.
Synonyms: Pirimecidan; Pirimetamin; NSC 3061
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Identification of efflux substrates using a riboswitch-based reporter in Pseudomonas aeruginosa
Verónica Urdaneta-Páez ; Randy Hamchand ; Karen Anthony ; Jason Crawford ; Alan G. Sutherland ; Barbara I. Kazmierczak
Abstract: Pseudomonas aeruginosa is intrinsically resistant to many classes of antibiotics, reflecting the restrictive nature of its outer membrane and the action of its numerous efflux systems. However, the dynamics of compound uptake, retention, and efflux in this bacterium remain incompletely understood. Here, we exploited the sensor capabilities of a Z-nucleotide-sensing riboswitch to create an experimental system able to identify physicochemical and structural properties of compounds that permeate the bacterial cell, avoid efflux, and perturb the folate cycle or de novo purine synthesis. In the first step, a collection of structurally diverse compounds enriched in antifolate drugs was screened for ZTP (5-aminoimidazole-4-carboxamide riboside 5′-triphosphate) riboswitch reporter activity in efflux-deficient P. aeruginosa, allowing us to identify compounds that entered the cell and disrupted the folate pathway. These initial hits were then rescreened using isogenic efflux-proficient bacteria, allowing us to separate efflux substrates from efflux avoiders. We confirmed this categorization by measuring intracellular levels of select compounds in the efflux-deficient and -proficient strain using high-resolution liquid chromatography-mass spectrometry (LC-MS). This simple yet powerful method, optimized for high-throughput screening, enables the discovery of numerous permeable compounds that avoid efflux and paves the way for further refinement of the physicochemical and structural rules governing efflux in this multidrug-resistant Gram-negative pathogen. IMPORTANCE: Treatment of Pseudomonas aeruginosa infections has become increasingly challenging. The development of novel antibiotics against this multidrug-resistant bacterium is a priority, but many drug candidates never achieve effective concentrations in the bacterial cell due to its highly restrictive outer membrane and the action of multiple efflux pumps. Here, we develop a robust and simple reporter system in P. aeruginosa to screen chemical libraries and identify compounds that either enter the cell and remain inside or enter the cell and are exported by efflux systems. This approach enables the development of rules of compound uptake and retention in P. aeruginosa that will lead to more rational design of novel antibiotics.
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Keywords: Pseudomonas aeruginosa ; antimicrobial resistance ; drug efflux
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| CAS No. : | 58-14-0 |
| Formula : | C12H13ClN4 |
| M.W : | 248.71 |
| SMILES Code : | NC1=NC(CC)=C(C2=CC=C(Cl)C=C2)C(N)=N1 |
| Synonyms : |
Pirimecidan; Pirimetamin; NSC 3061
|
| MDL No. : | MFCD00057350 |
| InChI Key : | WKSAUQYGYAYLPV-UHFFFAOYSA-N |
| Pubchem ID : | 4993 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H302-H315-H319-H335-H351-H361 |
| Precautionary Statements: | P261-P305+P351+P338 |
| Target |
|
In Vitro:
| Concentration | Treated Time | Description | References |
| human foreskin fibroblast (HFF) | 2 μM | used for selecting stable transfected parasite clones | PLoS Genet. 2015 Aug 20;11(8):e1005434. |
In Vivo:
| Administration | Dosage | Frequency | Description | References |
| Mice | Malaria infection model | Drinking water | 0.07 mg/ml | Administered continuously starting from day 1 post-infection | Used for selecting genetically transformed malaria parasites, inhibiting parasite growth | mBio. 2019 Jun 4;10(3):e01106-19 |
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| NCT00948896 | - | Completed | - | - | |
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| NCT01707199 | Uncomplicated P. Falciparum Ma... More >>laria Less << | Not Applicable | Unknown | December 2013 | Afghanistan ... More >> Narang, Asadabad, Watapoor district health centres Recruiting Kunar, Afghanistan Contact: Ghulam Rahim Awab, MD awabgr@yahoo.com Principal Investigator: Ghulam Rahim Awab, MD Less << |
| NCT00125489 | Malaria Plasm... More >>odium Falciparum Malaria Less << | Phase 4 | Completed | - | Malawi ... More >> Blantyre Malaria Project Blantyre, Malawi Less << |
| NCT00000666 | Toxoplasmosis, Cerebral|HIV In... More >>fections Less << | COMPLETED | 1992-03-01 | Community Consortium of San Fr... More >>ancisco, San Francisco, California, 94110, United States|Denver CPCRA / Denver Public Hlth, Denver, Colorado, 802044507, United States|Hill Health Corp, New Haven, Connecticut, 06519, United States|Wilmington Hosp / Med Ctr of Delaware, Wilmington, Delaware, 19899, United States|AIDS Research Consortium of Atlanta, Atlanta, Georgia, 30308, United States|AIDS Research Alliance - Chicago, Chicago, Illinois, 60657, United States|Louisiana Comm AIDS Rsch Prog / Tulane Univ Med, New Orleans, Louisiana, 70112, United States|Comprehensive AIDS Alliance of Detroit, Detroit, Michigan, 48201, United States|Henry Ford Hosp, Detroit, Michigan, 48202, United States|North Jersey Community Research Initiative, Newark, New Jersey, 071032842, United States|Bronx Lebanon Hosp Ctr, Bronx, New York, 10456, United States|Addiction Research and Treatment Corp, Brooklyn, New York, 11201, United States|Clinical Directors Network of Region II, New York, New York, 10011, United States|Harlem AIDS Treatment Group / Harlem Hosp Ctr, New York, New York, 10037, United States|Portland Veterans Adm Med Ctr / Rsch & Education Grp, Portland, Oregon, 972109951, United States|Richmond AIDS Consortium, Richmond, Virginia, 23298, United States Less << | |
| NCT00167739 | Malaria | Phase 4 | Completed | - | Gabon ... More >> Medical Research Unit, Lambaréné Lambaréné, Moyen Ogooué, Gabon, B.P. 118 Less << |
| NCT01136850 | Malaria in Pregnancy ... More >> Sexually Transmitted Infections Anaemia Less << | Phase 3 | Completed | - | Papua New Guinea ... More >> Papua New Guinea Institute of Medical Research Madang, Madang Province, Papua New Guinea Less << |
| NCT00131235 | Malaria Sexua... More >>lly Transmitted Diseases Preterm Birth Pregnancy Less << | Phase 3 | Completed | - | Malawi ... More >> College of Medicine, University of Malawi Mangochi, Mangochi District, Malawi Less << |
| NCT00065390 | Autoimmune Disease|Lymphatic D... More >>isease|Lymphoproliferative Disorder Less << | PHASE1 | COMPLETED | 2025-06-05 | National Institute of Allergy ... More >>and Infectious Diseases (NIAID), Bethesda, Maryland, 20892, United States Less << |
| NCT02524444 | Malaria in Pregnant HIV + Pati... More >>ents Less << | Phase 1 | Completed | - | Nigeria ... More >> University College Hospital Ibadan, OYO State, Nigeria, 200001 Less << |
| NCT03083847 | Malaria | Phase 1 | Recruiting | June 30, 2019 | United States, Maryland ... More >> National Institutes of Health Clinical Center Recruiting Bethesda, Maryland, United States, 20892 Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov Less << |
| NCT00453856 | Malaria | Phase 4 | Terminated(The study was termi... More >>nated because of Early Treatment Failure in child.The justification for this decision are concerns about safety of children.) Less << | - | Gabon ... More >> Medical Research Unit of the Albert Schweitzer Hospital Lambaréné, Moyen Ogooué, Gabon, B.P. 118 Less << |
| NCT00120809 | Malaria | Phase 3 | Completed | - | Gambia ... More >> Medical Research Council Laboratories Banjul, Gambia, PO Box 273 Less << |
| NCT02527005 | Malaria Pregn... More >>ant HIV Less << | Phase 1 | Completed | - | Nigeria ... More >> University College Hospital, Ibadan, Oyo, Nigeria, 200001 Less << |
| NCT01054651 | Schistosoma Mansoni | Phase 3 | Completed | - | Kenya ... More >> KEMRI Centre for Global Health Research Kisumu, Kenya Less << |
| NCT01115439 | - | Completed | - | Afghanistan ... More >> Provincial Malaria Control Centers (MRC) Maimana, Faryab, Afghanistan Provincial Malaria Control Centers (MRC) Asadabad, Kunar, Afghanistan Provincial Malaria Control Centers (MRC) Jalalabad, Nangarhar, Afghanistan Provincial Malaria Control Centers (MRC) Taloqan, Afghanistan Less << | |
| NCT00399074 | Sickle Cell Anemia ... More >> Malaria Less << | Phase 3 | Completed | - | Uganda ... More >> Mulago Hospital Kampala, Central, Uganda, 256 Less << |
| NCT00623155 | Malaria | Not Applicable | Completed | - | Mali ... More >> Malaria Research and Training Center, Faculty of Medicine Pharmacy and Dentistry, University of Bamako Bamako, Mali Less << |
| NCT00380146 | Malaria | Not Applicable | Completed | - | Mozambique ... More >> Ndlavela Health Centre Ndlavela, Maputo, Mozambique Less << |
| NCT00331708 | Malaria | Not Applicable | Terminated(Lack of suitable pa... More >>rticipants) Less << | - | Mozambique ... More >> Ndlavela Health Centre Ndlavela, Maputo, Mozambique Less << |
| NCT01184911 | Intermittent Preventive Treatm... More >>ent Placental Malaria Less << | Phase 4 | Withdrawn(Research plan change... More >>d; no longer conducting clinical trial.) Less << | September 2011 | Uganda ... More >> Infectious Disease Research Center Tororo, Uganda Less << |
| NCT00679744 | G(M2) Ganglioside|Tay-Sachs Di... More >>sease Ganglioside|Sandhoff Disease Ganglioside Less << | PHASE1 | WITHDRAWN | - | New York University, School of... More >> Medicine, Department of Neurology, New York, New York, 10016, United States|University Hospitals of Cleveland, Cleveland, Ohio, 44106, United States|Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada Less << |
| NCT01328990 | Malaria | Phase 1 Phase 2 | Completed | - | Senegal ... More >> Universite Chiekh Anta Diop Dakar, Senegal Less << |
| NCT01083667 | Familial Amyotrophic Lateral S... More >>clerosis Less << | PHASE1|PHASE2 | COMPLETED | 2025-05-16 | Weill Cornell Medical Center/N... More >>ew York Presbyterian Hospital, New York, New York, 10021, United States|Methodist Neurological Institute, Houston, Texas, 77030, United States|Universit?ts- und Rehabilitationskliniken Ulm, Ulm, Germany|Milano Neurological Institute, Milan, Italy|Umea University, Umea, Sweden Less << |
| NCT01189448 | Congenital Toxoplasmosis | Phase 3 | Completed | - | France ... More >> Hôpital Louis Mourier Colombes, Hauts-de-Saine, France, 92700 Less << |
| NCT00951106 | Malaria, Vivax ... More >> Malaria, Falciparum Less << | Not Applicable | Completed | - | Peru ... More >> Naval Medical Research Center Detachment Lima, Peru Less << |
| NCT01083667 | Familial Amyotrophic Lateral S... More >>clerosis Less << | PHASE1|PHASE2 | COMPLETED | 2025-05-16 | Weill Cornell Medical Center/N... More >>ew York Presbyterian Hospital, New York, New York, 10021, United States|Methodist Neurological Institute, Houston, Texas, 77030, United States|Universit?ts- und Rehabilitationskliniken Ulm, Ulm, Germany|Milano Neurological Institute, Milan, Italy|Umea University, Umea, Sweden Less << |
| NCT01066663 | Chronic Lymphocytic Leukemia ... More >> Small Lymphocytic Leukemia Less << | Phase 1 Phase 2 | Recruiting | February 2022 | United States, Massachusetts ... More >> Beth Israel Deaconess Medical Center Recruiting Boston, Massachusetts, United States, 02115 Principal Investigator: Robin Joyce, MD Dana-Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02115 Principal Investigator: Jennifer Brown, MD, PhD Less << |
| NCT03258762 | Toxoplasmosis | Phase 1 | Completed | - | Australia, Victoria ... More >> GSK Investigational Site Melbourne, Victoria, Australia, 3004 Less << |
| NCT01973933 | Healthy | Phase 1 | Completed | - | Korea, Republic of ... More >> Seoul National University Bundang Hospital Seoul, Korea, Republic of Less << |
| NCT01120145 | - | Completed | - | Malawi ... More >> Machinga District Hospital Liwonde, Machinga District, Malawi Less << | |
| NCT03599596 | Malaria | Phase 1 | Not yet recruiting | February 1, 2019 | - |
| NCT03057990 | Myelodysplastic Syndromes | PHASE1 | WITHDRAWN | 2021-06-29 | Montefiore Medical Center, Bro... More >>nx, New York, 10467, United States Less << |
| NCT01102686 | Gangliosidoses, GM2 ... More >> Sandhoff Disease Tay-Sachs Disease Less << | Phase 1 Phase 2 | Completed | - | Canada, Ontario ... More >> The Hospital for Sick Children Toronto, Ontario, Canada, M5G 1X8 Less << |
| NCT00206739 | Malaria Anemi... More >>a Less << | Phase 4 | Completed | - | Ghana ... More >> Kumasi Centre for Collaborative Research in Tropical Medicine Kumasi, Ashanti Region, Ghana Less << |
| NCT05678348 | Head and Neck Cancer|Cancer of... More >> the Head and Neck Less << | EARLY_PHASE1 | RECRUITING | 2026-04-15 | Washington University School o... More >>f Medicine, Saint Louis, Missouri, 63110, United States Less << |
| Bio Calculators | ||||
| Preparing Stock Solutions | ![]() |
1mg | 5mg | 10mg |
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1 mM 5 mM 10 mM |
4.02mL 0.80mL 0.40mL |
20.10mL 4.02mL 2.01mL |
40.21mL 8.04mL 4.02mL |
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