Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection
| Autor: | Jim Pace, Vivian Cody, Sherry F. Queener, Khushbu Shah, Aleem Gangjee |
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| Rok vydání: | 2019 |
| Předmět: |
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Molecular Clinical Biochemistry Pharmaceutical Science Pharmacology Pneumocystis carinii Pneumocystis pneumonia 01 natural sciences Biochemistry Article Trimethoprim Structure-Activity Relationship Drug Discovery Dihydrofolate reductase medicine Humans Pneumocystis jirovecii Molecular Biology IC50 chemistry.chemical_classification biology Pneumocystis 010405 organic chemistry Organic Chemistry Active site medicine.disease biology.organism_classification 0104 chemical sciences Amino acid 010404 medicinal & biomolecular chemistry Pyrimidines Trimetrexate chemistry biology.protein Folic Acid Antagonists Molecular Medicine medicine.drug |
| Zdroj: | Bioorg Med Chem Lett |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2019.06.004 |
| Popis: | Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors. |
| Databáze: | OpenAIRE |
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