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Bioorg Med Chem Lett. 2019 Aug 1;29(15):1874-1880. doi: 10.1016/j.bmcl.2019.06.004. Epub 2019 Jun 4.

Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection.

Author information

1
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh PA 15282, United States.
2
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
3
Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, United States.
4
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh PA 15282, United States. Electronic address: gangjee@duq.edu.

Abstract

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.

KEYWORDS:

DHFR; PCP; Pneumocystis jirovecii; Pyrido[3,2-d]pyrimidines

PMID:
31176699
PMCID:
PMC6588427
[Available on 2020-08-01]
DOI:
10.1016/j.bmcl.2019.06.004

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