Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection
DOI
10.1016/j.bmcl.2019.06.004
Document Type
Journal Article
Publication Date
8-1-2019
Publication Title
Bioorganic and Medicinal Chemistry Letters
Volume
29
Issue
15
First Page
1874
Last Page
1880
ISSN
0960894X
Keywords
DHFR, PCP, Pneumocystis jirovecii, Pyrido[3, 2-d]pyrimidines
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.
Open Access
Green Accepted
Preprint
Repository Citation
Shah, K., Queener, S., Cody, V., Pace, J., & Gangjee, A. (2019). Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection. Bioorganic and Medicinal Chemistry Letters, 29 (15), 1874-1880. https://doi.org/10.1016/j.bmcl.2019.06.004