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

Khushbu Shah, Sherry Queener, Vivian Cody, Jim Pace, Aleem Gangjee

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1874-1880
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number15
DOIs
StatePublished - Aug 1 2019

Fingerprint

Pneumocystis Infections
Folic Acid Antagonists
Pneumocystis Pneumonia
Pneumocystis carinii
Tetrahydrofolate Dehydrogenase
Trimetrexate
Amino Acids
Sulfamethoxazole
Trimethoprim
Molecular modeling
Enzyme Assays
Immunocompromised Host
Inhibitory Concentration 50
pyrido(3,2-d)pyrimidine
Assays
Catalytic Domain
Health
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection. / Shah, Khushbu; Queener, Sherry; Cody, Vivian; Pace, Jim; Gangjee, Aleem.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 15, 01.08.2019, p. 1874-1880.

Research output: Contribution to journalArticle

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