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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Shah, Khushbu¹  Queener, Sherry²  Cody, Vivian³  Pace, Jim³  Gangjee, Aleem¹ 

[1] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA

[2] Indiana Univ Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA

[3] Hauptman Woodward Med Res Inst, 700 Ellicott St, Buffalo, NY 14203 USA

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

DOI  :  10.1016/j.bmcl.2019.06.004

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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