Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection.
Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection.
复制标题
开发取代吡啶并[3,2-d]嘧啶作为肺孢子虫肺炎感染的有效和选择性二氢叶酸还原酶抑制剂。
DOI：
10.1016/j.bmcl.2019.06.004
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发表时间：
2019
影响因子：
2.7
通讯作者：
Gangjee,Aleem
中科院分区：
文献类型：
--
作者：
Shah,Khushbu;Queener,Sherry;Cody,Vivian;Pace,Jim;Gangjee,Aleem
由耶氏肺孢子虫 (pj) 引起的肺孢子虫肺炎 (PCP) 可能会给免疫系统低下的患者带来严重的健康后果。甲氧苄啶 (TMP) 与磺胺甲恶唑联合用作一线治疗，是一种选择性但效力中等的 pj 二氢叶酸还原酶 (pjDHFR) 抑制剂，而非临床 pjDHFR 抑制剂，例如吡曲昔和曲美曲沙，是有效但非选择性的 pjDHFR 抑制剂。为了满足用于 PCP 治疗的有效和选择性 pjDHFR 抑制剂的临床需求，开发了 14 种 6-取代吡啶并[3,2-d]嘧啶。 pjDHFR 和人 DHFR (hDHFR) 活性位点的氨基酸残基的比较揭示了显着的氨基酸差异，可利用这些差异在结构上设计有效的选择性 pjDHFR 抑制剂。分子建模和随后的化合物酶测定表明 15 是该系列中最好的化合物，其 IC50 为 80nM，抑制 pjDHFR 的选择性是 hDHFR 的 28 倍。化合物 15 作为进一步结构变化的主要类似物，以提供更有效和选择性的 pjDHFR 抑制剂。
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 revealed15as the best compound of the series with an IC50of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound15serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors.