National Laboratory for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Tiantan Xili #1, Beijing 100050, PR China.
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China.
Bioorg Chem. 2021 Sep;114:105110. doi: 10.1016/j.bioorg.2021.105110. Epub 2021 Jun 21.
Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids in Mtb. Therefore, Pks13 is a promising drug target for tuberculosis treatment. We used a structure-guided approach to identify novel chemotype inhibitors of Pks13 and assessed them using a Pks13 enzymatic assay and surface plasmon resonance. The structure-activity relationships (SAR) results demonstrated that the substituents at the 2, 5, and 6 positions of the 4H-chromen-4-one scaffold are critical for maintaining the MIC. Compound 6e with 2-hydroxyphenyl at the 2 position of the 4H-chromen-4-one scaffold, exhibited potent activity against Mtb H37Rv (MIC = 0.45 μg/mL) and displayed good Pks13 affinity and inhibition (IC = 14.3 μM). This study described here could provide an avenue to explore a novel inhibitor class for Pks13 and aid the further development of antituberculosis drugs.
聚酮合酶 13（Pks13）是 Mtb 合成分枝菌酸的必需酶。因此，Pks13 是治疗结核病的有前途的药物靶点。我们使用基于结构的方法来鉴定 Pks13 的新型化学型抑制剂，并使用 Pks13 酶测定法和表面等离子体共振来评估它们。结构活性关系（SAR）结果表明，4H-色满-4-酮支架上 2、5 和 6 位的取代基对于维持 MIC 至关重要。具有 2-羟基苯基取代的 4H-色满-4-酮支架上的 6e 化合物对 Mtb H37Rv 表现出强大的活性（MIC = 0.45μg/mL），并且表现出良好的 Pks13 亲和力和抑制作用（IC = 14.3μM）。本研究为 Pks13 探索新型抑制剂类药物提供了途径，并有助于进一步开发抗结核药物。
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