The direct inhibition of bacterial β-glucuronidase (βG) activity is expected to reduce the reactivation of glucuronide-conjugated drugs in the intestine, thereby reducing drug toxicity. In this study, we report on the effects of pyrazolo[4,3-c]quinolines acting as a new class of bacterial βG-specific inhibitors in a pH-dependent manner. Refinement of this chemotype for establishing structure–activity relationship resulted in the identification of potential leads. Notably, the oral administration of 3-amino-4-(4-fluorophenylamino)-1H-pyrazolo[4,3-c]quinoline (42) combined with chemotherapeutic CPT-11 treatment prevented CPT-11-induced serious diarrhea while maintaining the antitumor efficacy in tumor-bearing mice. Importantly, the inhibitory effects of 42 to E. coli βG was reduced as the pH decreased due to the various surface charges of the active pocket of the enzyme, which may make their combination more favorable at neutral pH. These results demonstrate novel insights into the potent bacterial βG-specific inhibitor that would allow this inhibitor to be used for the purpose of reducing drug toxicity.

中文翻译：

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吡唑并[4,3- c ]喹啉衍生物通过pH依赖性方式特异性抑制细菌β-葡萄糖醛酸酶，从而抑制化疗诱导的肠道毒性。

预期直接抑制细菌β-葡萄糖醛酸苷酶（βG）活性会减少肠道中与葡萄糖醛酸苷结合的药物的再激活，从而降低药物毒性。在这项研究中，我们报告了吡唑并[4,3- c ]喹啉以pH依赖性方式作为新型细菌βG特异性抑制剂的作用。为建立结构-活性关系而对这种化学型的改进导致了潜在潜在顾客的鉴定。值得注意的是，口服施用3-氨基-4-（4-氟苯基氨基）-1 H-吡唑并[4,3- c ]喹啉（42）结合CPT-11化疗可预防CPT-11-引起的严重腹泻，同时保持荷瘤小鼠的抗肿瘤功效。重要的是，由于酶活性口袋表面的各种表面电荷导致pH降低，42对大肠杆菌βG的抑制作用降低，这可能会使它们的组合在中性pH下更有利。这些结果证明了对有效的细菌βG特异性抑制剂的新颖见解，该抑制剂将使该抑制剂可用于降低药物毒性。