ADINACO Research Group, Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Biomolecules. 2022 Jun 17;12(6):844. doi: 10.3390/biom12060844.
Tuberculosis (TB) is a widespread infectious disease caused by . The increasing incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has created a need for new antiTB agents with new chemical scaffolds to combat the disease. Thus, the key question is: how to search for new antiTB and where to look for them? One of the possibilities is to search among natural products (NPs). In order to search for new antiTB drugs, the detailed phytochemical study of the whole plant was performed isolating wide spectrum of isoquinoline alkaloids (IAs). The chemical structures of the isolated alkaloids were determined by a combination of MS, HRMS, 1D, and 2D NMR techniques, and by comparison with literature data. Alkaloids were screened against H37Ra and four other mycobacterial strains (, , , and ). Alkaloids and showed moderate antimycobacterial activity against all tested strains (MICs 15.625-31.25 µg/mL). Furthermore, ten semisynthetic berberine (-) derivatives were developed and tested for antimycobacterial activity. In general, the derivatization of berberine was connected with a significant increase in antimycobacterial activity against all tested strains (MICs 0.39-7.81 μg/mL). Two derivatives (, ) were identified as compounds with micromolar MICs against H37Ra (MIC 2.96 and 2.78 µM). All compounds were also evaluated for their in vitro hepatotoxicity on a hepatocellular carcinoma cell line (HepG2), exerting lower cytotoxicity profile than their MIC values, thereby potentially reaching an effective concentration without revealing toxic side effects.
结核病（TB）是一种由 引起的广泛传染病。耐多药（MDR）和广泛耐药（XDR）菌株的发病率不断上升，需要新的具有新化学结构的抗结核药物来对抗这种疾病。因此，关键问题是：如何寻找新的抗结核药物，以及从哪里寻找它们？一种可能性是在天然产物（NPs）中寻找。为了寻找新的抗结核药物，对整株植物进行了详细的植物化学研究，分离出了广泛的异喹啉生物碱（IAs）。通过 MS、HRMS、1D 和 2D NMR 技术的组合以及与文献数据的比较，确定了分离出的生物碱的化学结构。对 H37Ra 和其他四种分枝杆菌菌株（ 、 、 、 ）进行了生物碱筛选。生物碱 和 对所有测试菌株均显示出中等的抗分枝杆菌活性（MICs 15.625-31.25 μg/mL）。此外，还开发并测试了十种半合成小檗碱（-）衍生物的抗分枝杆菌活性。总的来说，小檗碱的衍生化与对所有测试菌株的抗分枝杆菌活性显著增加有关（MICs 0.39-7.81 μg/mL）。两种衍生物（ 、 ）被鉴定为对 H37Ra 具有微摩尔 MIC 的化合物（MIC 2.96 和 2.78 μM）。所有化合物还在肝癌细胞系（HepG2）上进行了体外肝毒性评估，其细胞毒性谱低于其 MIC 值，从而有可能在不产生毒副作用的情况下达到有效浓度。
