Singh Manisha, Kidawi Saqib, Das Ujjalkumar S, Velpandian Thirumurthy, Singh Ramandeep, Rawat Diwan S
Department of Chemistry, University of Delhi, New Delhi, India.
Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, Faridabad, India.
J Biochem Mol Toxicol. 2021 Jun;35(6):1-10. doi: 10.1002/jbt.22754. Epub 2021 Mar 10.
Tuberculosis, an airborne infectious disease, results in a high morbidity and mortality rate. The continuous emergence of TB resistance strains including MDR (multidrug-resistant tuberculosis), XDR (extensive drug-resistant tuberculosis), and especially TDR (totally drug-resistant tuberculosis) is a major public health threat and has intensified the need to develop new antitubercular agents. A natural product, curcumin, possesses diverse biological activities but suffers due to a lack of water solubility and bioavailability. To overcome these limitations, a series of 17 water-soluble monocarbonyl curcuminoids was synthesized and evaluated for antimycobacterial activity. All compounds exhibited good to moderate anti-TB activity with MIC in the range of 3.12-25.0 µM, out of which 7c and 7p were found the most potent compounds with MIC in the range of 3.12-6.25 µM. Furthermore, these compounds were observed to be nonhaemolytic, nontoxic, and stable under both physiological as well as reducing conditions. In-vitro metabolic stability data of the representative compound 7p with the human liver microsome revealed that these compounds possess a moderate metabolism with a half-life of 1.2 h and an intrinsic clearance of 1.12 ml/h/mg.
结核病是一种空气传播的传染病，发病率和死亡率都很高。包括耐多药结核病（MDR）、广泛耐药结核病（XDR），尤其是完全耐药结核病（TDR）在内的结核耐药菌株的不断出现是一个重大的公共卫生威胁，加剧了开发新型抗结核药物的需求。天然产物姜黄素具有多种生物活性，但由于缺乏水溶性和生物利用度而存在缺陷。为克服这些局限性，合成了一系列17种水溶性单羰基姜黄素类似物，并对其抗分枝杆菌活性进行了评估。所有化合物均表现出良好至中等的抗结核活性，最低抑菌浓度（MIC）在3.12 - 25.0 μM范围内，其中7c和7p被发现是最有效的化合物，MIC在3.12 - 6.25 μM范围内。此外，观察到这些化合物在生理条件和还原条件下均无溶血、无毒且稳定。代表性化合物7p与人肝微粒体的体外代谢稳定性数据表明，这些化合物具有中等代谢水平，半衰期为1.2小时，内在清除率为1.12 ml/h/mg。
