Yadav Sidhant, Vashisth Chanchal, Chaudhri Vishwas, Singh Karan, Raghav Neera, Pundeer Rashmi
Department of Chemistry, Indira Gandhi University, Rewari, Haryana 122502, India.
Department of Chemistry, Kurukshetra University, Kurukshetra 136119, Haryana, India.
Int J Biol Macromol. 2024 Nov;281(Pt 2):136290. doi: 10.1016/j.ijbiomac.2024.136290. Epub 2024 Oct 9.
Cysteine cathepsins play a crucial role in cancer, inflammation, and the regulation of degenerative processes such as apoptosis, making them significant targets in drug development. In this study, we designed, synthesized, and characterized sixteen novel bi-thiazole derivatives, confirmed by H NMR, C NMR, HRMS, and X-ray analysis, which demonstrated significant therapeutic potential as inhibitors of cathepsin B. The synthesized thiazoles showed % inhibition in the range of 59.11-77.32, out of which bis-methoxyphenyl derivative 8k showed the highest inhibition of 77.32 % with IC and k values of 1.04 nM and 0.52 nM, respectively. Methoxy-containing derivatives 8c, 8g, 8i, 8j, 8l, and 8o showed improved inhibition over methyl and chloro. In silico studies of the new bis-thiazole compounds at cathepsin B active sites supported the in vitro findings, indicating that the synthesized bis-thiazole esters are promising therapeutic candidates for conditions involving elevated cathepsin B levels.
半胱氨酸组织蛋白酶在癌症、炎症以及细胞凋亡等退行性过程的调节中起着至关重要的作用，因此成为药物开发的重要靶点。在这项研究中，我们设计、合成并表征了十六种新型双噻唑衍生物，通过 1H NMR、13C NMR、高分辨质谱和 X 射线分析确证了其结构，这些衍生物作为组织蛋白酶 B 的抑制剂具有显著的治疗潜力。合成的噻唑类化合物的抑制率在 59.11-77.32%之间，其中双甲氧基苯基衍生物 8k 的抑制率最高，达到 77.32%，IC50 和 k 值分别为 1.04 nM 和 0.52 nM。含有甲氧基的衍生物 8c、8g、8i、8j、8l 和 8o 的抑制作用优于甲基和氯。在组织蛋白酶 B 活性部位对新的双噻唑化合物进行的计算机研究支持了体外研究结果，表明合成的双噻唑酯是涉及组织蛋白酶 B 水平升高的疾病的有前途的治疗候选物。
