AUTHOR=Hou Haodong , Qu Bin , Su Chen , Hou Guihua , Gao Feng 

TITLE=Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.801580

DOI=10.3389/fphar.2021.801580

ISSN=1663-9812

ABSTRACT=<p>A series of 1,2,3-triazole tethered dihydroartemisinin-isatin hybrids 8a-c and 9a-k were designed and synthesized. Their antiproliferative activity against A549, doxorubicin-resistant A549 (A549/DOX) as well as cisplatin-resistant A549 (A549/DDP) lung cancer cell lines was also investigated in this study. All hybrids (half maximal inhibitory concentration/IC<sub>50</sub>: 7.54–73.8 <italic>μ</italic>M) were more potent than the parent drug dihydroartemisinin (IC<sub>50</sub>: 69.4–88.0 <italic>μ</italic>M) and also non-cytotoxic towards mouse embryonic fibroblast cells NIH/3T3 (IC<sub>50</sub>: &gt;100 <italic>μ</italic>M). The structure-activity relationships illustrated that the substituents on C-3 and C-5 position of isatin moiety influenced the activity significantly. Imine at C-3 position decreased the activity, whereas fluoro at C-5 position enhanced the activity. In particular, hybrids 8a,c (IC<sub>50</sub>: 7.54–12.1 <italic>μ</italic>M) and 9i (IC<sub>50</sub>: 9.10–15.9 <italic>μ</italic>M) were comparable to cisplatin (IC<sub>50</sub>: 7.54–15.9 <italic>μ</italic>M <italic>vs</italic> 9.38–19.7 <italic>μ</italic>M) against A549 and A549/DOX, but 4.6–7.6 folds more potent than that of cisplatin (IC<sub>50</sub>: 8.77–14.3 <italic>μ</italic>M <italic>vs</italic> 66.9 <italic>μ</italic>M) against A549/DDP cells. Moreover, hybrids 8a,c exhibited excellent stability (liver microsomes: 68–83%) in mouse/human microsomes and good pharmacokinetic properties, demonstrating their potential as a novel anti-lung cancer chemotherapeutic candidates.</p>