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

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: 7.54-73.8 M) were more potent than the parent drug dihydroartemisinin (IC: 69.4-88.0 M) and also non-cytotoxic towards mouse embryonic fibroblast cells NIH/3T3 (IC: >100 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: 7.54-12.1 M) and 9i (IC: 9.10-15.9 M) were comparable to cisplatin (IC: 7.54-15.9 M 9.38-19.7 M) against A549 and A549/DOX, but 4.6-7.6 folds more potent than that of cisplatin (IC: 8.77-14.3 M 66.9 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.