Design,Synthesis And Biological Activity Of Isatin Derivatives

Isatin derivatives easily penetrate the blood brain barrier and possess a variety of biological activities,inclusive of antibacterial,antitubercular,and anticancer activity.The structure-activity relationship indicated that substituents at N-1,C-3,and C-5 positions of isatin moiety have great influence on their biological activity and pharmacokinetic properties.Therefore,structural modification of the N-1,C-3,and C-5 positions is the most important research direction in this field in recent years.In recent years,our research team has conducted various structural modifications on isatin and selected several candidates with in-depth research value.As a further extension of this design idea,we focus on modifying the N-1,C-3,and C-5 positions to generate novel isatin hybrids.Benzofuran and artemisinin derivatives also have a variety of biological activities and good safety.Hybridization of isatin with benzofuran/artemisinin moiety is an effective strategy for developing lead compounds with rapid onset,short course of treatment,no drug resistance,no drug interactions,and low toxicity.Therefore,the research work of this paper is divided into the following two aspects:The structure-activity relationship illustrated that the carbonyl at the C-3position and long alkyl linkers were beneficial to antibacterial activity.Among them,the representative hybrids I-17 and I-35 have good antibacterial activity,and their MIC values for the vast majority of Gram-negative and-positive bacteria were≤1μg/m L,and its in vitro activity against Gram-positive bacteria was comparable to that of vancomycin（MIC:0.5～4μg/m L）,but its activity against Gram-negative bacteria was only slightly lower than that of ciprofloxacin（MIC:≤0.03～0.5μg/m L）.In addition,most isatin-benzofuran hybrids also exhibited considerable in vitro anti-tubercular activity（MICs for drug-sensitive and drug-resistant MTBs are<0.016 to 0.218,respectivelyμg/m L and 0.062-14.15μg/m L）and has high selectivity.The most active hybrid I-35（MIC<0.016,0.062,and 0.16μg/m L,respectively）was 4.8 times and≥48 times superior to the first-line anti-tubercular agents rifampicin and isoniazid,but its pharmacokinetic properties were inferior to those of TAM16 and ciprofloxacin.However,the hybrid I-35 can still be used as a lead compound for further optimization.Dihydroartemisinin has a good anticancer effect,and the structure-activity relationship revealed that for isatin-dihydroartemisinin hybrids,the linker between isatin and dihydroartemisinin has a significant impact on the activity.Based on this,we designed a series of isatin-dihydroartemisinin hybrids tethered by different alkane carboxylates,and evaluated their antiproliferative activity against drug-sensitive（MCF-7 and MDA-MB-231）and multidrug-resistant（MCF-7/ADR and MDA-MB-231/ADR）breast cancer cell lines.The results showed that these hybrids had significant inhibitory effects on drug-sensitive and drug-resistant breast cancer cell lines.The structure-activity relationship demonstrated that the length of alkyl carboxylates was closely related to their activity,and short chain linkers were beneficial to the activity.The representative hybrids II-7,II-14 and II-17 were comparable to doxorubicin against MDA-MB-231 cells and also showed excellent inhibitory activity to multidrug-resistant breast cancer cell lines（IC50<10μM）,suggesting that such hybrids have the potential to overcome drug resistance.In addition,these three hybrids（IC50>100μM）have no toxic effects on normal breast cells MCF-10A.Therefore,these three hybrids merited further investigations.In summary,a total of 93 compounds were synthesized through the above research work.The structures of the new compounds were confirmed by ¹H NMR and MS,and some of the target compounds were further confirmed by ¹³C NMR.The research work in this paper further enriched the structure-activity relationship,providing a practical basis for the next step of rational design.