Synthesis And Biological Activity Of Novel Triazolothiadiazine Indole Derivatives

Indole,also known as 2,3-benzopyrrole,is a valuable reactive group,which is widely used in research fields such as medicine,pesticides,spices and dyes,etc.Its derivatives usually have important physiological functions and strong pharmacological activities,such as:antitumor,bacteriostatic,anti-inflammatory,anti-viral,anti-convulsant,anti-hypertension.Currently,various indole drugs have been marketed,including Nintedanib for the treatment of idiopathic pulmonary fibrosis,Vinorelbine for non-small cell lung cancer and breast cancer,Acemetacin for rheumatoid arthritis and Sunitinib for renal cancer and gastrointestinal stromal tumor and so on.Based on the application prospect of indole compounds in marketed drugs,in this paper,with 2-indolone as a raw material,a total of 49 indole derivatives which have not been reported in the literature were designed and synthesized by introducing pyridine,thioether,1,2,4-triazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine into the indole molecule(including 10 1,2,4-triazole thiol indole Schiff base compounds,21 of 3-thioether-4-indolimino-4H-1,2,4-triazole and 185,6-dihydro-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives bearing indolyl moiety).The target compounds were identified by ¹H NMR,¹³C NMR and HRMS.The anticancer activity of all target compounds against human non-small cell lung cancer cells(A549),human liver cancer cells(HepG2),human leukemia cells(K562),human prostate cancer cells(PC-3)and normal rat renal tubular epithelial cells(NRK-52E)was evaluated by MTT assay in vitro.The results showed that most of the compounds exhibited a certain inhibitory effect on the four cancer cells at 10?M,especially compound Bi17(IC₅₀=14.22±0.60,13.70±0.42,9.90±3.85 and11.36±2.72?M)showed comparable or better inhibitory activity against A549,K562,PC-3 and HepG2 cells than the positive control drug 5-fluorouracil(IC₅₀=6.29±1.12,18.06±4.61,11.84±1.90 and 15.47±4.23?M).Compounds Bi3(IC₅₀=11.86±3.67?M)and Bi4(IC₅₀=14.39±0.65?M)showed superior inhibitory activity against K562cells than the positive control drug 5-fluorouracil(IC₅₀=18.06±4.61?M).Compound j11(IC₅₀=11.69±1.75?M)showed superior inhibitory activity than the positive control drug5-fluorouracil(IC₅₀=11.84±1.90?M)against PC-3 cells.Annexin V-FITC/PI apoptosis assay was used to analyze the ability of compound Bi17 to promote the apoptosis of A549 cells.The results showed that as the concentration increasing,the compounds increasingly induced A549 cells apoptosis and the apoptosis ratios(including the early and late apoptosis rates)of A549 was remarkable influenced by Bi17 in a dose-dependent manner.The antibacterial activity of the target compounds against Xanthomonas oryzae pv.oryzae(Xoo)at 50?g/mL and 100?g/mL was evaluated according to the method of the turbidimetric assay.The results showed that most compounds have higher inhibitory activity against Xoo,especially compounds Bi2,Bi5 and Bi8 showed prominent inhibition rate compared to the positive drugs Bismerthiazol(BMT)and Thiodiazole copper(TDC),which can be used for the further research of antibacterial drugs.