Design,Synthesis,and Anti-influenza A Virus Activity Evaluation Of Novel Indole Containing Derivatives Of Triazole

Influenza A virus（IAV）is a contagious virus that can cause respiratory infections.According to the World Health Organization,there are about 1 billion infections per year,of which 3-5 million are severe cases and 300,000-500,000 deaths Therefore,the research and development of new anti-influenza A virus drugs is an important topic related to human life,health,social and economic development.At present,a variety of influenza A virus inhibitors have been used in clinical practice,which has greatly reduced the mortality rate of infected patients,but existing drugs have serious side effects,and drug-resistant strains are constantly developing,so research on a new type of IAV inhibitor with significant anti-influenza A virus activity are of great practical significance.In our previous work designed on the design and synthesize of a series IAV inhibitors,compound 4-32-2 was accidentally synthesized,and verified as effective influenza A virus inhibitors in A549 and MDCK cells.The IC₅₀ value of compound 4-32-2 was 1.5-2.7μM.However,it is unstable in buffer as a non-cyclic diimide which can be hydrolyzed to the corresponding amide within 48 h.Based on the above work,this paper uses the principle of bioelectronic isosteres and scaffold hopping to modify the lead compound 4-32-2.The triazole skeleton replaced the imide structure to enhance the stability of the compound,and one of the indole fragments was replaced with a different substituted benzyl group to investigate the effect on activity.A series of new triazole containing indole compounds were designed and synthesized,which can be divided into 2,6-dichlorophenyl triazole indole compounds（TM1-TM16）,2,6-dimethylphenyl triazole indole（TM17-TM47）and phenyltriazole indole（TM48-TM62）,and their anti-IAV activity and cytotoxicity were preliminarily determined.A total of 72 new compounds that have not been reported in the literature were synthesized,including 62 target compounds,and the structure was confirmed by ¹H NMR,¹³C NMR and HRMS spectra.Experimental results show that most of the new containing triazole indole compounds（TM1,TM4,TM5～TM10,TM12,TM13,TM15,TM17,TM22,TM31,TM32,TM33,TM37,TM42,TM44,TM45,TM49,TM51,TM52,TM54,TM56,TM59）exhibit good anti-influenza A virus activity and low cytotoxicity in vitro.TM17 showed the best anti-IAV activity(IC₅₀:1.01±0.40μM),the lowest cytotoxicity(CC₅₀:>100μM),and the highest selectivity index（SI:>99.01）.A study found that compounds that replaced diaimide fragments with triazole backbones had similar anti-IAV activity to lead compound 4-32-2.For the replacement of lead compounds 4-32-2 indole fragments with substituent benzyls,differences in the type and position of substituents of the substituted benzyl groups have a small effect on the anti-IAV activity of the target compound.The activity test results of 2,6-dimethylphenyl triazole indole and 2,6-dichlorophenyl triazole phenyl compound found that the anti-IAV activity was the best(IC₅₀:1.01μM～1.34μM)when the substituent was benzyl;the substituent is 2-trifluoromethoxybenzyl contributes better to anti-IAV activity than halogens,which provides a new idea for the development of new anti-IAV drugs.