From Synthesis to Efficacy: Synthesis, Structural Analysis, and Antiviral Activity of 5‐(Trifluoromethoxy)‐ 1 H ‐indole‐2,3‐dione 3‐Thiosemicarbazones

ABSTRACT Viral infections are a global cause of serious morbidity and mortality. The recent COVID‐19 pandemic further testifies to the continued need to develop novel classes of antiviral agents with broad activity and high selectivity. In this work, 5‐(trifluoromethoxy)‐1 H ‐indole‐2,3‐dione 3‐(4‐phenylthiosemicarbazones) bearing a methyl or ethyl group at position 1‐ of the indole ring were synthesized. Along with previously synthesized compounds 5a‐j , 5l , 6b‐d , 6g , 6i , and 6k‐n , the novel compounds 5k , 6a , 6e , 6f , 6h , 6j , and 6o were evaluated in cytopathic effect (CPE) reduction assays with a broad range of DNA and RNA viruses. Favorable activity was observed in human embryonic lung (HEL) fibroblast cells infected with herpes simplex virus type 1 (HSV‐1, wild type or thymidine kinase‐deficient) and type 2, or with vaccinia virus (VV). In general, the ethyl substituted compounds ( 6a–o ) had higher antiviral activity and lower cytotoxicity than the methyl substituted analogues ( 5a–l ). The antiviral potency was markedly enhanced by substitution at position 4‐ of the phenyl ring, with the analogues bearing a 4‐methyl ( 6c ), 4‐fluoro ( 6l ), or 4‐chloro ( 6n ) moiety exhibiting average EC 50 values of 1.6 to 6.6 μM against HSV‐1, HSV‐2, and VV, besides selectivity indices (i.e., ratio of cytotoxic over antiviral concentration) of 21–40. Within the series bearing a substituent at position 3‐, the trifluoromethyl analogue 6d was unique in suppressing human adenovirus type 2 (AdV‐2) and coronavirus HCoV‐229E. To conclude, our study highlights the versatility and relevance of the 5‐(trifluoromethoxy)‐1 H ‐indole‐2,3‐dione 3‐(4‐phenylthiosemicarbazones) for developing antiviral agents against different virus families.