Synthesis, Biological Evaluation and In Silico Studies of 1,2,4‐Triazole and 1,3,4‐Thiadiazole Derivatives as Antiherpetic Agents

• Published in: ChemistrySelect (Weinheim) Vol. 4; no. 21; pp. 6421 - 6428
• Main Authors: Goma'a, Hebat‐Allah M., Ghaly, Mariam A., Abou‐zeid, Laila A., Badria, Farid A., Shehata, Ihsan A., El‐Kerdawy, Mohamed M.
• Format: Journal Article
• Language: English
• Published: 07-06-2019
• Subjects: anti-HSV-1; in silico studies; synthesis; thiadiazole; triazole
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.201900814

Two isosteric series of 1,2,4‐triazole and 1,3,4‐thiadiazole derivatives were designed and synthesized in this work to be evaluated for their antiviral activity. Compounds 2–9 and 11–19 were synthesized and their antiviral activity was tested against herpes simplex virus type 1, HSV‐1, using acyclovir, ACV, as a reference drug. In addition, molecular docking into the active site of HSV‐1 thymidine kinase was performed to interpret the data obtained from biological testing, and all compounds were subjected to an in silico screening of their physicochemical properties to estimate their drug‐likeness and safety. The results revealed that compound 7 was able to reduce the viral plaques by 50% at a dose of 80 μM, but interestingly, retained high selectivity compared to ACV (>200 μM vs. 80 μM). The best effective and safe compound in this study, 7, was further tested for its combined effects with ACV on the anti‐HSV‐1 activity in the plaque reduction assay. Compound 7 proved to improve the selectivity of ACV and reduce its effective dose that produced 100% inhibition of viral plaques. The triazolopyrimidine 7 is suggested to be a promising candidate for further development as an antiherpetic agent. Molecular docking into the active site of HSV‐1 thymidine kinase emphasized the superior interaction of compound 7.
Two isosteric series of 1,2,4‐triazole and 1,3,4‐thiadiazole derivatives were synthesized and subjected to antiherpetic evaluation. The most active compound was the triazolopyrimidine 7, with structure similarity to acyclovir, ACV. Compound 7 revealed to be safer than ACV against normal cells with IC50< 200 μM. In addition, in silico screening of the drug‐likeness of all compounds was performed. The docking simulation of compound 7 into thymidine kinase 2KI5 active site suggested that it could exert its anti‐HSV‐1 activity through thymidine kinase interaction.