RESUMO
BACKGROUND: Herpes simplex virus 1 (HSV-1) affects a large part of the adult population. Anti-HSV-1 drugs, such as acyclovir, target thymidine kinase and viral DNA polymerase. However, the emerging of resistance of HSV-1 alerts for the urgency in developing new antivirals with other therapeutic targets. Thus, this study evaluated a series of 1,4-disubstituted-1,2,3-triazole derivatives against HSV-1 acute infection and provided deeper insights into the possible mechanisms of action. METHODS: Human fibroblast cells (HFL-1) were infected with HSV-1 17syn+ and treated with the triazole compounds at 50 µM for 24 h. The 50% effective drug concentration (EC50) was determined for the active compounds. Their cytotoxicity was also evaluated in HFL-1 with the 50% cytotoxic concentration (CC50) determined using CellTiter-Glo® solution. The most promising compounds were evaluated by virucidal activity and influence on virus egress, DNA replication and transcription, and effect on an acyclovir-resistant HSV-1 strain. RESULTS: Compounds 3 ((E)-4-methyl-N'-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol1yl)benzylidene)benzenesulfonohydrazide) and 4 (2,2'-(4,4'-((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1 diyl)) dibenzaldehyde) were the most promising, with an EC50 of 16 and 21 µM and CC50 of 285 and 2,593 µM, respectively. Compound 3 was able to inhibit acyclovir-resistant strain replication and to interfere with virus egress. Both compounds did not affect viral DNA replication, but inhibited significantly the expression of ICP0, ICP4 and gC. Compound 4 also affected the transcription of UL30 and ICP34.5. CONCLUSIONS: Our findings demonstrated that these compounds are promising antiviral candidates with different mechanisms of action from acyclovir and further studies are merited.
Assuntos
Herpes Simples , Herpesvirus Humano 1 , Aciclovir/farmacologia , Aciclovir/uso terapêutico , Adulto , Antivirais/farmacologia , Antivirais/uso terapêutico , Replicação do DNA , DNA Viral , Farmacorresistência Viral/genética , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 2 , Humanos , Triazóis/farmacologia , Triazóis/uso terapêutico , Replicação ViralRESUMO
A new series of 1,4-disubstituted-1,2,3-triazole derivatives were synthesized through the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (Click chemistry) and their inhibitory activities were evaluated against different human glioblastoma (GBM) cell lines, including highly drug-resistant human cell lines GBM02, GBM95. The most effective compounds were 9d, containing the methylenoxy moiety linked to triazole and the tosyl-hydrazone group, and the symmetrical bis-triazole 10a, also containing methylenoxy moiety linked to triazole. Single crystal X-ray diffraction analysis was employed for structural elucidation of compound 9d. In silico analyses of physicochemical, pharmacokinetic, and toxicological properties suggest that compounds 8a, 8b, 8c, 9d, and 10a are potential candidates for central nervous system-acting drugs.