Anti-Herpes Simplex Virus Type 1 Activity of Humic Acid-Like Polymers and Their O-Diphenolic Starting Compounds

Abstract

Phenolic polymers of the humic acid (HA) type, like other polyanionic substances, are inhibitors of herpes simplex virus type 1 (HSV-1) replication. The antiviral potency of the low molecular weight (MW) phenolic starting compounds has not been investigated systematically up to now. To reveal possible relationships between the chemical structure of o-diphenolic starting compounds and the anti-HSV-1 activity of HA-like polymers, nine polymers were synthesized by oxidation of the corresponding o-dihydroxybenzene derivatives. They were characterized by MW distribution, Fourier transform infra-red spectra and functional group analysis. Using an XTT-based tetrazolium reduction assay, both the low MW starting compounds and the synthesized polymers were examined for their antiviral and cytotoxic activities in HSV-1-infected Vera cells. The results demonstrate that most of the starting compounds failed to inhibit herpesvirus replication. The polymeric oxidation products (OP), however, developed detectable anti-HSV-1 activity with IC50 values in the range 2.3 [the OP of 3,4 dihydroxycinnamic acid (caffeic acid); KOP] to 42.1 μg mL−1 (3,4-dihydroxy-toluene OP). The CC50 of polymers varied between 40.8 (3,4-dihydroxybenzaldehyde OP) and >128 μg mL−1 (most polymers). Functional group analysis revealed that the presence of carboxylic groups in the starting compounds enhanced the antiviral activity and reduced the cytotoxicity of polymers. The introduction of a C=C double bond into the side chain [i.e. caffeic acid; 3-O-(3,4-dihydroxycinnamoyl)-d-chinic acid (chlorogenic acid; CH)] yielded the most effective polymers (KOP, CHOP). These may be considered as leader substances for HSV-1 inhibitors of the HA type.