In this work, a library of (+)‐camphor and (−)‐fenchone based N‐acylhydrazones, amides, and esters, including para‐substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure‐activity relationship revealed the significance of the substituent at the para‐position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p‐Cl, p‐Br, p‐CF3, and p‐NO2 substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time‐of‐addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.

Although the World Health Organisation had announced that smallpox was eradicated over 40 years ago, the disease and other related pathogenic poxviruses such as monkeypox remain potential bioterrorist weapons and could also re-emerge as natural infections. We have previously reported (+)-camphor and (−)-borneol derivatives with an antiviral activity against the vaccinia virus. This virus is similar to the variola virus (VARV), the causative agent of smallpox, but can be studied at BSL-2 facilities. In the present study, we evaluated the antiviral activity of the most potent compounds against VARV, cowpox virus, and ectromelia virus (ECTV). Among the compounds tested, 4-bromo-Nʹ-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2ylidene)benzohydrazide 18 is the most effective compound against various orthopoxviruses, including VARV, with an EC 50 value of 13.9 μM and a selectivity index of 206. Also, (+)-camphor thiosemicarbazone 9 was found to be active against VARV and ECTV.

A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors was found among resin acid derivatives. Several novel ureas and thioureas derived from dehydroabietylamine were synthesized and tested for TDP1 inhibition. The synthesized compounds showed IC50 values in the range of 0.1 to 3.7 μM and demonstrated low cytotoxicity against the human tumor cell lines U-937, U-87MG, MDA-MB, SK-Mel8, A-549, MCF7, T98G, and SNB19. Several compounds showed enhancement of the cytotoxic activity of the alkylating agent temozolomide, which is used as a first line therapy against glioblastoma (GBM), in the GBM cell lines U-87MG and SNB19.

CamphorN-acylhydrazones showed promising antiviral activity towards vaccinia and influenza viruses.

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In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotoxicity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.

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