Anti-Infectivity against Herpes Simplex Virus and Selected Microbes and Anti-Inflammatory Activities of Compounds Isolated from Eucalyptus globulus Labill.

Abstract

Herpes simplex virus (HSV) causes numerous mild-to-serious human diseases, including mucocutaneous herpes infections and life-threatening herpes encephalitis. Moreover, herpes viral lesions can be complicated by inflammation and secondary bacterial infections. The development of resistance to antiviral drugs along with the undesirable side effects of these drugs are relevant argue for the development of new anti-HSV drugs with diverse mechanisms of action. Eucalyptus extracts have been used for decades to combat various infectious diseases. We isolated and studied 12 pure compounds and one mixture of two constitutional isomers from the leaves and twigs of E. globulus. The structures were identified by spectroscopic methods (NMR, HR-MS, IR) and all of them were tested for antiherpetic activity against the replication of antigen types HSV-1 and HSV-2. Tereticornate A (12) (IC50: 0.96 μg/mL; selectivity index CC50/IC50: 218.8) showed the strongest activity in the anti-HSV-1 assay, even greater than acyclovir (IC50: 1.92 μg/mL; selectivity index CC50/IC50: 109.4), a standard antiviral drug. Cypellocarpin C (5) (EC50: 0.73 μg/mL; selectivity index CC50/EC50: 287.7) showed the most potent anti-HSV-2 activity, also more intensive than acyclovir (EC50: 1.75 μg/mL; selectivity index CC50/EC50: 120.0). The antimicrobial activity of the isolated compounds was also evaluated against the bacteria Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and the yeast Candida albicans. The anti-inflammatory potential was examined using LPS-stimulated THP-1-XBlue™-MD2-CD14 and THP-1 macrophages and focusing on the influences of the NF-κB/AP-1 activity and the secretion of pro-inflammatory cytokines IL-1β and TNF-α.

Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development

“…Each group of terpenoids-monoterpenes, sesquiterpenes, diterpenes and triterpenes (including steroidal compounds)-gave us at least one positive hint in the search. The least abundant are monoterpenes, that are represented only by cypellocarpin C (63) isolated from E. globulus (63, arising from the combination of monocyclic monoterpene with a methylchromone), geraniol (64), here obtained from T. bovei essential oil [57], showing effects against HSV-2, both IC 50 and SI, greater than acyclovir [58], and (+)-rhodonoid C (64) (a cross-metabolite of monoterpene and polyketide [59]). In comparison to acyclovir, positive results were also obtained for cucurbitacin B (94) [73], meroditerpenes from Brazilian seaweed Stypopodium zonale 79 and 80 [67], dollabene diterpenes (85 and 86) from brown alga Dictyota pfaffi [70], which were inhibiting reverse transcriptase of HSV-1, as well as for halistanol derivatives (95)(96)(97), a steroidal type compound obtained from Brazilian marine sponge Petromica citrina [74] which, interestingly, showed a synergistic effect when tested together with acyclovir, but a lower selectivity index when tested alone.…”

“…In comparison to acyclovir, positive results were also obtained for cucurbitacin B (94) [73], meroditerpenes from Brazilian seaweed Stypopodium zonale 79 and 80 [67], dollabene diterpenes (85 and 86) from brown alga Dictyota pfaffi [70], which were inhibiting reverse transcriptase of HSV-1, as well as for halistanol derivatives (95)(96)(97), a steroidal type compound obtained from Brazilian marine sponge Petromica citrina [74] which, interestingly, showed a synergistic effect when tested together with acyclovir, but a lower selectivity index when tested alone. Triterpenic tereticornate (106) from E. globulus, showed an interesting effect against HSV-1 with an SI slightly better than acyclovir [58].…”

“…This compound is also a very effective antibacterial agent-its MIC values against S. aureus and MRSA were found to be 0.20 and 0.12 µg/mL, respectively [73]. However, cypellocarpin C (63), an effective terpenoid molecule against HSV-2 with IC 50 = 0.73 µg/mL and SI > 287.7, did not show any antibacterial activity against several Gram-positive and Gram-negative bacteria [58], and, as in the case of phenolics, this can be a selective criterion for further research.…”

Prediction and validation of potent peptides against herpes simplex virus type 1 via immunoinformatic and systems biology approach

“…The herpes viruses are DNA viruses (Miranda-Saksena, Denes, Diefenbach, & Cunningham, 2018) which belong to the Herpesviridae family and are an epitome for viral entry into the host cell that is facilitated by a complex multi-component fusion system. HSV pathogen is classified into two separate types which are known as HSV-1 and HSV-2 (Brezáni et al, 2018). These viruses account for a number of human diseases ranging from mild to chronic infections such as herpes keratitis, neonatal herpes, mucocutaneous herpes infections, and herpetic encephalitis (Shinder & Devor, 1994).…”

“…A few reports also confirmed the occurrence of antibodies to HSV in children diagnosed with ASD, but the conflict is observed in final outcomes (Jörgensen, Vejlsgaard Goldschmidt, & Vestergaard, 1982;Mora et al, 2009). The infection can be life-threatening in case of aged patients, immune-compromised persons, neonates, transplant patients under immune suppression, and patients with acquired immune deficiency syndrome (Brezáni et al, 2018). The primary means of spreading HSV infection is direct contact with infected exudations (Drew, 2004).…”