β-Carboline derivatives as novel antivirals for herpes simplex virus

Abstract

Several commercial and novel synthetic β-carbolines (βCs) were evaluated for their antiviral activity against herpes simplex virus type 1 (HSV-1) using an adapted MTS assay. Of 21 drugs tested, although 11 exerted antiviral activity at non-cytotoxic concentrations, only 3 of them [9-methyl-norharmane (9-Me-nHo), 9-methyl-harmane (9-Me-Ho) and 6-methoxy-harmane (6-MeO-Ho)] completely avoided virus-driven cytopathic effects. Half-maximal effective concentrations (EC values) (4.9 ± 0.4, 5.9 ± 0.8 and 19.5 ± 0.3 µM, respectively) and selectivity indexes (88.8, 40.2 and 7.0, respectively) of the latter three βCs against HSV-1 were determined by MTS, flow cytometry and plaque reduction assays. The mode of action of these drugs was also evaluated. According to time-of-addition assays, the selected compounds were not virucidal and did not interfere with attachment or penetration of HSV-1, but interfered with later events of virus infection. Western blot studies showed that early and late protein expression was significantly delayed or even suppressed. Herpes simplex virus type 2 (HSV-2) was also inhibited by the selected substances in a similar manner. Interestingly, 6-MeO-Ho, 9-Me-Ho and 9-Me-nHo restricted HSV-1 ICP0 localisation to the nucleus during later stages of infection, possibly affecting its functionality in the cytoplasm where ICP0 normally inhibits antiviral signalling and promotes viral replication. In silico prediction of ADME (Absorption, Distribution, Metabolism and Excretion) properties showed that all compounds fulfilled Lipinski's rule and their calculated absorptions were >95%.

N-Methyl-β-carboline alkaloids: structure-dependent photosensitizing properties and localization in subcellular domains

“…In particular, they can help to understand/assess the neurotoxic effect of quaternary βCs played at the mitochondrial domain. Also, these results shed light into the mechanism of anti-parasitic 22 and antiviral 35 activity of 1c, 2c and 3c.…”

“…21 (vi) N-Methyl-βCs are also quite promising antimicrobial agents with remarkable activity against a great variety of microorganisms. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] For example, 1b and 2b showed anti-Plasmodium activity, even against the chloroquine-and pyrimethamine-resistant Plasmodium falciparum K1 type. 32,33 In addition, 1b and its chloro-derivatives displayed potent cyanobactericidal and algicidal activity against a group of photosynthetic aquatic organisms including Microcystis aeruginosa, Synechococcus sp.…”

“…In particular, 9-methyl-derivatives 1c and 2c showed the highest inhibitory effect on virus replication. 35 The mechanism of action appears to be at the transcriptional level where these alkaloids could bind to the viral genome and block transcription, giving rise to a delay (or even suppression) in the early and late protein expression. 35,36 Interestingly, 1c and 2c could also play a role at the post-translational level, interfering with the late location of HHV infected cell polypeptide 0 (ICP0) at the cytoplasm where this protein normally inhibits antiviral signalling and promotes viral replication.…”

A Computational Framework of Host-Based Drug Repositioning for Broad-Spectrum Antivirals against RNA Viruses

“…This compound ranked the best because of its maximal multi-targeting potential for a plethora of HDGs. Other selected natural compounds such as sophocarpine and β-carboline derivatives have been reported to exhibit antiviral activities against enterovirus 71 (EV71) and HSV-1, respectively (Gonzalez et al, 2018;Jin et al, 2017). Interestingly, Asari Radix et Rhizoma (Xi Xin) and Codonopsis Radix (Dang Shen), the TCM herbs that contain selected compounds 4,9-Dimethoxy-1-vinyl-beta-carboline and sophocarpine, respectively, are included in the current TCM formula to treat COVID-19 in China according to Chinese National Health Commission Guidelines for COVID-19 Treatment, 8 th edition (http://www.nhc.gov.cn/yzygj/).…”

In Vitro and In Silico Anti‐plasmodial Evaluation of Newly Synthesized β‐Carboline Derivatives

“…[8] Natural alkaloids and drugs containing β-carboline moiety possesses wide spectrum of biological activity against malaria, tumor, HIV, cancer etc. [8][9][10][11] Additionally, β-carboline has been tagged as a promising scaffold in several marketed and upcoming drugs under development. [12] The synthesis, extraction and biological evaluations of β-carboline derivatives have attracted increasing interest of most of the medicinal chemists.…”