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Following our studies on structure-activity relationships of anti-rhinovirus chromene and chroman derivatives, we designed and synthesized new series of 3-phenylalkyl-2H-chromenes and -chromans bearing differently sized, aliphatic linker chains between the two cycles. The cytotoxicity and the antiviral activity of the new compounds on human rhinovirus (HRV) serotype 1B and 14 infection were evaluated in HeLa cell cultures. Most of the tested compounds interfered with HRV1B multiplication in the micromolar or submicromolar concentrations while HRV14 was less susceptible. 3-[3-(4-Chlorophenyl)propyl]chroman (9c) was selected for preliminary mechanism of action studies due to its potent activity against both serotypes (IC 50 of 0.48μM and 1.36μM towards HRV1B and 14, respectively) coupled with high selectivity (SI=206.18 and 73.26, respectively). Results of time of addition/removal studies suggest that 9c, similarly to related derivatives, behaves as a capsid binder interfering with some early events of the HRV1B infectious cycle., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

As part of an effort to generate broad-spectrum inhibitors of rhinovirus replication, novel series of (E)-3-[(E)-3-phenylallylidene]chroman-4-ones 1a-e, (E)-3-(3-phenylprop-2-yn-1-ylidene)chroman-4-ones 2a and 2b, (Z)-3-[(E)-3-phenylallylidene]chromans 3a-e, and (E)-3-(3-phenylprop-1-en-1-yl)-2H-chromenes 4a-d were designed and synthesized. All the compounds were tested in vitro for their efficacy against infection by human rhinovirus (HRV) 1B and 14, two representative serotypes for rhinovirus group B and A, respectively. Most of the analogues were found to be potent and selective inhibitors of both HRVs, although HRV 1B was generally more susceptible than HRV 14. Mechanism of action studies of (E)-6-chloro-3-(3-phenylprop-1-en-1-yl)-2H-chromene 4b, the most potent compound on HRV 1B infection, suggested that 4b behaves as a capsid-binder probably acting at the uncoating level., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A series of 3-benzyl chromenes and chromans were synthesized and tested in vitro against human rhinovirus (HRV) 1B and 14, two representative serotypes for rhinovirus group B and A, respectively. All the new compounds, with the exception of 3-benzyl-2H-chromene (3a), showed a potent activity against HRV serotype 1B within micro or submicromolar range (IC(50)s from 0.11 to 6.62 microM). The low cytotoxicity of all the derivatives resulted in compounds with high therapeutic index (TI). On the contrary, HRV 14 infection was only weakly inhibited by the majority of these compounds. The 3-benzylidenechromans 2b and 2c showed the highest anti-HRV 1B activity (IC(50) 0.12 and 0.11 microM, respectively) coupled with remarkable TI (625.00 and 340.91, respectively). Mechanism of action studies on (Z)-3-(4-chlorobenzylidene)chroman (2b) suggest that the new compounds behave as capsid binders and interfere with very early stages of HRV 1B replication, similarly to related flavanoids.

Fluoro-substituted flavones and 2-styrylchromones, related to natural and synthetic flavonoids previously described, were prepared, characterized and tested for anti-rhinovirus activity. Structural elucidation of the new compounds was performed by IR, NMR spectra and X-ray crystal structure analysis for 6-fluoro-3-hydroxy-2-styrylchromone. The antiviral potency was evaluated by a plaque reduction assay in HeLa cell cultures infected with rhinoviruses 1B and 14, selected as representative serotypes for viral groups B and A of human rhinoviruses, respectively. In comparison with results previously obtained, the introduction of the fluorine atom seems to exert a positive influence on the activity against serotype 14 while counteracting the effect against serotype 1B.

Recently, we identified 2-styrylchromones as a new class of antirhinovirus flavonoids with moderate activity against both rhinovirus groups A and B. In order to improve the antiviral effect of the first series of tested 2-styrylchromones, a hydroxy or methoxy group was introduced in position 3 of the chromone ring. Cytotoxicity and antiviral activity of the new synthesized compounds were evaluated in HeLa cell cultures infected with rhinoviruses 1B and 14, selected as representative serotypes for viral groups B and A of human rhinoviruses (HRVs), respectively. These antiviral results compared to those obtained for 3-unsubstituted 2-styrylchromones indicate the greater potency of 3-hydroxy and 3-methoxy derivatives against both serotypes.