(E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors

A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino) pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC50 ¼ 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC50 ¼ 19.60 nM, IC50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent

Synthesis and anti-picornavirus activity of homo-isoflavonoids

Substituted homo-isoflavonoids were synthesized in order to study their in vitro anti-picornavirus activity. The maximum non-toxic concentration of the compounds for susceptible cells (HeLa) was determined, and the ability of non-cytotoxic concentrations to interfere with plaque formation by human rhinovirus (HRV) 1B and 14 and poliovirus (PV) 2 was examined. All the tested compounds were weakly effective against PV-2, while they exhibited a variable degree of activity against HRV-1B and -14 infection. Serotype 1B was much more sensitive than 14 to the action of the compounds, and the presence of one or more chlorine atoms increased the antiviral effect in all homo-isoflavonoids tested, confirming the positive influence of this substituent on activity

Synthesis and antirhinovirus activity of new 3-benzyl chromene and chroman derivatives

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 mu M). 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 mu M, 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. (C) 2009 Elsevier Ltd. All rights reserved

New 4H-chromen-4-one and 2H-chromene derivatives as anti-picornavirus capsid-binders

Substituted (E)-3-styryl-4H-chromen-4-ones 1a-d, 3-[(1E,3E)-4-phenylbuta-1,3-dienyl]-4H-chromen-4-ones 2a-d, (E)-3-styryl-2H-chromenes 3a-d and 3-[(1E, 3E)-4-phenylbuta-1,3-dienyl]-2H-chromenes 4a-d were designed and synthesized to improve the anti-picornavirus activity of previously tested analogues. The new compounds were evaluated in vitro against human rhinovirus (HRV) serotypes 1B and 14 and enterovirus (EV) 71. All the compounds interfered with the replication of picornaviruses, although considerable differences were observed in the sensitivity of viruses to each compound. Generally, both HRVs were more susceptible than EV71 and their sensitivity was dependent upon the linker chain length as well as upon the oxidation state of the heterocyclic ring. (E)-3-Styryl-2H-chromene (3a) emerged as the most effective inhibitor of both HRVs showing IC50 values of 0.20 mu M and 1.38 mu M towards serotype 1B and 14, respectively. The potent activity was also coupled with low cytotoxicity resulting in high therapeutic indexes (250 and 36, respectively). Mechanism of action studies indicated that 3a, like structurally related compounds, behaves as a capsid binder interfering with the early stages of rhinovirus infection, probably at the adsorption and/or uncoating level. (C) 2010 Elsevier Ltd. All rights reserved

Synthesis and evaluation of antirhinovirus activity of 3-hydroxy and 3-methoxy 2-styrylchromones

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