Novel 4h-chromen-4-one, 2h-chromene and chroman derivatives: design, synthesis and biological evaluation

La progettazione e sintesi di nuovi antivirali strutturalmente correlati a flavanoidi e flavonoidi sia naturali che sintetici e lo studio della relativa attività anti-picornavirus dei 4H-cromen-4-oni e 2H-cromeni ha portato ad identificare l’(E)-3-stiril-2H-cromene come un inibitore potente, selettivo e ad ampio spettro d’azione nei confronti dei rhinovirus umani (HRV). l’(E)-3-stiril-2H-cromene è stato perciò selezionato come hit compound sul quale effettuare uno studio sistematico di ottimizzazione della struttura. Sono stati quindi progettati e sintetizzati un ampio numero di arilalchil cromeni, cromanoni e cromoni che sono stati saggiati in vitro nei confronti dei sierotipi 14 e 1B di HRV, scelti come rappresentati rispettivamente dei gruppi A e B di HRV. L’estensione dello screening ad altri virus ad RNA conferma la bassa citotossicità e la selettività dell’azione anti-HRV. Sono stati così selezionati i composti più potenti, ad ampio spettro d’azione anti-HRV e con alto indice terapeutico per valutarne il meccanismo d’azione. I risultati ottenuti sia sulla particella virale che sulla moltiplicazione virale suggeriscono che tutti i composti selezionati si comportano da capsid-binder, interferendo con le prime fasi dell’infezione virale, ma mentre l’(E)-3-stiril-2H-cromene agisce sull’adsorbimento del virus al recettore cellulare gli altri composti studiati non interferiscono in questa fase ma solo sul processo di uncoating. Il risultato è di notevole interesse dal momento che l’utilizzo di combinazioni di farmaci che agiscono su fasi successive della replicazione virale potrebbe essere utile per superare il problema delle mutazioni virali che rendono rapidamente inefficace la monoterapia

Novel 4h-chromen-4-one, 2h-chromene and chroman derivatives: design, synthesis and biological evaluation

La progettazione e sintesi di nuovi antivirali strutturalmente correlati a flavanoidi e flavonoidi sia naturali che sintetici e lo studio della relativa attività anti-picornavirus dei 4H-cromen-4-oni e 2H-cromeni ha portato ad identificare l’(E)-3-stiril-2H-cromene come un inibitore potente, selettivo e ad ampio spettro d’azione nei confronti dei rhinovirus umani (HRV). l’(E)-3-stiril-2H-cromene è stato perciò selezionato come hit compound sul quale effettuare uno studio sistematico di ottimizzazione della struttura. Sono stati quindi progettati e sintetizzati un ampio numero di arilalchil cromeni, cromanoni e cromoni che sono stati saggiati in vitro nei confronti dei sierotipi 14 e 1B di HRV, scelti come rappresentati rispettivamente dei gruppi A e B di HRV. L’estensione dello screening ad altri virus ad RNA conferma la bassa citotossicità e la selettività dell’azione anti-HRV. Sono stati così selezionati i composti più potenti, ad ampio spettro d’azione anti-HRV e con alto indice terapeutico per valutarne il meccanismo d’azione. I risultati ottenuti sia sulla particella virale che sulla moltiplicazione virale suggeriscono che tutti i composti selezionati si comportano da capsid-binder, interferendo con le prime fasi dell’infezione virale, ma mentre l’(E)-3-stiril-2H-cromene agisce sull’adsorbimento del virus al recettore cellulare gli altri composti studiati non interferiscono in questa fase ma solo sul processo di uncoating. Il risultato è di notevole interesse dal momento che l’utilizzo di combinazioni di farmaci che agiscono su fasi successive della replicazione virale potrebbe essere utile per superare il problema delle mutazioni virali che rendono rapidamente inefficace la monoterapia

(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-rhinovirus activity of novel 3-[2-(pyridinyl)vinyl]substituted -2H-chromenes and -4H-chromen-4-ones.

Human rhinoviruses (HRVs) are the most common cause of viral respiratory infections and their complications. So far, no anti-viral agent has been approved for prevention or treatment of HRV infections. Pursuing our researches on small molecules with anti-rhinovirus activity, in this paper we describe the synthesis and in vitro anti-HRV 1B and 14 properties of new [2-(2H-chromen-3-yl)vinyl]pyridines and 3-[2-(pyridinyl)vinyl]-4H-chromen-4-ones. Generally, the synthesized compounds interfered with the replication of both serotypes at the micromolar or submicromolar concentrations. Preliminary results on their mechanism of action, performed on selected (E)-2-[2-(2H-chromen-3-yl)vinyl]pyridine, indicate an interference with the early step(s) of HRV 1B and 14 replication, probably at the uncoating level. (C) 2013 Elsevier Ltd. All rights reserved.Human rhinoviruses (HRVs) are the most common cause of viral respiratory infections and their complications. So far, no anti-viral agent has been approved for prevention or treatment of HRV infections. Pursuing our researches on small molecules with anti-rhinovirus activity, in this paper we describe the synthesis and in vitro anti-HRV 1B and 14 properties of new [2-(2H-chromen-3-yl)vinyl]pyridines and 3-[2-(pyridinyl)vinyl]-4H-chromen-4-ones. Generally, the synthesized compounds interfered with the replication of both serotypes at the micromolar or submicromolar concentrations. Preliminary results on their mechanism of action, performed on selected (E)-2-[2-(2H-chromen-3-yl)vinyl]pyridine, indicate an interference with the early step(s) of HRV 1B and 14 replication, probably at the uncoating level

3-Phenylalkyl-2H-chromenes and -chromans as novel rhinovirus infection inhibitors

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 (IC50 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

Design, synthesis and in vitro evaluation of novel chroman-4-one, chroman, and 2H-chromene derivatives as human rhinovirus capsid-binding inhibitors

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. (C) 2011 Elsevier Ltd. All rights reserved

Homoisoflavonoids: Natural Scaffolds with Potent and Selective Monoamine Oxidase-B Inhibition Properties

A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones la-w, 3-benzyl-4H-chromen-4-ones 2a-g, and 3-benzylchroman-4-ones 3a-e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones la-w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B. The reduction of the exocyclic double bond results in compounds 3a-e selective against isoform B and active in the micromolar range. In contrast, the endocyclic migration of the double bond (compounds 2a-g) generally produces the loss of the inhibitory activity or a marked reduction in potency. (E)-3-(4-(Dimethylamino)benzylidene)chroman-4-one (1l) and (E)-5,7-dihydroxy-3-(4-hydroxybenzylidene)chroman-4-one (1h) were the most interesting compounds of the entire series of inhibitors, showing hMAO-B affinity better than the selective inhibitor selegiline. Molecular modeling studies have been carried out to explain the selectivity of the most active homoisoflavonoids 1h and 1l